Oral delivery of anticancer drugs: Challenges and opportunities

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Journal of Controlled Release xxx (2013) xxx–xxx

COREL-06705; No of Pages 26

Contents lists available at SciVerse ScienceDirect

Journal of Controlled Release

j ourna l homepage: www.e lsev ie r .com/ locate / jconre l

Review

Oral delivery of anticancer drugs: Challenges and opportunities

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Kaushik Thanki a, Rahul Gangwal b, Abhay T. Sangamwar b, Sanyog Jain a,⁎a Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar (Mohali), Phase X, Sector-67,Punjab 160062, Indiab Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar (Mohali), Phase X, Sector-67, Punjab 160062, India
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⁎ Corresponding author.E-mail addresses: [email protected], sanyogjain

0168-3659/$ – see front matter © 2013 Published by Elhttp://dx.doi.org/10.1016/j.jconrel.2013.04.020

Please cite this article as: K. Thanki, et al., Odx.doi.org/10.1016/j.jconrel.2013.04.020

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Article history:Received 3 December 2012Accepted 26 April 2013Available online xxxx

Keywords:Oral deliveryAnticancerSolubilityPermeabilityGastroPlusNanoparticlesLipidPolymer

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RThe present report focuses on the various aspects of oral delivery of anticancer drugs. The significance of oraldelivery in cancer therapeutics has been highlighted which principally includes improvement in quality oflife of patients and reduced health care costs. Subsequently, the challenges incurred in the oral delivery of an-ticancer agents have been especially emphasized. Sincere efforts have been made to compile the variousphysicochemical properties of anticancer drugs from either literature or predicted in silico via GastroPlus™.The later section of the paper reviews various emerging trends to tackle the challenges associated withoral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipient-and nanocarrier based-approaches. The role of drug nanocrystals and various others such as polymerbased- and lipid based-nanocarriers in the bioavailability enhancement along with their clinical outcomeshas also been discussed exhaustively. Furthermore, an insight on the various absorption mechanisms ofthese nanocarriers across the gastrointestinal tract has also been highlighted.

© 2013 Published by Elsevier B.V.

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RRE1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2. Challenges to the oral delivery of anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.1. Physicochemical properties of the drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2. Biological barriers to drug delivery of anticancer drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.2.1. Transmembrane efflux of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2.2. Pre systemic metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3. Emerging trends in addressing the challenges to oral delivery of anticancer drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.1. Absorption enhancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3.1.1. P-Gp inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.1.2. Functional excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3.2. Nanocarrier based approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2.1. Drug nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2.2. Polymeric nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2.3. Lipid based nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2.4. Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05. Future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

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1. Introduction

Cancer is defined as a complex series of disease condition causedby persistent tissue injury and host–environment interactions. The

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[email protected] (S. Jain).

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ral delivery of anticancer dr

repeated exposure of carcinogens such as tobacco, ultraviolet lightand infections leads to various genetic (mutations), epigenetic (lossof heterozygosity) and global transcriptome changes (via inflamma-tion pathways) and is associated with increased cancer risk [1].Owing to increased occurrence of cancer and worldwide prevalenceduring the last decade, it has posed a great challenge to the healthcare professionals. The latest WHO statistics suggests about 45%

ugs: Challenges and opportunities, J. Control. Release (2013), http://

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increase in the global cancer deaths by 2030, of which 70% would becontributed from developing countries like India [2]. With continuousupgradation in the field of science and technology, the need for ad-dressing the practical problems associated with the drug therapiesincreased proportionately. The major portion of cancer therapy tillthe last couple of decades was based on parenteral route of adminis-tration [3,4]. However, looking at the quality of life and need offollow-up therapy after the diagnosis of the disease, oral route hasgained major focus as compared to the parenteral route [4–6]. Oralroute is considered as one of the most abundant and traditionalways of drug delivery; main advantage being greatest safety, conve-nience and patient compliance. The possibility of tailor-made designas per physicochemical properties of the drug substances further in-creases the attraction of the scientific community. However, diverseproperties of drug substances, limitations in the choice of excipientsand principally, physiological barriers pose great challenge for designand development of oral drug delivery system.

The use of oral anticancer therapy affects the many clinically rele-vant aspects such as the following [7]:

1. An appropriate plasma drug concentration can be maintained toachieve a prolonged exposure of drugs to cancerous cells. Thiswill increase the efficacy and decrease the side effects of the anti-cancer drugs.

2. Modulation of drug release from the dosage forms also provides anadded advantage compared to that in other routes of administration.

3. It further facilitates the use of more chronic treatment regimens.This is especially important for cell cycle specific agents, especiallythose of predominantly cytostatic effect such as angiogenesis inhibi-tors and signal transduction inhibitors. For these agents, prolongedexposure to the drug may lead to pharmacodynamic advantagesover intermittent intravenous administration.

4. Oral chemotherapy avoids the discomfort of injection and can beconducted at home. This approach may enhance the patient coop-eration and their quality of life, which is an important issue andthus deserves high attention for any medical treatment.

5. The risks of infection and extravasations associated with intrave-nous infusion lines is avoided.

6. The treatment cost for the patient can be highly reduced due toavoidance of hospitalization, sterile manufacturing and trainedpersonnel assistance.

7. Apart from the therapeutic applications, oral therapy can also beexplored in the segment of prophylactics due to high level ofease in administration.

An interesting study has been carried out to evaluate the patient'spreference for route of administration and it was found that almost

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Fig. 1. Chemotherapeutic agents implemented to combat cancer. £P-gp modulator; #novelmetalloprotease inhibitors; ¥tetracycline analogue; ‡selective nonpeptide potent MMPI; TKI

Please cite this article as: K. Thanki, et al., Oral delivery of anticancer drdx.doi.org/10.1016/j.jconrel.2013.04.020

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78.7%wanted themselves to be treated by oral route for recurring breastcancer disease, whereas nearly 2.7% preferred parenteral route while18.6% landed with no preference [8]. Synchronizing with these results,the current scenario for development of new drug molecules has alsorapidly shifted towards oral delivery. Approximately 20 molecules arealready present in market for oral therapy of cancer, whereas a numberof them are pipeline. This clearly indicates the developer's insight andintentions for oral delivery. Fig. 1 shows the list of drugs presentlyutilized for cancer therapy [4,9–11].

However, oral delivery of anticancer drugs is a great challengeowing to their peculiar physicochemical properties, and physiologicalbarriers such as pre-systemic metabolism and gastrointestinal insta-bility. Upon oral administration of such drugs, only a fraction ofdose is available to systemic circulation for execution of therapeuticresponse e.g. oral bioavailability of paclitaxel, docetaxel, doxorubicin,tamoxifen, etc. is in the range of 5–20% [12–15]. Broadly, this could beattributed to low aqueous solubility, poor intestinal permeability,high level of P-glycoprotein (P-gp) efflux and pre-systemic metabo-lism. The P-gp efflux also has a key role in the execution of multidrugresistance in the tumor cells and thereby needs special considerationwhile designing the formulation of poor biopharmaceutical proper-ties, as the amount which is required to achieve the therapeutic re-sponse might be very high ultimately leading to multidrug resistance.

Furthermore, cost of manufacturing novel formulations of theexisting parenteral drugs and limited therapeutic window of the anti-cancer drugs leading to sub-therapeutic or toxic dose, also restrictsthe developability for oral route of administration [16]. However, recentadvances in nanotechnology based drug delivery system posed poten-tial advantages in overcoming these limitations. This includes polymer-ic nanoparticles, polymeric micelles, microemulsion, self-emulsifyingdrug delivery systems (SEDDS), carbon nanotubes, layersomes, lipo-somes, lipid–drug conjugates, nanocrystals, etc.

The therapeutic efficacy of the formulation depends upon its capa-bility to deliver the drug at the right place and at the right time inamount adequate enough to yield a therapeutic response. Compara-tive therapeutic equivalence of oral and intravenous routes has beenstudied for wide variety of drugs and promising results were ob-served in most of the cases. Cyclophosphamide yields no statisticalsignificant difference in the area under the plasma disappearancecurve (AUC) and generated similar cytotoxic metabolic products uponadministration through oral and parenteral routes thereby suggestingthe therapeutic equivalence, irrespective of the route of delivery [17].Paclitaxel in nanoparticulate dosage form administered by oral routehad shown promising tumor reduction in animals compared tocommercially available intravenous formulation at 50% reduced dose[18]. Co-administration of cyclosporin A further potentiated its oral

oral taxane; ΔDeoxycytidine-type antimetabolite; €Oral fluoropyrimidine; MMPImatrixtyrosine kinase inhibitor; FTIfarnesyl transferase inhibitor.




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bioavailability, due to inhibition of the P-gp efflux pump and CYP 3A4,both being limitations for oral bioavailability [19]. Similarly, topotecanhas also been found to be equally effective irrespective of the route ofadministration with upper hand in reduced toxicity via oral route[20,21]. The other drugs which have been evaluated include docetaxel,paclitaxel, doxorubicin, cisplatin [22], ifosfamide/mesna combination[23] and melphalan [24] to name a few. The studies suggest that byvirtue of appropriate pharmaceutical/pharmacological interventions,the inherent problems associated with oral route (owing to variousphysiological barriers) can be overcome in comparison to intravenousroute of administration.

The present review highlights comprehensive coverage of variouschallenges encountered for efficient oral delivery of anticancer drugs.In contrast to other literature reports published recently, a correlationbetween physicochemical properties of these anticancer drugs withits in vivo performance has been included specifically. In absence ofthe availability of these data, appropriate in silico predictions havebeen made. Furthermore, various conventional and novel approachesincluding emerging trends to overcome these challenges have alsobeen discussed in detail with special emphasis on polymer and lipidbased drug delivery systems.

2. Challenges to the oral delivery of anticancer agents

Bioavailability is staging of in vivo performance of drug and re-flects the rate and extent to which the drug is absorbed into the sys-temic circulation and thereby available for therapeutic response. Thekey factors affecting the oral bioavailability of drug include its stabil-ity in the gastrointestinal tract, aqueous solubility, dissolution ratefrom the dosage form, intestinal epithelium permeability, stabilityagainst intestinal and liver cytochrome P450 metabolic enzymes,and P-gp efflux pump. Therefore, on these grounds the principal chal-lenges to the oral delivery can be categorized broadly into physico-chemical properties of the drugs and physiological barriers posed bythe body (Fig. 2).

2.1. Physicochemical properties of the drugs

The critical physicochemical properties of the drug affecting itsoral deliverability include solubility and permeability which are fur-ther dependent on the fundamental properties such as log P andpKa. The classical relationship between the solubility, permeabilityand potency has been reported by Lipinski according to which thequantity sufficient solubility of the drug can be determined on thebasis of the potency and permeability of the drug [25]. The in vivo per-formance (biopharmaceutics) of a drug is dependent on pharmacoki-netics (ADME profile) and pharmacodynamics (extent of clinicalresponse). The absorption segment of the pharmacokinetics can bedetermined by the Fick's First law of diffusion, which states that flux(J) of drug for systemic exposure is directly proportional to the per-meability coefficient (inclusive of drug efflux) and drug concentrationin the gastrointestinal lumen (inclusive of solubility, dissolution andstability of drug within the GIT) [26].
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• Intrinsic solubility• Permeability• Stability

Physicochemical properties of

drugs

• Gastrointestinal transit time• Absorption window• Transmembrane efflux of drugs• Pre-systemic metabolism

Biological barriers

Limited oral bioavailability

of drugs

Fig. 2. Schematic representation of the various challenges to the oral delivery of drugs.


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The limited oral bioavailability of the drugs can therefore be desig-nated as solubility/dissolution rate limited, permeability limited, andboth solubility and permeability limited [27]. The quantity sufficientsolubility of a drug candidate could be predicted on the basis of dosenumber and dose number ≫ 1 is considered as poorly soluble [28].According to BCS classification, these candidates are categorized as IIand need attempt for solubility enhancement which could otherwiseresult in either solubility or dissolution limited absorption leading topoor bioavailability. Classical examples include tamoxifen, rubitecan,sorafenib, gefitinib, etc. On the other hand, candidates with sufficientsolubility but poor permeability are categorized as III and includecyclophosphamide, anastrozole, letrozole, doxorubicin, methotrexate,etc. The permeability values b 10 × 10−6 cm/s are considered poorand need appropriate efforts for improvement [29]. However, veryfew (~25% of literature of drug compounds) pose permeability relatedissues (Table 1). But at the same time, >60% drugs are substrate forone or other types of efflux, suggesting dominating role of drug effluxin the oral bioavailability. Further, >65% of anticancer drugs are avail-able in oral dosage form for clinical use but very few of themare actuallyused which could be attributed to the limited oral bioavailability owingto poor physicochemical properties and efflux mechanisms. However,the exact usage needs to be identified so that rationalized drug deliverysystems can be designed to propagate research in the field of oral anti-cancer drug delivery.

2.2. Biological barriers to drug delivery of anticancer drugs

2.2.1. Transmembrane efflux of drugsTransmembrane efflux of drugs is defined as the expulsion of the

drugmolecules across the cellularmembrane from the cells via a clinical-ly significant systematic transportation system such as P-glycoprotein(P-gp), breast cancer resistant protein (BCRP), cytoplasmic transport,multidrug resistant associated protein (MRP), flurochrome efflux,methotrexate efflux (folates), etc. [91–93]. Table 2 represents an ex-haustive list of anticancer drugs that are potential substrate for variousmembrane efflux proteins present in liver and intestine thereby limit-ing their oral delivery [94].

P-Glycoprotein, encoded by the multidrug resistance-1 (MDR1)gene, localized in enterocytes, is one of the significant efflux trans-porters leading to the excretion of drug back in to the intestinallumen. It is extensively distributed in intestinal epithelia, hepatocytes,kidneys, various glands and capillary endothelial cells comprisingblood–brain and blood–testis barriers. This is a membrane associatedprotein belonging to the superfamily of ATP binding cassette (ABC)transporters with the molecular weight of 170 kDa and N terminal gly-cosylation. Its structure constitutes two homologous chains of equallength, each comprising six units of transmembrane domains and twoATP binding sites separated by a flexible linker polypeptide regionbetween the two homologous chains [95]. It mainly operates at threemajor locations, luminal (apical) membrane enterocytes: the drug islimited by entering in the body; canalicular membrane of hepatocytes:increased elimination in to bile and urine; and, sensitive tissues such asbrain, lymphocytes, testis, and fetal circulation: limiting the drug pene-tration [96]. Most of the anticancer drugs are the substrates for P-gpincluding paclitaxel, docetaxel, etoposide, vinblastine, vincristine anddoxorubicin to name a few (Table 1).

P-Gp expresses two types of ATPase activity: basal stimulated byendogenous lipids and other hydrophobic peptides and drug stimu-lated ATPase activity. Different drugs owing to their unique bindingimpart different types of ATPase activities on the P-gp. Dependingon this property of the drug substances, they can be classified inthree different categories [97]. Class I agents (e.g. vinblastine, verapa-mil, and paclitaxel) stimulate ATPase activity at low concentrationsbut inhibit the activity at high concentrations. Class II compounds(e.g. bisantrene, valinomycin, and tetraphenylphosphonium) enhanceATPase activity in a dose dependent manner without any inhibition.




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Table 1t1:1

t1:2 Physicochemical properties of various anticancer drugs.

t1:3 Drug pKa Log P Solubility(mg/ml)

Permeability(cm/s × 10−6)

Efflux Clinically used orally? Reference

t1:4 5-Fluro uracil 11.5, 7.26 −0.9a 1.070a 65 Substrate Yes [30]t1:5 Altretamine 5.65, 0.09 1.25a 0.091a 877 Non-substrate Yes [31]t1:6 Anagrelide 3.08 1.13a 0.0322 35 Substrate Yes [32,33]t1:7 Anastrazole 3.17 2.1a 0.5a 324 Non-substrate Yes [34]t1:8 Bexarotene 4.4 6.9a 0.00385 266 Non-substrate Yes [35]t1:9 Bicalutamide 12 2.92a 0.005 170 Noncompetitive inhibitora Yes [36,37]t1:10 Bleomycin 13.91, 7.68 −3.62a 8.39 b1 Substrate No [38]t1:11 Capecitabine 8.86 0.4a 26a 33 Non-substrate Yes [39]t1:12 Carboplatin None −2.30a 4.50 11 Substrate No [40]t1:13 Cisplatin 3.16, 0.77 −2.53a 2.530a 18 Non-substratea No [41,42]t1:14 Cladribine 1.91 0.498a 3.42 25 Substrate No [43]t1:15 Cyclophosphamide 8.91 0.73a 12.5 446 Substrate Yes [44]t1:16 Cytarabine 4.30 −2.8a 25.8 7 Substrate No [39]t1:17 Dasatinib 10.29,7.07 1.8a 0.0501 30 Substratea Yes [45,46]t1:18 Docetaxel 10.97 4.1a 0.000025a 1 Substratea No [30,47]t1:19 Doxorubicin 9.99, 6.74 1.3a 0.429 22 Substratea No [30,42]t1:20 Erlotinib 10, 6.15 2.7a 0.4a 194 Substratea Yes [48,49]t1:21 Etoposide 9.21 0.698a 0.0587a 5 Substratea Yes [47,50]t1:22 Exemestane None 3.7a 0.00789a 48 Substrate Yes [51]t1:23 Fadrozole 11 2.18 0.693 280 Substrate No –

t1:24 Finasteride 11.88 3.03a 0.0117a 2 Substrate Yes [52]t1:25 Fludarabine 6.33 −2.83 2.76 17 Substrate Yes –

t1:26 Gefitinib 7.08, 5.32 4.85a 0.0367 206 Inhibitora Yes [53,54]t1:27 Hydroxycarbamide 12.52, 10.82, 9.99 −1.4a 1,000,000a 10 Substrate Yes [55]t1:28 Ibandronic acid 10.09, 8.18 2.33a 31.1 18 Substrate Yes [56]t1:29 Idarubicin 10.06, 8.41 3.0a 0.0772a 38 Substratea Yes [38,57]t1:30 Ifosphamide 14.83, 11.27 0.8a 3.780a 230 Substrate No [58,59]t1:31 Imatinib 13.45 1.99a 0.0412 78 Substratea Yes [45,60]t1:32 Irinotecan 8.1 3.2a 0.106 22 Substratea No [61,62]t1:33 Lapatinib 6.55, 4.27 5.1a 0.000223 121 Substratea Yes [63,64]t1:34 Lenalidomide 9.55 −1.09a 0.4a 10 Substrate Yes [56]t1:35 Letrozole 2.19 2.49a 0.0329 384 Substrate Yes [65]t1:36 Lonafarnib 13.22 5.59 0.0167 656 Inhibitora No [66]t1:37 Melphalan 1.93 −1.70a 0.1a 456 Non-substratea Yes [67,68]t1:38 Mercaptopurine 11.25, 7.54 −0.4a 6.85a 16 Substrate Yes [69]t1:39 Mesna None 0.78 8.55 61 Non-substrate No –

t1:40 Methotrexate 4.7a −1.4a 2.60a 58 Non-substratea Yes [70,71]t1:41 Mitomycin 10.9a −1.6a 8.43a b1 Inhibitora No [38,72]t1:42 Nilutamide 9.68 1.8a 0.029 148 Non-substrate Yes [73]t1:43 Oxaliplatin 3.03, 0.1 −0.47/1.73a 2.75a b1 Non-substratea No [74,75]t1:44 Paclitaxel 11.51 3.5a 0.00612 5.2a Substratea No [28,30,42]t1:45 Procarbazine 11.97 0.06a 1.420a 144 Non-substrate Yes [76]t1:46 Raloxifene 9.30, 8.49 5.7a 0.00025a 157 Substratea Yes [77,78]t1:47 Rubitecan 0.87 1.52 0.00875 286 Non-substrate Yes –

t1:48 Sorafenib 11.50, 8.53 3.8a 0.00199 243 Substratea No [39,45]t1:49 Sobuzoxane 5.12 1.49 0.465 1 Substrate Yes –

t1:50 Sunitinib 12.60, 10.33 2.5a 0.00308a 51 Substratea Yes [39,46]t1:51 Tamibarotene 11.45 5.87 0.0101 142 Non-substrate Yes –

t1:52 Tamoxifen 8.40 7.87a 0.000167a 445 Substratea Yes [79,80]t1:53 Temozolomide 10.33 −0.75 0.951 78 Non-substrate Yes –

t1:54 Thalidomide 9.87 0.04a 0.545a 10 Non-substrate Yes [31]t1:55 Thioguanine 11.51, 8.67 −0.46 0.0658 17 Non-substrate Yes –

t1:56 Tipifarnib 5.95, 3.61 4.94 0.00142 389 Inhibitora No [81]t1:57 Topotecan 11.7 0.8a 1a 159 Substratea Yes [82,83]t1:58 Toremifene 8.33 6.35a 0.000801 440 Substrate Yes [84]t1:59 Treosulfan None −2.11 922.0 10 Non-substrate Yes –

t1:60 Trilostane 5.51 1.76 0.117 9 Substrate No –

t1:61 Trimetrexate 7.67, 4.08 1.99 0.0318 108 Substrate No –

t1:62 Ubenimex 8.62 −1.79 7.36 110 Non-substrate No –

t1:63 Vinblastine 14.55, 6.10 1.68a 0.0138 8 Substratea No [47,85]t1:64 Vincristine 5a 1.16a 0.003a 3 Substratea No [47,86]t1:65 Vinorelbine 14.31, 6.73 1.32a 0.00206 11 Substratea No [86,87]t1:66 Vorinostat 9.2a 12.84, 10.70 0.512 255 Substrate Yes [88]

a Experimental/reported values; rest of values have been predicted in silico. Briefly, for predicting solubility and permeability, 3D structures of molecules were sketch usingSYBYL7.1 [89]. The molecules were later minimized by applying Tripos molecular mechanics force field with conjugate gradient method. The minimization was terminatedwhen the energy gradient convergence criterion of 0.05 kcal/mol was reached or when the 10,000 steps minimization cycle was exceeded. Minimized molecules were then sub-mitted to ADMET Predictor 5.5, GastroPlus, Simulations Plus, USA for prediction of physicochemical properties. All the calculations were performed at pH 6.8. The substrate spec-ificity for efflux was predicted using web server developed based on Support Vector Machine and molecular docking methods [90].t1:67


In contrast, Class III compounds (e.g. cyclosporin A, rapamycin, andgramicidin D) inhibit both basal- and verapamil-stimulated ATPaseactivities.


The mechanism of drug efflux by P-gp can be assessed on the basisof various models such as pore model, flippase model, and hydropho-bic vacuum cleaner (HVC) model, among which HVC model has




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t2:2 List of drugs that are potential substrates for various membrane efflux proteins.

t2:3 Membrane effluxproteins

Drug

t2:4 ABCB1(P-Glycoprotein)

Actinomycin D, Daunorubicin, Docetaxel, Doxorubicin, Etoposide, Mitoxantrone, Paclitaxel, Teniposide, Vinblastine, Vincristine, Mitomycin C

t2:5 ABCB4 (MDR2/3) Daunorubicin, Paclitaxel, Vinblastinet2:6 ABCB11 (BSEP) Vinblastinet2:7 ABCC1 (MRP1) Daunorubicin, Doxorubicin, Etoposide, Methotrexate, Vinblastine, Vincristinet2:8 ABCC2 (MRP2) Camptothecin, Cisplatin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Methotrexate, Paclitaxel, SN-38 (active metabolite of irinotecan), Vincristinet2:9 ABCC3 (MRP3) Etoposide, Etoposide glucuronide, Methotrexate, Teniposide,t2:10 ABCC4 (MRP4) 6-Mercaptopurine, 6-Thioguanine, Methotrexatet2:11 ABCC5 (MRP5) 5-Flurouracil, 6-Mercaptopurine, Cisplatin, Doxorubicin, Methotrexate, Oxaliplatin, Thioguanine, Pemetrexedt2:12 ABCC6 (MRP6) Cisplatin, Doxorubicin, Etoposide, Teniposidet2:13 ABCG2 (BCRP) Daunorubicin, Doxorubicin, Epirubicin, Epirubicin, Gefitinib, Genistein, Imatinib, Irinotecan, Methotrexate, Methotrexate diglutamate, Methotrexate

triglutamate, Mitoxantrone, Quercetin, SN-38 (active metabolite of irinotecan), SN-38 glucuronide, Teniposide, Topotecan.t2:14 OAT 1 Methotrexate, Azathioprine, Doxorubicin, 5-fluouracilt2:15 MCT Ifosfamide and its metabolites, S-carboxymethylcysteine, thiodiglycolic acid

t2:16 BSEP: Bile salt efflux pump; MDR: Multidrug resistance; MRP: Multiple resistance protein; BCRP: Breast cancer resistance protein; OAT: Organic anionic transporter; MCT:t2:17 Monocarboxylate transporter.


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gained wider acceptance [98]. ATP binding and hydrolysis are the im-portant processes for the drug efflux. At the cost of two molecules ofthe ATPs, one molecule of the drug is effluxed. The drug efflux occursin two cycles, each cycle consuming one ATP molecule. The first cyclestarts with the binding of the drug and ATP at their respective sitesfollowed by the conformational change which is regained in the sec-ond cycle at the cost of hydrolysis of yet another ATP molecule [99]. Itis generally found to be overexpressed in the multidrug resistant cellsand is capable to expelling large variety of non-host compounds fromthe cells. It acts both at intracellular compartments and cell surface.P-Gp has major contributions in ADME of the drug molecules dueits wider spectrum of presence throughout the body. This has alsobeen supported experimentally where the oral bioavailability of anti-cancer drugs such as paclitaxel has been increased significantly inP-gp knockout mice [100].

2.2.2. Pre systemic metabolismOral bioavailability is a cumulative function of fraction of dose

absorbed through the gastrointestinal tract, fraction of drug absorbedfrom the entero-hepatic circulation and drug available post first passhepatic metabolism [101]. Gastro-intestinal and hepatic availability isdefined as the drug escaping the metabolizing effects of the gastro-intestinal tract and the liver. The gastro-intestinal metabolism, alsoreferred as luminal metabolism is performed by digestive enzymessecreted by pancreas such as amylase, lipase, and peptidases andfrom the bacterial flora present especially in the lower part of the gas-trointestinal tract. The first pass intestinal metabolism includes thebrush border metabolism and the intracellular metabolism [102].The brush border activity is generally to its highest in the proximalsmall intestine and is destined by enzymes such as alkaline phospha-tase, sucrase and isomaltase and various peptidases [103]. The intra-cellular metabolism in the gut is principally carried out by extra-hepatic microsomal enzymes present within the cytoplasm on theendoplasmic reticulum. Cytochrome P4503A family, especially CYP3A4, phase I metabolizing enzymes, are present in the enterocyteswhich leads to the metabolism of the drug substances at the gastroin-testinal wall. Phase II metabolizing enzymes such as glutathione-S-transferases, esterases, etc. are also reported to present in the intestine[104]. Though intestinal epithelium acts as a site for pre-absorptivemetabolism, contributing to low bioavailability of therapeutic peptidesand ester type drugs like capecitabine [105], it can also serve as a keytarget for delivery of ester or amide prodrugs.

Once the drug gets absorbed from the gastrointestinal tract, it en-ters in to the entero-hepatic portal vein and reaches to liver, where afraction of absorbed dose is metabolized, being referred as First PassHepatic Metabolism (FPHM). Liver is the hub of various enzymes


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chemicals (e.g., cholesterol, steroid hormones, fatty acids, and pro-teins) and xenobiotics [106]. This first pass metabolism is consideredas major contributor for low oral bioavailability of many drugs e.g. ta-moxifen [15]. Worsening the case, the drugs which are substrates forcytochromes are also substrates for P-gp, thereby leading to furtherdecrease in the bioavailability. Both these work in tandem and needscareful consideration while designing of oral drug delivery systemfor their substrates, e.g. level of CYP 3A4 decreases from proximal tosmall intestine whereas P-gp expression increases in same flow [107].

3. Emerging trends in addressing the challenges to oral delivery ofanticancer drugs

Nevertheless, in spite of abovementioned challenges, oral delivery ofvarious anticancer drugs has been evaluated for their efficacy and toxic-ity profiles. Themost conventional approach includes co-administrationof a therapeutic agent or functional excipient that either circumvents thebiological barriers or facilitates the absorption of the drug across gastro-intestinal tract by altering the physicochemical properties of drug sub-stances. Recently, carrier based approaches have been implementedwhich can bypass majority of the challenges and is able to achievedesired delivery in most efficient form. However, the selection, designand development of drug specific carrier system are a state-of-art andrequire thorough understanding of the physicochemical properties ofdrug substances and its behavior in physiological conditions. The subse-quent sections report various such approaches implemented to achieveoral delivery of various difficult-to-deliver anticancer drugs. Fig. 3 dem-onstrates various strategies to improve the oral bioavailability of drugsubstances.

3.1. Absorption enhancers

3.1.1. P-Gp inhibitorsTransmembrane efflux of drugs can be tackled by co-administration

of various P-gp modulators or inhibitors along with the drugs. The po-tential mechanisms by which the inhibition of efflux pump occurs in-clude altered membrane fluidity, inhibited ATPase activity, blocking ofdrug binding site, decreasing P-gp expression (e.g. Peceole), depletionof ATP (e.g. Pluronics), interaction with membrane (e.g. Triton X 100)and interference with the ATP binding sites [108]. Fig. 4 reflects variousP-gp based approaches for improving the oral bioavailability of drugs.

P-gp inhibitors/modulators have been broadly classified to threeclasses viz. first generation, second generation and third generationinhibitors [93]. First-generation comprised of pharmacological agentsthat act as competitive inhibitors and hence block the drug efflux




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Fig. 3. Strategies to improve the oral bioavailability of drug substances.


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e.g. verapamil and cyclosporin A. But considering their poor bindingaffinities (needing higher doses to achieve desired results) and pharma-cokinetic interactions (due to induction/inhibition of CYP 3A enzymes)these are not clinically advisable. Cyclosporin A is widely used as P-gpinhibitor for improving the oral bioavailability of various drug sub-stances. About 10-fold increase in the oral bioavailability of paclitaxel[109] and docetaxel [110] was observed upon co-administration withcyclosporin A. Second generation included those lacking pharmacolog-ical activity andwere developedwith the intention of high P-gp bindingand inhibiting effect alongwith lower toxicities. However, they fail to re-main inert with CYPs thereby limiting their use e.g. the cyclosporin A an-alogue valspodar (PSC833). Therefore the third generation came in toplay and highly P-gp specific inhibitors such as elacridar (GF120918),zosuquidar (LY335979) and tariquidar (XR9576) were developed.

This approach is scarcely used clinically owing to associated clinicalcomplications such as suppression of immune system thus causing longterm medical complications. Hence, the novel approach of exploitingsimilar properties of excipients can be sought. Some commonly used

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P-gp inhibition

Decrease in P-gp

expression

Depletion of ATP

Inhibition of ATPase activity

Interference with ATP

binding sites

Blockade of drug

binding site

Interaction with

membrane

Altered membrane

fluidity

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efflu• 10-f

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•

Third• High• E.g.

Tari

Fig. 4. Various P-gp based approaches for im


EDfunctional excipients, such as surfactants, polymers, lipids, etc. can be

employed as bioavailability enhancers [98].

3.1.2. Functional excipientsA large variety of the functional excipients have been studied to in-

crease the oral bioavailability of drugs. Mechanistically, they are foundto modulate the activity of the P-gp efflux pump, facilitate wetting, in-crease solubilization, increase permeability across the gastrointestinaltract, etc. These include polysaccharides, polyethylene glycols and de-rivatives, surfactants, lipids, thiolated polymers and amphiphilic blockcopolymers to name a few.

3.1.2.1. Natural polymers. The natural polymers such as dextrans, an-ionic gums and sodium alginate are reported to inhibit the P-gp effluxpumps [111]. Anionic gums such as xanthan gum, gellan gum, algi-nates, flavicam and ascophyllum with carboxyl functional groups orsalts thereof increase serosal transport of drugs such as vinblastineand doxorubicin by inhibiting their efflux [112]. In addition, some

generationse act as competitive inhibitors and hence block the drug x. E.g. Verapamil and cyclosporin Aold increase in the oral bioavailability of paclitaxel and etaxel upon co-admintration with Cyclosporin A

econd generationLacks pharmacologiocal activity, high p-gp binding and inhibiting effect and lower toxicities. Fail to remain inert with CYPs thereby limiting their use. E.g. Valspodar (PSC833).

generationly specific P-gp inhibitors Elacridar (GF120918), Zosuquidar(LY335979) and quidar (XR9576).

proving the oral bioavailability of drugs.




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polymers such as acacia also possess MDR reversal capability e.g. in-tracellular accumulation of epirubicin was significantly increasedwhen tested against MDR Caco-2 cell lines in the presence of acacia[113].

Recently, amember of flavanoid class, quercetin, has been evaluatedas a potential P-gp modulator and CYP modulator [114]. Quercetin isfound to interact either with the ATP binding site or with the substratebinding site of P-gp. Co-administration of quercetin with tamoxifen cit-rate has led to an increase in relative bioavailability by about 1.5 fold, in-dicative of its inhibitory effect on transmembrane efflux and CYPs [15].Similar appreciation in the oral bioavailability in the order of 2-fold wasalso observed with paclitaxel [115], doxorubicin [116] and etoposide[117]. Furthermore, co-administration of other functional agents suchas narigrin, geniestein, morin, biochanin A, schisandrol B, kaempferol,myricetin, silymarin, baicalein, recombinant interleukin-2 (pretreat-ment) and curcumin has also been reported to substantially increasethe oral bioavailability of anticancer agents such as paclitaxel, docetaxel,doxorubicin, etoposide, etc. Similarly, quinidine is also found to inhibitthe carrier mediated efflux of etoposide when tested against Caco-2cell monolayers, rat and human intestine. The inhibitory effect wasfound to be concentration- and temperature-dependent suggestingthe involvement of active process [118].

3.1.2.2. Polyethylene glycol (PEG) and its derivatives. These are wellreported to inhibit the P-gp efflux of drug compounds, although themechanistic understanding is still elusive [119–122]. PEGs were foundto inhibit the secretory transport of various compounds such as rhoda-mine 123, paclitaxel, doxorubicin, etc. irrespective of the molecularweights, when tested against Caco-2 cell monolayers [120,121]. How-ever, PEGs withmolecular weight b 200 lacked the P-gp interaction ca-pabilitywhile satisfactory P-gp inhibitionwas observed in case of >300molecular weight [123]. The P-gp inhibition capability is also retainedwhen PEGylation of drug is practiced, e.g. PEGylated paclitaxel poseshigher oral bioavailability as compared to plain paclitaxel [124]. Apartof efflux inhibition, solubilization potential of PEGs also contributes sig-nificantly in increasing the oral bioavailability of drugs. Similar inhibito-ry response on the P-gp efflux of doxorubicin was also observed inMCF-7/ADR cells when administered in the micellar form preparedwith PEGylated phosphatidylethanolamine [125]. The inhibitory activi-ty of PEG could be further enhanced by thiol modification and about3.3-fold increase in the transport of rhodamine with PEG-g-PEIco-polymer was observed with significant decrease in the secretorytransport at tested concentrations as compared to free rhodamine. Sub-strate competition or ATP depletion was proposed to be the probablemechanism of P-gp inhibition by such novel grafted polymer systems[126].

3.1.2.3. Thiolated polymers. Thiolated polymers have recently beenstudied for their P-gp and CYP enzyme inhibitory activity [126–129].The rationale for such studies was based on the feasibility of the cova-lent binding of sulfhydryl substituted purines with P-gp [130]. Thethiolated polymer chitosan-4-thio-butylamidine (chitosan-TBA) signif-icantly increased the absorptive transport (+118%) and markedlyreduced the secretory transport (−37%) of rhodamine 123 [131]. Thisinhibitory effect was attributed to the capability of the sulfhydrylgroup to react with the cysteine residues located within the Walker Aconsensus sequences of each of the two ATP binding domains of P-gp[132].While these cysteine residues are not important for P-gp functionthere lays a probability of steric hindrance at the catalytic activities ofthe P-gp [133,134]. Additionally, considering the non-penetrating char-acteristics of the modified chitosan, due to high molecular weight, theinhibitory activity ismainly concentrated at the cell surface [131]. In ad-dition, a significant decrease in the transepithelial electrical resistancein the Caco-2 cell monolayers was also observed in the presence ofchitosan [135]. It was further revealed that the modified chitosans arecapable of altering the microviscosity of the surrounding lipid bilayer


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and thus imparts molecular conformational changes in the structureof P-gp, thereby inhibiting the efflux of drugs. Additionally, themolecu-lar weight of these modified chitosans also plays a crucial role inexhibiting the polymeric characteristics. At lower molecular weight,lower mucoadhesive and cohesive properties are exhibited, which arebeneficial for immobilization of thiol groups on polymeric backbone,but at the same time the higher interpenetration is exhibited, hence-forth an optimum molecular weight of chitosan should be chosen tohave desired results [136]. The added advantage of these modified chi-tosan resides in the fact that they are not significantly absorbed fromthe GIT and remain concentrated on the gastrointestinal membrane[137]. However, the gastrointestinal irritation of the said polymersshould be carefully monitored. Thiolated polycarbophil has also beenfound to significantly improve the plasma levels of paclitaxel and reduc-tion in tumor growth when administered orally in mammary cancerbearing rats. The effects were attributed to the P-gp inhibition propertyof these novel polymers [138].

Mechanistically, the alteration in the concentration of a tyrosinephosphatase inhibitor, glutathione, initiation of the tight junction open-ing cascade is also reported in the literature [139,140]. Glutathione iscapable of raising the absorptive transport to 200% and lowers thesecretory transport to−42%, viamodulation of tight junctions. Concur-rently, the thiolated polymer also prevents the oxidation of the glutathi-one at the mucosal surface [141]. The cysteine groups were found tohave very critical role in the inhibition of the tyrosine phosphatases,enzyme responsible for the dephosphorylation to render the tight junc-tions in closed state [142]. The hypothesis could be corroborated by theexperimental finding that chitosan–N-acetyl cysteine conjugates in-creased the absorptive transport of rhodamine-123 by 1.5 fold anddecreased the secretory transport by 1.9 fold [143].

3.1.2.4. Surfactants. Surfactants have been widely used in formulationswith the intention of enhanced drug absorption by means of wettingand solubilization. However, their P-gp inhibition capability has re-cently gained widespread acceptance [144]. Mainly polysorbates,pluronic block co-polymers, castor oil derivatives, fatty acid ester sur-factants such as hydroxyl stearates e.g. Solutol HS 15, Cremophor EL,etc. and vitamin E derivatives have been evaluated for their P-gp ef-flux inhibition [145]. Fig. 5 reflects the inhibitory activity of varioussurfactants on the uptake of [3H] mitoxantrone via different mem-brane transporter proteins such as P-gp and BCRP. Among the testedsurfactants, Cremophor EL, Tween 20, Span 20, Pluronic P85 and Brij30 exhibited significant increase in the uptake of [3H]mitoxantronein BCRP-expressing cells whereas Cremophor EL, Cremophor RH40,Tween 20, Tween 80, Span 20, Pluronic P85, vitamin E TPGS, Brij 30,Myrj 52 and Gelucire 44/14 posed significant increase in the uptakeof [3H]mitoxantrone in P-gp-expressing cells [146]. These surfactantsact even at very low concentration, e.g. ~0.01% v/v Tween 80 signifi-cantly increased the accumulation of the daunorubicin in the resistantEhrlich Ascites Tumor cells [147]. Similarly, the basolateral to apicaltransport of the epirubicin on the Caco-2 cell lines was significantlyreduced in presence of Myrj [148]. The oral bioavailability of the rho-damine 123 increased by ~2.8 fold upon co-administration with Myrj[149]. P-gp inhibition is often found to be concentration dependentwith most of the surfactants such as Cremophor EL, Tween 80, etc.Mechanistically, these alter the membrane fluidity and bind with hy-drophobic domain of P-gp thereby changing its conformation leadingto reduced functionality [150]. On the other hand some surfactantssuch as Labrasol open the tight junctions of intestinal epithelium viainteraction with F-actin and ZO-1 [151]. A dose dependent increasein the intestinal permeability of mannitol was observed when co ad-ministered with Labrasol.

Pluronic block co-polymers are known to sensitize the P-gp ofoverexpressing MDR cancer cells and are reported to deplete theATP pool of the cells; adhere to the cell membranes and alter thelipid bilayer leading to significant decrease in the ATPase activity




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Fig. 5. Comparative inhibitory activity of various surfactants on the uptake of [3H]mitoxantrone in BCRP-(A) and P-gp-expressing MDCK-II cells (B); BCRP: breast cancerresistance protein, GFP: green fluorescent protein, P-gp: P-glycoprotein, MDCK:Mardin Darby canine kidney.Adapted with permission from [146].


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RR[152]. Microgel formulations containing hydrophobic (L-68) and hy-

drophilic (F-127) pluronic co-polymer significantly increased the oralbioavailability of megestrol acetate [153]. However, vitamin E TPGShad shown a dose dependent inhibition only on the substrate inducedATPase activity of the P-gp owing to its PEG content [154]. The oral bio-availability of the paclitaxel increased by about 6-fold as compared tothe control group upon co-administration with vitamin E TPGS. Addi-tionally, the absorption permeability increased by about 4.7-fold andsecretory permeability decreased by about 0.66-fold as measured onthe bidirectional-transport in excised rat ileum. These results wereattributed to micellar solubilization and enhanced permeability of pac-litaxel due to inhibition of P-gp efflux pump by vitamin E TPGS [155].

3.1.2.5. Cyclodextrins. Yet another class of functional excipients, cyclo-dextrins, has been evaluated for their P-gp interaction capability.Methylated cyclodextrins have been reported to interact with thelipid components of the biological membranes, especially cholesterol,modifying their fluidity and permeability [156]. Mechanistically,these are reported to reduce the activation energy required to incor-porate cholesterol in the hydrophobic cavity of the membranes[157–159]. Furthermore, the solubility advantage also contributes tooverall bioavailability enhancement by these cyclodextrins. Signifi-cant increase in the susceptibility of MCF-7 and MDA-MB-231 celllines to carboplatin and 5-fluorouracil was observed when pretreatedwith methylated cyclodextrins [160]. Intracellular accumulation ofdoxorubicin was found to about 2–4-fold higher in HL-60 S and


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HL-60 R cell lines pretreated with methyl cyclodextrins as comparedto those treated with doxorubicin alone [161]. Similar results werealso obtained with docetaxel when tested against K562 S, MCF7 S andA2780 S cell lines [162]. Furthermore, significant increase in the invitro cytotoxicity against cancer cell lines was observed when paclitaxelwas complexed with cyclodextrins; probable reason identified was in-creased solubilization and permeation, owing to inhibition of effluxpumps [163]. Extrapolating these findings, the permeation studiesacross excised intestinal epithelium of the rats were performed andabout 12-fold increase in the apparent permeability of paclitaxel wasfound from cyclodextrin-polyanhydride nanoparticles as comparedto Taxol® [164]. Furthermore, significant increase in the oral bio-availability of the tacrolimus was also found when complexed withdimethyl-β-cyclodextrin (DM-β-CD). Permeability studies revealed de-creased basolateral to apical transport thereby contributing to the over-all bioavailability enhancement along with the solubility advantage[165]. Recently, nanosponges made up of β-cyclodextrins have beenimplemented to improve the oral bioavailability of paclitaxel andabout 3-fold increase in the area under the plasma concentrationcurve (AUC) was observed for paclitaxel loaded nanosponges as com-pared to Taxol® [166]. Similarly, about 3-fold increase in the apparentpermeability of exemestane across Caco-2 cell monolayers was ob-served upon complexation with hydroxypropyl β-cyclodextrin [167].

3.2. Nanocarrier based approaches

Nano-engineered drug delivery systems have shown their poten-tial to increase the oral delivery of various anticancer drugs. Substan-tial efforts have been made to improve the oral bioavailabilityvis-à-vis therapeutic efficacy and safety profile. It has now becomequite evident that a variety of nanocarriers have gained a substantialattention for enhancing the oral deliverability of anticancer drugs.The maintenance of an optimal drug concentration in plasma and inthe vicinity of tumors is the prime requirement of the effective cancertherapy. Carrying forward the discussion of utilizing functional excip-ients in improving the oral delivery of anticancer drugs, a more logicaland scientific approach could be formulating the nanoparticles ofthese functional excipients capable of altered absorption pathways.These altered absorption pathways further appreciate the incrementin oral bioavailability of difficult to deliver drugs.

The principal advantages of nanocarriers include their increasedsolubilization potential, superior encapsulation, altered absorptionpathways, prevention of metabolic degradation within gastrointesti-nal tract, chemical versatility of materials eligible for nanomedicines,flexibility in surface functionalization, drug and disease specific tailormade design capability, targeting potential and ability to incorporatewide variety of drug substances. Recently, the prevalence of drug–drug interactions in cancer patients treated with oral anticancerdrugs is reported which is alarming in the sense that conventionaldrug delivery system (both oral and intravenous) is dangerous to pa-tients. About 46% of patients receiving oral anticancer therapy devel-oped potential drug–drug interactions among which ~16% wereconsidered major [168]. These drug interactions could be fruitfullyavoided by utilization of carrier based approach where drug is encap-sulated within carrier matrices. In addition, it also prevents the cyto-toxic effects to the gastrointestinal tract which is very critical forpatients on chronic cancer therapy via oral route. A variety of bio-pharmaceutical parameters have been reviewed to manipulate theirin vivo fate upon oral administration. Briefly, particle size, shape andsurface properties of the nanoparticles play a crucial role in the up-take across the gastrointestinal membrane and were found to signifi-cantly affect the absorption profile. The nanocarriers with particlesize of 50–300 nm, positive zeta potential and hydrophobic surfacewere found to have preferential uptake from gastrointestinal tractas compared to their counterparts [169]. However, the retention ofthese properties in the gastrointestinal lumen is equally important




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and efforts should be made in this direction to maximize the deliveryefficiency of the carrier system.

Numerous research groups, including ours, are actively involved inidentifying the different absorption mechanisms of these nanocarriersacross the intestinal epithelium and a significant success has beenachieved in this area. Nanocarriers by the virtue of their ability areable to bypass thedifferent hurdles that are responsible for poor oral ab-sorption of majority of anticancer drugs. Various identified absorptionmechanisms through which nanocarriers increase the oral bioavailabil-ity of drug molecules include increased absorption from enterocytes(due to increased solubilization and dissolution), mucoadhesion (inter-action between the positively charged nanocarrier with negativelycharged mucin) [170], tight junction modulation (capability of nano-carriers to interact with the tight junction proteins) [171], receptorme-diated endocytosis and transcytosis (clathrin- and calveolae-dependentand -independent endocytosis) [172], phagocytosis via specializedmicrofold cells (M cells) of the Peyer's patches and other mucosa asso-ciated lymphoid tissues (MALT) [173] and lymphatic absorption viachylomicron uptake mechanism from the enterocytes (mediated by li-pase for various lipid based drug delivery systems) [174]. The readersare redirected to the specific literature for further details on variousmechanisms. Hitherto, substantial efforts have been dedicated in thedevelopment of wide variety of nanoformulations with the aim to aug-ment the oral bioavailability vis-à-vis the efficacy of the anticancerdrugs. Various formulation strategies include nanocrystals, drug–poly-mer conjugates, polymeric nanocapsules, polymericmicelles, polymericnanoparticles, lipid based nanocarriers and surfacemodified liposomes.The subsequent sections convey the information on recent develop-ments in the formulation of a variety of nanocarriers which wereemployed for the oral bioavailability enhancement of anticancer drugs.

3.2.1. Drug nanocrystalsRecently, nanocrystal approach has gained a great deal of impor-

tance considering its capability to impart higher saturation solubility,enhanced dissolution and reproducibility for oral absorption of drugmolecules, encompass high dose drugs, thereby increasing the overallbioavailability (Fig. 6) [175]. The residence time of nanocrystals in theGIT could be increased by improving the adhesiveness of nanocrystalsto lumen by mucoadhesive polymers. Various approaches have beenreported to impart mucoadhesion to the nanocrystals which includesuspension layering, spray drying, etc. However, there is always a limi-tation in choice of excipients with dual functionality of mucoadhesionand nanocrystal stabilization. Hence, a novel approach of incorporatingthe nanocrystal in mucoadhesive gels was implemented [176]. In addi-tion, increased permeability is also reported to contribute to the overallbioavailability enhancement to some extent [177]. The other advan-tages with nanocrystal approach include high drug pay load, drug sta-bility, improved drug efficacy, high level of scalability and widespreadindustrial adaptability. Currently, two approaches i.e. bottom-up andtop-down methods have been reported for the formulation of drugnanocrystals and on that basis various technologies have been adaptedby the industry such as pearl milling (NANOCRYSTALS™, Elan), homog-enization inwater (NANOEDGE™, Baxter), homogenization in alternatedispersion media (NANOPURE™, Pharamasol), homogenization withmicrofluidizers (IDD-P™, SkyePharma), piston gap homogenizationin surfactant based aqueous phase (DISSOCUBES™, SkyePharma), pre-cipitation to yield amorphous material (NANOMORPH™, Soliqs) andcombination of approaches such as precipitation, spray drying andlyophilization (SMARTCRYSTAL™, Abbott).

Incorporation of the functional excipients, such as P-gp inhibitors,solubilizers, in the nanocrystals may further potentiate the efficacy ofthe final formulation [178].

Nanocrystals for the oral bioavailability enhancement of antican-cer drugs have been scarcely reported. A few research groups likeLiu et al. have reported the development of paclitaxel nanocrystalsby surface stabilization with Pluronic F127 and studied the effect of


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stabilizer and stability of paclitaxel nanocrystals in the mechanisticmanner [179]. The same group further employed D-α-tocopheryl poly-ethylene glycol 1000 succinate (TPGS) as a surface stabilizer for thedevelopment which posed superior and significant efficacy in themulti drug resistant cancer cell lines as compared to marketed controlgroup and free drug [178]. On the similar line, novel nanocrystal formu-lation of paclitaxel and camptothecin has been developed usingthree-phase nanoparticle engineering technology (3PNET technology),which includes a 3 step process: amorphous precipitate; hydratedamorphous aggregate and finally stabilized nanocrystal utilizing F127as polymer stabilizer [180]. The developed nanocrystal formulationupon oral administration showed comparable antitumor efficacy asthat of intravenous administration of taxol at lower doses (20 mg/kg)and significantly higher efficacy at higher doses of 60 mg/kg. Further-more, the efficacy was 3-fold greater as compared to that of free drugsuspension, clearly indicative of advantage of nanocrystal in the drugabsorption. However, the authors still feel need to improve the oral bio-availability of nanocrystal to achieve comparable to that attained by itsintravenous counterpart. Henceforth folate receptor targeted nanocrys-tal design is under evaluation. However, principal problems associatedwith nanocrystal strategy includes higher toxicity potential to the gas-trointestinal tract, poor intellectual property perks and classical to BCSclass II drugs. Therefore, efforts should bemade in the direction of func-tional coating to nanocrystals, stabilization of nanocrystals with hydro-phobic amino acids, absorption enhancers, etc. Further efforts canalso be made to stabilize the nanocrystals in gastrointestinal tract andthus make them eligible for M cell uptake classical to polymericnanoparticles (Fig. 6). β-Casein stabilized paclitaxel nanocrystals wereformulated and no significant depreciation in the in vitro cytotoxicitywas found as compared to the free drug when tested against humangastric cancer N-87 cell lines in the presence of simulated gastrointesti-nal fluids. The authors proposed the protective role of β-casein in theformulation to avoid the toxicity to the oral and esophagus liningswhen administered orally without compromising the cytotoxicity[181]. However, the systemic bioavailability of drug from such systemsis questionable and hence a rationalized system, paclitaxel nanocrystalsloaded porous quaternized chitosan nanoparticleswas developed [182].These modified nanocrystals exhibited significantly higher intracellularaccumulation and in vitro cytotoxicity as compared to free drug whentested inCaco-2 cell lines and Lewis lung carcinoma (LLC) cell lines, re-spectively. Synchronizing with the in vitro results, in vivo studies re-vealed about 5-fold increase in the accumulation of drug at the tumorsite alongwith higher antitumor efficacy and safety profile as comparedto standard formulation. Recently, an investigational new chemical en-tity, 2-methoxyestradiol (2ME2), has been developed as Nanocrystal®dispersion (NCD) and is presently under phase II clinical trial in patientswith taxanes refractory, metastatic castrate-resistant prostate cancer(CRPC) [183].

3.2.2. Polymeric nanocarriers

3.2.2.1. Polymeric nanoparticles. Polymeric nanoparticles are nano-colloidal cargos, preferably in the size range of 10–1000 nm, made upof wide variety of polymers. They have been widely studied and evalu-ated for the oral delivery of chemotherapeutic agents. The principal ad-vantage of this system includes their robust structural characteristicsimparting very high stability in the gastrointestinal tract. Furthermore,the hydrophobicity and hydrophilicity within the polymeric systemcan be manipulated to accommodate wide variety of drug molecules[184]. The properties of biocompatibility and biodegradation furtherenhance their delivery potential. A large number of polymers includingthe co-polymers have been employed for the preparation of polymericnanoparticles (nanocapsules and matrix based nanoparticles). Theseinclude natural polymers such as gelatin, dextran, albumin, chitosanand alginate to name a few, among which chitosan and its derivativeshave been widely explored [185]. Recent trends include the utilization




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Fig. 6. Mechanistic representation of absorption via nanocrystals.


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of the synthetic biodegradable polymers such as polylactic acid (PLA),polyglycolic acid (PGA), copolymers of lactic and glycolic acid (PLGA),poly(ε-caprolactone) (PCL), poly-alkyl cyanoacrylate (PACA), polyeth-ylene imine (PEI), poly(L-lysine), poly(aspartic acid), etc. [186].

The polymeric nanoparticles tend to show very high degree ofsustained release of drug molecules, which could be of special signifi-cance for oral delivery in terms of ensuring that no drug is releasedfrom the formulation till it reaches systemic circulation therebybypassing various physiological barriers to oral delivery of difficult-to-deliver drugs [187]. Numerous reports on rapid absorption of polymericnanoparticles from gastrointestinal tract upon oral administration andsubsequent drug release from longer period of time (exceeding gas-trointestinal transit time) have been reported. The same could be at-tributed to the preferential uptake of polymeric nanoparticles byspecialized Peyer's patches (M cells) and the isolated follicles of thegut-associated lymphoid tissue present in the gastrointestinal tract(Fig. 7). Our group has exhaustively studied PLGA nanoparticles fororal delivery of various anticancer agents including tamoxifen anddoxorubicin. Significant improvement in the cellular uptake of doxo-rubicin loaded PLGA nanoparticles (Dox-NPs) was observed inmouse breast cancer, C127I cell lines as compared to free drug [188].The internalized Dox-NPs were found to preferentially localize in thevicinity of nucleus, site of action of doxorubicin (Fig. 8). Furthermore,the developed formulation posed both time- and concentration-dependent increases in the Caco-2 cell uptake as compared to freedrug solution. Considering increased permeation across the gastroin-testinal tract, the developed formulation showed ~49.06% reductionin the tumor burden upon oral administration of Dox-NPs in30 days; whereas in contrast 158% increase in tumor burden wasobserved in untreated group. Although, intravenous administrationof free doxorubicin could reduce the tumor burden to greater extent(~69.28%) as compared to developed formulation, significantly highercardiotoxicity was observed. The developed formulation in contrastposed significantly lower cardiotoxicity. Therefore, it could be con-cluded that efforts should be made in improving the therapeutic effi-cacy of a formulation without compromising the safety profile andthe same could be achieved using nanocarrier based approaches. Onthe similar line of action, tamoxifen loaded PLGA nanoparticles(Tmx-NPs) were also developed and evaluated for their in vitro and


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in vivo performances. Although, similar cellular cytotoxicity profile offree Tmx and Tmx-NPswas observed against C127I cell lines at all test-ed time points till 72 h, significantly higher cytotoxicity was observedin case of recovery experiments which could be attributed to rapid in-ternalization and retention of nanoparticles within cells as comparedto free drug.

About 3.84-fold and 11.19-fold increase in the oral bioavailability oftamoxifenwas observedupon incorporation in to PLGAnanoparticles ascompared to commercial analogue, tamoxifen citrate and free base, re-spectively. Furthermore, significantly higher antitumor efficacy of ta-moxifen and reduced hepatotoxicity were also observed from PLGAnanoparticles as compared to free base (Fig. 9) [189]. Similar resultswere also observed in case of CoQ10 loaded PLGA nanoparticles [190].

Very often the surfacemodification of the polymeric nanoparticles iscarried out to achieve desired properties meeting intended application.The hydrophobicity and surface charge of the prepared nanoparticlescan be manipulated to modulate the absorption kinetics from thegastrointestinal tract. This includes surface functionalization such asPEGylation, co-polymerization with functional polymers, polyelectro-lyte coatings and ligand anchoring [191]. An exhaustive study onengineered polymeric nanoparticles for cancer therapeutics has beenrecently reviewed by our group [192]. PEGylation is one of the mostcommon approaches implemented to circumvent classical problemsassociated with nanoparticles such as particle aggregation, stability inthe biological milieu and rapid clearance from body. Various aspectsof nanoparticle PEGylation and their pros and cons in the drug deliveryhave been reviewed recently [193,194]. PEG chains are reported toimpart stealth characteristics to the nanoparticles [195], improvebioadhesion in the gastrointestinal tract [196], provide surface hydro-philicity and facilitate passive targeting via EPR effect [197].

Ligand anchoring on the polymeric nanoparticles is also one of theapproaches to improve their oral deliverability. However, this ap-proach is less studied owing to existence of very few receptor medi-ated transport systems in the gastrointestinal tract. The principalligands that are exploited for the said purpose include folic acid[198], bioadhesins such as lectins, pectins [199]; peptidic ligandssuch as RGD (arginine–glycine–aspartate) [200]; and bile acids suchas deoxycholic acid [201]. Bioadhesins are the wide variety of pro-teins and glycoproteins capable of interacting preferentially with




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Fig. 7. Potential absorption mechanisms implemented by polymeric nanocarriers for increasing oral bioavailability of drug substances.


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carbohydrate residues. Among the wide variety of known bioadhesins,lectins are themostwidely studied for targeted drug delivery to specificlocations along the gastrointestinal tract for variety of purposes such astumor targeting, mucosal immunization, etc. [202]. The lectin anchoredpolymeric nanocarriers are specifically taken up by antigen samplingcells of gastrointestinal tract, M-cells of the Peyer's patches; whichfurther process it to transepithelial antigen transport system. Once in-ternalized, these carriers pave their way to systemic circulation via lym-phatic system; thereby bypassing various absorption barriers [203].In addition, lysosomal targeting mediated by lectin has also been pro-posed in Caco-2 cell lines [204]. On the other hand, peptidic ligandssuch as RGDpeptide are found to interact with the β1 integrin receptorslocalized at apical pole on the M cells of the Peyer's patches alongthe gastrointestinal tract [205]. Similarly, various bile acids have alsobeen evaluated for improving the oral deliverability of polymericnanoparticles. These bile acids such as deoxycholic acid are activelytransported via bile acid transporters from the gastrointestinal tract toliver. Therefore, bile acid as a targeting ligand can be used specificallyfor liver targeting via oral route of administration [201]. Table 3 reveals

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Fig. 8. Critical quality attributes of doxorubiciAdapted with permission from [188].


Evarious types of polymeric nanoparticles that have been implementedto improve the oral delivery of anticancer drugs.

The principle disadvantages associated with polymeric nanopar-ticles especially PLGA based drug delivery system are excessive cost in-curred. However, as far as oral anticancer therapy is concerned, everyeffort should be made to have cost effective formulations. Hence, rela-tively inexpensive polymeric materials should be sought such as chito-san. But the concern associated with crosslinking of chitosan forpreparation of nanoparticles should be carefully addressed.

3.2.2.2. Polymeric micelles. Polymeric micelles are the systems con-taining hydrophobic cores surrounded by hydrophilic corona that isexposed to aqueous environment. The hydrophobic cores act as a res-ervoir for lipophilic drug molecules and corona acts as the steric stabi-lizer of the overall system thereby assuring the integrity of the systemin aqueous environment holding the adequate amount of guest drugmolecules [226]. Polymeric micelles have recently gained wide accep-tance as the carrier systems considering their various advantagessuch as superior stability compared to surfactant micelles, enhanced

n loaded PLGA nanoparticles (Dox-NPs).




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Fig. 9. (A) Plasma concentration time profiles of tamoxifen (Tmx) after oral administration to SD rats at 10 mg/kg dose formulated in the PLGA NPs, compared with the oral ad-ministration of Tmx free base and Tmx salt; (B) tumor progression after repetitive oral administration of Tmx citrate and Tmx-NPs (3 mg/kg). Tumor volume was taken as 100%at the start of drug treatment and tumor progression monitored till the end of the study; each data point is represented as mean ± SEM (n = 6).Adapted with permission from [189].

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solubilizing power, longer circulating time due to outer hydrophilicshell, small size and targeting capability [227]. An exhaustive reviewon the various mechanisms of drug absorption via polymeric micellesfrom gastrointestinal tract is already available in literature and hencebeen kept out of the scope of this report [226]. Briefly, these include al-teration in the membrane permeability, absorption of micelles via fluidphase pinocytosis, receptor mediated endocytosis (upon attachment ofspecific ligands to themicellar structures), inhibition of the efflux trans-porter proteins (majority of the polymers formingmicelles are reportedto interact with efflux transporter proteins) and mucoadhesion alongthe gastrointestinal tract (Fig. 7). These systems generally have A–Bdiblock structure; A, hydrophilic polymers constituting coronawhereasB, hydrophobic polymers, forms cores. However, tri block copolymerA–B–A systems have also been studied to some extent and under consid-eration for its use as potential drug delivery system. The cores of the poly-meric micelles are generally made of biodegradable polymer such as

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List of polymers implemented to improve the oral deliverability of various anticancer agen

Polymeric system Functionalization Active Outcome

Chitosan TPP cross linking (−)-Epigallocatechin gallate 1.5-FoldChitosan Caseinophosphopeptides (−)-Epigallocatechin gallate SuperiorPAA-cysteine GSH Paclitaxel About 7-

bioavailaPCCL-PEG-PCCL Chitosan 10-Hydroxycamptothecin SignificanPolyanhydrides Cyclodextrins Paclitaxel Relative BPolyanhydrides PEG 2000 Paclitaxel Relative bPolymethylmethacrylate

Thiolated chitosan Docetaxel Significanfor 72 h

PLA Vitamin E TPGS Docetaxel BioavailaPLA TPGS Paclitaxel 1.8-Fold

nanopartPLGA DMAB-TPGS Docetaxel About 16

lines as cPLGA Montmorillonite Paclitaxel Significan

and 11–5PLGA Dextran sulfate Vincristine sulfate 12.4-FoldPLGA Vitamin E TPGS – 4–6-FoldPLGA Pectin Thymopentin IncreasedPLGA Deoxycholic acid Rhodamine BioavailaPLGA WGA Paclitaxel About 2-

comparePLGA WGA Paclitaxel SignificanNMA622 – Rapamycin SignificanPLGA – 5-Fluorouracil BioavailaPLGA – Curcumin BioavailaPLGA – Doxorubicin BioavailaPLGA – Paclitaxel 7-Fold hi

2780 ADPLGA – Tamoxifen Bioavaila

PLGA: Polylactide-co-glycolic acid; PCL: Polycaprolactones; PCCL: poly(caprolactone-co-lacacid; NMA622: N-isopropylacrylamide, methylmethacrylate, and acrylic acid in the molar rat


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Opoly(β-benzyl-L-aspartate), poly(DL-lactic acid), poly(ε-caprolcatones),etc. whereas the shell is made up of biocompatible polymers such aspolyethylene oxide. Themicellesmay either be functionalizedwith cer-tain polymers such as poly(N-isopropylacrylamide) [228] or poly(alkyl-acrylic acid) [229] to impart temperature or pH sensitivity, or canfurther be conjugated with ligands to impart targeting characteristics[230,231].

Recently, functional micelles for intracellular targeting via oralroute of administration have been reported [232]. These sophisticatedsystems utilize dequalinium, as a targeting ligand for preferentialco-localization in the mitochondria, guided by transmembrane elec-tric potential within the cell. The cell culture experiments revealedstrong inhibitory action of these functional nanomicelles againstMCF-7 and MCF-7/Adr cell lines with selective accumulation in themitochondria and endoplasmic reticulum within the cells. The per-meability studies revealed about 36.4-fold higher transport of these

ts.

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increase in oral bioavailability [206]biocompatibility, increased Caco-2 permeability and oral bioavailability [207]fold increase in apparent permeability and about 5-fold increase in oralbility as compared to free paclitaxel

[208]

t improvement in the absorptive transport across Caco-2 cell monolayers [209]ioavailability up to 80% [210]ioavailability up to 70% [196]t increase in the in vitro cytotoxicity against MCF-7 cell lines maintainedas compared to free drug

[211]

bility increased by 22-fold [212]increase in the cellular uptake by HT29 cell lines as compared to plain PLGAicles and 40% reduction in IC50 values as compared to taxol

[213]

-fold decrease in the IC50 value for in vitro cytotoxicity against MCF-7 cellompared to marketed formulation at 72 h

[214]

t improvement in the entrapment efficiency by 57–177% for Caco-2 cells5% for HT-29 cells was observed

[215]

higher uptake by MCF-7/Adr cells as compared to free drug [216]increase in the cellular uptake by Caco-2 cells [217]in vivo efficacy [218]

bility increased by 1.8-fold [201]fold increase in the cellular uptake by Caco-2 and HT-29 cell lines asd to plain nanoparticles

[219]

tly higher cytotoxicity against A549 and H1299 cell lines [220]t reduction in tumor inhibition [221]bility increased by 2.27-fold [222]bility increased by 22-fold [223]bility increased by 3.63-fold [224]gher toxicity of formulation in A2780 cell lines and significant activity inresistant cell lines

[225]

bility increased by 11-fold [189]

tide); PLA: Polylactic acid; PEG: Polyethylene glycol; RGD: Arginine–Glycine–Asparticios of 60:20:20; WGA:Wheat germ agglutinin; PAA: polyacrylic acid; GSH: glutathione.




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functional micelles as compared to free drug when evaluated againstCaco-2 cell monolayers. Furthermore, everted gut sac method revealedabout 52.9-fold higher permeability of these functionalmicelles as com-pared to free drug.Moreover, these functionalmicelles revealed compa-rable in vivo antitumor efficacy against xenografted resistant MCF-7/Adr cancer bearing mice by oral and intravenous routes of administra-tion; both being higher than free drug by ~5-fold and 3-fold, respective-ly. This remarkable antitumor efficacy could also be attributed to thepharmacological activity of dequalinium which shows significantlyhigher antitumor efficacy as compared to most of the established anti-cancer agents [233]. However, preferential localization of dequaliniumat the tumor site via oral route is a state-of-art which can be achievedby nanocarriers, per se. Table 4 reflects the list of anticancer drugsbenefitted with the polymeric micelle approach for improving theiroral deliverability.

3.2.2.3. Polymer–drug conjugates. Polymer–drug conjugates are thenovel drug delivery systems comprised of covalently linked drugmole-cules to the polymer backbone. Along with the drug molecules, addi-tional functional excipients such as diagnostic agent, targeting ligand,PEG chains to improve hydrophilicity can also be accommodated inthe polymer backbone thereby resulting in to formation of nanocargosthat are highly specific to disease condition. The resulting conjugate isthen eligible for active transport from gastrointestinal tract to facilitateimproved absorption (Fig. 7). In addition, functional excipients havingcapability to inhibit drug efflux can also be employed. Further, targetingpotential offered by polymer–drug conjugate is especially important incase of cancer therapy owing to highly toxic effects of anticancer agentsto the normal tissues of the body. This also facilitates the stabilizationand subsequent delivery of various enzymes and immunocomponents[246]. Furthermore, upon exploitation of the structure–activity relation-ship of the drug molecules, various benefits such as increased solubili-zation, enhanced plasma half-life, bioavailability enhancement due toincrease in the hydrodynamic volume and reduced excretion by kid-neys, protection towards degrading enzymes, prevention or reductionof aggregation or immune responses, reduction in toxic side effectsand targeting capability can be achieved via polymer–drug conjugates[246,247].

The most critical aspect in case of polymer–drug conjugate ap-proach is identification of functional group for covalent modification.The said functional group should preferably be not involved in phar-macological activity. In absence of the same, it should be ensured thatthe drug in concern is released in free form upon exposure to physio-logical conditions or at target site. Secondly, type of linkage could also

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Table 4List of anticancer drugs benefitted by polymeric micelles approach for improving their oral

Drug System Outcome

Paclitaxel Dequalinium-Vit TPGS1000-PEG2000-DSPE Oral antitumcomparable

Paclitaxel PEG-DSPE-TPGS Solubility inPaclitaxel PEG-b-P(VBODENA) Solubility inPaclitaxel PEG-b-VBODENA-Acrylic acid Complete dTamoxifen PHEA-PEG-C(16) SignificantlyTamoxifen PAHy-PEG(2000)-C(16) 3000-fold inMeso-tetraphenyl porphine Pluronic F127/PEG–DSPE 90% drug loα-Mangostin PVP About 13,00Doxorubicin Stearic acid-g-chitosan Increased oDoxorubicin Pluronic-L92-PAA-EGDMA- ~2-Fold incDoxorubicin PLGA-dextran SignificantlyPaclitaxel N-deoxycholic acid-N,O-hydroxyethyl chitosan BioavailabilPaclitaxel N-octyl-O-sulfate chitosan BioavailabilQuercetin PEG-PE 110-Fold in

MOG: Monoethylene glycol; P(VBODENA): poly(2-(4-vinylbenzyloxy)-N,N-diethylnicotinaPAHy-PEG(2000)-C(16): PEG 2000 and palmitic acid grafted on polyaspartylhydrazide; PHEacid); EGDMA: ethylene glycol dimethacrylate; PE: phosphatidylethanolamine.


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be carefully employed for preparation of polymer–drug conjugate, toachieve target site specificity. The principal types of linkages includeamide linkages, ester linkages, sulfhydryl linkages, hydrazone link-ages, enzymatically degradable linkages, etc. [248]. It should benoted that ester and hydrazone linkages are acid labile and shouldbe less favored while designing oral drug delivery system. Thirdly,the release of drug from conjugate system in timely manner and ther-apeutically active state of released compound is one of the critical as-pects and should be ensured. This obviously necessitates highlysensitive analytical techniques while performing various in vitro andin vivo studies, which is a principal concern in case of polymer–drugconjugates. Further, owing to covalent attachment of the drug mole-cule with the polymer backbone, obvious concern for differentialpharmacokinetics in physiological conditions raises and should becarefully addressed.

The classical approach for formulation of polymer–drug conjugatescan be broadly categorized as PEGylation, involving covalent bindingof PEG chains to drug molecules. PEGylated paclitaxel showed about4-fold increase in the oral bioavailability as compared to free drug,which could be attributed to increased solubility, permeability andreduced presystemic metabolism [124]. Recently, nanoconjugates ofcamptothecin with polylactide have been successfully synthesized[249] and were found to preferentially circulate in body via lymphaticsystem [250]. A variety of carrier linked prodrugs for anticancer agentswith antibodies, proteins and polymers such as glutamic acid, PEG andpolylactic acid have been developed and are presently under clinicalstudies [251] but the aspects related to oral delivery are yet at infantstage and need serious efforts tomaterialize the concept. Recently, oral-ly administrable doxorubicin conjugated monomethoxy-polyethyleneglycol-polylactic acid was developed. The prepared conjugate wasabsorbed from intestine via the transepithelial pathway, accumulatedpreferentially in the liver and thus was exploited in the managementof liver metastasis in mice [252]. On the similar line of action, an oralcolon-specific drug delivery was developed for 9-aminocamptothecin(9-AC) by copolymerizationwithN-(2-Hydroxypropyl)methacrylamide(HPMA) and was found to have potential in management of colon can-cer [253]. Furthermore, lectin functionalization to these HPMA drugconjugates has been shown to improve the oral deliverability of difficultto deliver drugs such as insulin [254]. Henceforth attempts could bemade to apply the same principle for oral delivery of anticancer agents;however the careful selection of spacers for conjugation is one of thecritical steps.

Although, the conjugated systems are difficult to be delivered by oralroute considering their limited absorption, some functional excipients

bioavailability.

Ref

or efficacy in the xenografted resistant MCF-7/Adr cancers in miceto that of intravenous administration

[232]

creased to 5 mg/ml [234]creased to 39 mg/ml [235]rug release in 12 h [236]higher anticancer activity against MCF-7 cell lines as compared to free drug [237]crease in the solubility of Tamoxifenading efficiency could be achieved [238]0-fold increase in solubility of α-mangostin [239]ral bioavailability [240]rease in intracellular accumulation by Caco-2 cell monolayers [241]higher in vitro cytotoxicity against doxorubicin resistant HuCC-T1 cell lines [242]

ity increased by 3-fold [243]ity increased by 6-fold [244]crease in solubility and significant increase in the antitumor efficacy [245]

mide); SA: Succinic anhydride; POE: polyoxyethylene; HPC: Hydroxypropylcellulose;A-PEG-C(16): PEG and palmitic acid grafted on polyhexadecylamine; PAA: poly(acrylic




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along with formulation intervention have to be implemented. The clas-sical approaches include nanocarrier based approach alongwith surfacemodification by functional excipients. Recently, chitosan, owing to itsbiodegradable, biocompatible, mucoadhesive and non toxic nature,has been studied as a novel platform for oral delivery of drugs [255].Unlike high molecular weight chitosan, the low molecular weightchitosan (≤1 lac Dalton) possesses higher solubility, relative lower tox-icity profile and narrower molecular weight distribution [256]. Addi-tionally, these are also reported to reversibly open the tight junctionsbetween the epithelial cells of the Caco-2 cell lines more stronglyas compared to high molecular weight chitosans (≥20 lacs Dalton)[257]. Chitosans are proposed to preferentially interact with theF-actin present in the intestinal lamina in a charge dependent fashionleading to its depolarization and disbandment of ZO-1 protein, an inte-gral part of tight junction. Additionally, this effect leads to improvementin only apical transport of drugs confirming themechanismas increasedpermeability by paracellular pathway [258]. Furthermore, the effect ofdegree of acetylation and molecular weight was also found to signifi-cantly affect the absorption across the Caco-2 cell monolayers [259].Chitosan conjugated paclitaxel has been studied and offered several ad-vantages such as improved water solubility due to increased hydrophi-licity, prolonged retention of the conjugate in the gastrointestinalsystem due to mucoadhesive properties of chitosan resulting in overallincreased uptake, opening of tight junctions and enabling the para-cellular route for absorption and ability to bypass the CYP-450 depen-dent metabolism as the conjugated paclitaxel would no longer be thesubstrate of these enzymes. The absolute oral bioavailability of paclitax-el in rats was found to be ~42% upon conjugation with chitosan and asignificant increase in the in vivo antitumor efficacy and comparabletoxicity profile as compared to free drugwere observed. The hypothesiswas further confirmed by evaluating the effect of cyclosporin A on bio-availability of paclitaxel in the conjugate form. Significant increase incase of free drug and no effect on bioavailability were observed incase of conjugated paclitaxel, suggesting P-gp independent absorptionmechanism for chitosan conjugated systems [260].

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Fig. 10. Key advantages associated with


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3.2.3. Lipid based nanocarriersSince many decades, lipids have been widely used for improving

the oral bioavailability of various difficult-to-deliver drugs. The lipidicexcipients principally comprises of monoglycerides, diglycerides, tri-glycerides, oils constituting various combinations of glycerides, phos-pholipids, sphingolipids and even high fat meal [261]. This could beattributed to some unique properties of lipids such as high solubiliza-tion potential, biocompatibility, manufacturing scalability, industrialadaptability, and distinct route of absorption thereby eliminating var-ious physiological barriers such as pre-systemic metabolism, gastro-intestinal degradation, P-gp efflux and permeability related issues,etc. [262]. The usual problem associated with most of the drugs in-cludes either low aqueous solubility or poor intestinal permeability,both of which can adequately be taken care by lipid based drug deliv-ery systems.

The higher lipophilicity of the drug molecules can be fruitfullyexploited tomake them soluble in lipid based systemswhich can subse-quently be delivered via suitable route of administration, preferablyoral. Two critical quality attributes for development of lipid baseddrug delivery systems have been identified which include drug solubil-ity within lipidic system and subsequent physiological processing ofdrug loaded lipidic system to achieve adequate drug absorption(Fig. 10). The intraluminal processing of the lipidic excipients hasbeen exhaustively reviewed elsewhere [263]. Briefly, gastric and linguallipases digest triglycerides in diglycerides and fatty acids in stomachand are responsible for generation of crude emulsion of lipids which isstabilized bydietary proteins, polysaccharides, etc. However, the dietaryphospholipids and cholesterol esters are not attacked by these lipases.Subsequent to gastric emptying, the partially digested and crude emul-sified lipidic system gets exposed to bile salts, cholesterol and phospho-lipids preferentially phosphatidylcholine secreted by gall bladder andpancreatic lipase/co-lipase secreted by pancreas. The secreted compo-nents then get adsorbed on the surface of the crude emulsion droplets.The adsorption leads to further digestion and formation of stable smallsized emulsion droplets. These small sized lipid emulsion droplets are

lipid based drug delivery systems.




T

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1121


further acted by lipid digestion products such as 2-monoglycerides andfatty acids to form mixed micelles of lipidic system, thereby makingprocess of lipolysis self-promoting [264]. The formed micelles willthen be absorbed by enterocytes, where it gets converted to the chylo-microns upon re-esterification via monoacyl glycerol or phosphatidicacid pathway and subsequent stabilization by phospholipids. However,the penetration of unstirred water layer and mucin in gastrointestinaltract is rate limiting factor. The formed chylomicrons are then subjectedto lymphatic transport system via mesenteric lymph and ultimatelyenter the systemic circulation by lymphatic drainage at thoracic duct[265]. The other transcellular routes by which lipid based drug deliverysystems get transported across enterocytes include macropinocytosis,clathrin-mediated, caveolae-mediated, and clathrin- and caveolae-independent endocytosis (principally lipid rafts comprising ofsphingolipids- and cholesterol-rich microdomains) [172]. Fig. 11 de-picts various absorption mechanisms by which lipid nanocarriersimprove the oral bioavailability of drug substances. Various types oflipid based nanocarriers implemented for improving the oral deliveryof drugs include microemulsions, nanoemulsions, lipid nanocapsules,self-emulsifying systems, lipid nanoparticles, hybrid lipid nanoparticles,liposomes and surface engineered liposomes to name a few.

3.2.3.1. Emulsions. Emulsion based approach has been one of the mostancient methods for delivery of lipophilic drugs. Presently two ver-sions of emulsions viz. microemulsions and nanoemulsions havebeen employed for improving the oral deliverability of BCS class IIor IV drugs. The unique characteristics include thermodynamic(microemulsions) or kinetic (nanoemulsions) stability, supersolvency,small droplet size, high industrial scalability (as low energy require-ments formanufacturing) and use of lipidic excipients as absorption en-hancers [266]. Traditionally, these systems comprises of appropriateblend of oil, surfactant and co-surfactant dispersed in aqueous phasetailor made as per the physicochemical properties of drug substances.The most common oils used for preparation of nanoemulsions includeomega 3- and 6- containing polyunsaturated fatty acids (PUFA) such

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Lymphatic absor

Macrophage

Systemic c

Solid lipid Nanoparticles (SLNs)

M-cell

Uptake by M cells

Enterocy

LayersomeLiposome

Nanostructured lipid carriers (NLCs)

P-gpParacellular

absorption Fluid Phase Macropinocytosis

Pab

Fig. 11. Absorption mechanisms implemented by lipidic nanocarr


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as pine seed oil, fish oil, flax seed oil, safflower oil, hemp and wheatgerm oil, etc. The principal reasons for their widespread usages in prep-aration of nanoemulsions could be attributed to their preferential ab-sorption across the gastrointestinal barrier due to paucity of theseagents in physiological conditions [267]. Furthermore, reports suggesttheir probable interaction with cell membrane via lipid exchangeor endocytosis [268]. In addition, PUFA also contributes to reductionin the protein production and efflux transporters MDR1/P-gp. Re-cently this mechanismwas proposed to promote the in vitro cytotox-icity of paclitaxel against Caco-2 cell lines [269]. These interactionscan further be strengthened by incorporating surface charge to thenanoemulsions. The negative charge imparting agents include lecithin,cholesterol and PEGylated phospholipids while positive charge can beimparted by cationic lipids such as stearylamine and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), etc. Negatively charged nano-emulsions were found to have higher reticulo-endothelial system(RES) uptake while positively charged preferentially accumulated inlungs followed by redistribution in the liver and spleen [270].

Recently, nanoemulsions have also been reported to improve theoral deliverability of various protein based vaccines such as MAGE1-HSP70/SEA complex [271]. The antitumor immune responses fromnanoemulsion loaded vaccine via oral and subcutaneous routeswere studied and comparable efficacy in terms of delay in tumorgrowth and tumor occurrence in mice challenged with B16-MAGE-1tumor cells was observed. Sincere efforts in this direction are present-ly under pipeline and soon some deeper insights on various aspects ofsaid area are anticipated. Table 5 reveals various anticancer drugsbenefited from emulsion based approach.

3.2.3.2. Self-emulsifying drug delivery systems (SEDDS). SEDDS are themost advanced approach of emulsion based drug delivery systemsand relies on the physiological fluids for the in-situ formation ofmicro/nanoemulsion. This formulation strategy comprises of drugdissolved in oils and stabilized by surfactants and co-surfactants,which upon exposure to the aqueous environment under gentle

Fluid Phase Macropinocytosis

ption

irculation

Self emulsifying formulations

tes

ss

Lipid nanocapsules

Emulsified lipids

Mixed micelles

PhospholipidsCholesterol

Chylomicrons

Inhibition of P-gp

aracellularsorption

iers for improving the oral bioavailability of drug substances.




T

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1122

1123

1124

1125

1126

1127

1128

1129

1130

1131

1132

1133

1134

1135

1136

1137

1138

1139

1140

1141

1142

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1177

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1189

1190

1191

1192

1193

1194

1195

1196

1197

1198

1199

1200

1201

1202

1203

1204

1205

1206

1207

Table 5t5:1

t5:2 List of anticancer agents benefited by emulsion based carrier systems for improving their oral bioavailability.

t5:3 Drug Formulation Outcome Ref

t5:4 Benzylisothiocyanate

Flax seeds, egg phosphatidyl choline and glycerol based nanoemulsion About 3-fold increase in the apparent permeability across Caco-2 cellmonolayers and significantly higher in vitro cytotoxicity againstA549 and SKOV-3 cell lines as compared to free drug

[272]

t5:5 Curcumin Lecithin, soyabean oil and Tween 80 based microemulsion incombination with ultrasound energy

In vitro cytotoxicity established against two oral squamous cellcarcinoma cell lines, OSCC-4 and OSCC-25.

[273]

t5:6 Curcumin Curcumin oraganogel and Tween 20 based nanoemulsion 9-fold increase in the oral bioavailability in mice as compared tounformulated curcumin

[274]

t5:7 Docetaxel Capryol 90, Cremophor EL and Transcutol based microemulsion About 25-fold increase in the permeability across Caco-2 cell mono-layers and about 5.19-fold increase in the oral bioavailability wereobserved as compared to Taxotere®

[150]

t5:8 Melphalan Capmul MCM, Tween 80 and Transcutol P based nanoemulsion About 4.83-fold increase in oral bioavailability and 2-fold higherdistribution in ovaries as compared to free drug

[275]

t5:9 Methotrexate Soyabean oil, Cremophor EL, Span 80 and isopropyl alcohol basedmicroemulsion

Significantly higher in vitro cytotoxicity against MCF-7 cell lines ascompared to free drug

[276]

t5:10 Paclitaxel Pine nut oil and lecithin based nanoemulsion Significantly higher oral bioavailability as compared to aqueoussuspension with preferential distribution in liver, kidneys, and lungs

[270]

t5:11 Paclitaxel Capmul, polysorbate 80 and myvacet oil based microemulsion 11-Fold in the permeability across rat intestine and 3-fold increase inthe oral bioavailability as compared to taxol

[277]

t5:12 Paclitaxel Labrasol, vitamin E-TPGS and Labrafil M1944CS based nanoemulsion 70% absolute bioavailability upon oral administration; [278]t5:13 Paclitaxel Drug loaded nanoemulsion co-administered with curcumin 5.2-Fold increase in oral bioavailability and 3.2-fold increase in

tumor uptake was observed as compared to free drug[279]


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agitation leads to spontaneous formation of emulsion. Although theexact mechanism of self emulsification is yet to be understood andis unclear however it has been postulated that it happens when en-tropy change for dispersion exceeds the energy required to increasethe surface area of dispersion [280].

The self-emulsification process is also reported to be affected by theconstituent oils, surfactants, co-surfactants, co-solvents and physico-chemical properties of drug to be incorporated. The details of variousfactors affecting the SEDDS are already available in literature [281]. Innutshell, oils play a very critical role in the solubilization of drug andare responsible for facilitating the drug transport across the gastrointes-tinal barriers via specialized transport mechanisms such as intestinallymphatic system as discussed previously. Different types of oils thatare known to form SEDDS include long- and medium-chain triglycer-ides with different degrees of saturation. The selection of oils solelydepends on its capability to solubilize the drug in concern. The currenttrends in design of SEDDS include utilization of modified or hydrolyzedvegetable oils and novel semi synthetic medium chain derivatives;later having the upper hand in terms of amphiphilic naturewith surfac-tant properties. On the other hand, surfactants, co-surfactants andco-solvents play a major role in the formation and stabilization of thein-situ emulsion. Generally, nonionic surfactantswith higher hydrophil-ic lipophilic balance (HLB) values are preferred; however, based on ourexperience, it should be noted that precipitation of drug upon dilutionneeds careful monitoring in this case. Furthermore, the toxicity associ-ated with higher usage of surfactants is a major limiting factor.

A newer generation of SEDDS based on supersaturation principlehas been designed to exclude the side effects of surfactants and enhancethe rate of absorption of drugs from the gastrointestinal tract [282].These formulations include low levels of surfactants and polymeric pre-cipitation inhibitors to yield and stabilize a temporary supersaturatedstate of drug. HPMC and other cellulosic polymers are well recognizedfor their capability to inhibit the crystallization of drugs and therebyleading to formation of supersaturated state of drug for prolong dura-tion. Recently, solid supersaturable SEDDS of docetaxel via spray dryingtechnique have been prepared and it was found to have about 8.77-foldand 1.45-fold higher oral bioavailability as compared to free drug andconventional SEDDS, respectively; clearly indicating the superior bene-fits at reduced surfactant level by this novel approach [283]. Further-more, ligand anchored SEDDS have also been developed to exploit thetargeting potential of nanocarriers. Recently, folate modified SEDDSfor delivery of curcumin have been designed and developed for colontargeting [284]. The developed formulation was found to significantly


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Reffective against HELA and HT29 cell lines as compared to the plainSEDDS and free curcumin. Interestingly, the in vitro cytotoxicity was re-duced in the presence of external folate supplementation clearly reveal-ing the role of folate modification on the activity of formulation.

The principal advantage of the SEDDS lies in their superior stabil-ity profile that surpasses the stability related issues associated withthe conventional emulsions. However, the inherent stability of theoils should be critically assessed to predict the overall shelf life ofthe formulation. The stability of these formulations can further be en-hanced by adsorbing the liquid or semisolid SEDDS on to suitableinert adsorbents such as silicates, dextran, magnesium hydroxide,crosspovidone, carbon nanotubes, fullerenes, charcoal, etc. via variousprocess such as spray drying, lyophilization, melt granulation andmelt extrusion to name a few [285]. However, the process of adsorp-tion may also be associated with problems such as alterations in re-lease profile, process loss and increased manufacturing steps andexcess cost. Therefore, newer advancement includes utilization of ex-cipients that serve dual purpose of solidifying and emulsifying agentssuch as poloxamer 188 [286].

Our group is also actively involved in the formulation develop-ment of SEDDS for various difficult-to-deliver drugs. Recently, tamox-ifen loaded SEDDS have been developed and an Indian patentapplication has been filed [287]. A PCT application has also beenfiled and recently got favorable ISR/WO [288]. The developed formula-tion showed about 3.8-fold and 9-fold enhancement in oral bioavailabil-ity as compared to clinically used tamoxifen citrate and tamoxifen freebase, respectively. Furthermore, significantly higher antitumor efficacyin 7,12-dimethylbenz[α]anthracene (DMBA) induced breast cancermodel in rats was observed as compared to tamoxifen citrate. The tox-icity studies revealed no observable hepatotoxicity markers when test-ed in mice. The formulation was further found to be stable in simulatedgastrointestinal fluids for 8 h. In addition, accelerated stability was alsoestablished for developed formulation as per ICH guidelines. Usually thechronic therapy of anticancer agents is associated with the reduced an-tioxidant levels due to higher reactive oxygen species (ROS) generationmediated by these agents for execution of their cytotoxic effect. Hence-forth, co-administration of antioxidants is generally prescribed. Howev-er, the physicochemical properties of antioxidants such as CoenzymeQ10, quercetin and curcumin generally make them difficult-to-deliver,which can be specifically tackled by nanocarrier based approach [189].We have successfully developed and patented the SEDDS of quercetinfor improving its oral bioavailability [289]. About 4.98-fold increase inthe oral bioavailability of quercetin was observed as compared to free




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drug. Further, the developed formulation also posed significantly higherprophylactic and therapeutic antitumor efficacy as compared to freequercetin in DMBA induced breast cancer model in rats (unpublisheddata). In addition, combination of antioxidant loaded SEDDS with anti-cancer agents is also reported to have higher therapeutic efficacy ascompared to individual anticancer agents. Recently, co-administrationof docetaxel with curcumin loaded SEDDS led to about 3.2-fold increasein the oral bioavailability of docetaxel as compared to the free drug. Theinhibitory effect of curcumin on P-gp and cytochrome P450 was attrib-uted to this increment in oral bioavailability of docetaxel [290]. Table 6reflects the exhaustive list of self emulsifying formulation approach forimproving the oral bioavailability of anticancer agents.

3.2.3.3. Solid lipid nanoparticles (SLNs). SLNs are the alternative versionof emulsions in which the liquid oil is replaced by solid lipids. Specificadvantages include modulation of drug release, increased drug stabili-ty, exclusion of organic solvents from the manufacturing process,manufacturing scalability and industrial adaptability [303]. These aregenerally prepared by various commonly used techniques such as hothomogenization, cold homogenization, microemulsion technique,solvent emulsification/evaporation, spray drying and so on. The lipidsthat are used to prepare SLNs include fatty acids (e.g. stearic acid),fatty acid esters (e.g. glyceryl monostearate, glyceryl behenate), triglyc-erides (e.g. tristearin, trilaurin), steroids (e.g. cholesterol) and waxes(e.g. cetyl palmitate). Depending on the charge, molecular weight andtheir capability to stabilize the dispersion, single or combination ofemulsifiers are chosen and incorporated into the system. Commonlyused emulsifiers and co-emulsifiers include lecithin, poloxamers, cho-lates, and so on. Our group has exhaustively reviewed various aspectsof solid lipid nanoparticles for improving the oral bioavailability ofdifficult-to-deliver drugs [174]. Recently, paclitaxel has been formulat-ed as SLNs using stearic acid as lipid and lecithin and poloxamer as sur-factants [304]. The paclitaxel loaded SLNs showed superior in vitrocytotoxicity as compared to free drug. A similar study for camptothecinhas been carried with an intention of sustaining the drug release [305].In order to further modulate the drug release; SLNs were further conju-gated with dextran methacrylate hydrogels [306]. Reviewing the solidlipid nanoparticles, it has been generally found that the drug releaseis often retarded due to high lipophilic nature of the overall system,but considering the urge to increase the drug release rate; polymerlipid hybrid nanoparticles were developed [173]. These are based on

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Drug Oils Surfactants

9-Nitrocamptothecin Ethyl oleate Tween 80 and PEG 400Curcumin Castor oil Tween 80 and ethanolCurcumin Lauroglycol Labrasol and Transcutol HP

Curcumin Gelucire 44/14 Labrasol, Vitamin E TPGS and PEG 400

Curcumin Isopropyl myristate Cremophor RH 40 and ethanol

Docetaxel Glyceryl tricaprylate Cremophor RH 40, Diethylene Glycol MEther; HPMC as super-saturation prom

Etoposide PC-complexed; Octyl anddecyl mono-glyceride

Cremophor EL and PEG 400

Exemestane Capryol 90 Transcutol P and Cremophor ELP

Mitotane Capryol 90 Tween 80 and Cremophor EL

Raloxifene Capmul MCM C8 Tween-20 and Akrysol K140 and PEG-

Paclitaxel Vitamin E DOC-Na, TPGS, Propylene glycol, CremPaclitaxel Glyceryl dioleate Cremophor EL, PEG 400; HPMC as supe

promoterPaclitaxel DL-alpha tocopherol TPGS, tyloxapol, DOC-Na

PC: Phosphatidylcholine; DOC-Na: Sodiumdeoxy cholate; TPGS: D-alpha-tocopheryl polyethylen


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same principle of SLNs, and incorporation of the ionic polymers helpsin improving the encapsulation of water soluble ionic drugs such asdoxorubicin hydrochloride [307]. This system showed 8-fold highertumor cell inhibition in multi drug resistant cell lines compared tofree drug along with greater drug uptake and retention by cell lines[308]. Table 7 represents the applicability of SLNs in improving thedeliverability of various anticancer drugs.

3.2.3.4. Nanostructured lipid carriers (NLCs). NLCs are the advancedgeneration of SLNs overcoming the problems associated with thelater such as limited drug loading capacity, restructuring during stor-age and subsequently expulsion of drug during storage. The saidadvantages could be attributed to higher solubility of drugs in oilsas compared to solid lipids. However, inclusion of drug beyond oil/lipid solubility is practically difficult and often needs alternative strat-egy. Hence high dose compounds are poor candidates for these sys-tems. NLCs are prepared by similar technique as reported for SLNswith only difference that both solid lipid and liquid oil are mixedfor formation of NLCs in contrast to only solid lipid for SLNs. Thisleads to formation of porous matrix structure resulting in higherdrug pay load that is entrapped throughout the shelf life of the prod-uct [318]. The stability of NLCs can further be enhanced by addition ofpreservatives such as propylene glycol, pentylene glycol, etc. Variousstabilization aspects of NLCs have been recently studied. Briefly, theparameters which need consideration include affinity of the preserva-tive to the particle surface, surface hydrophobicity of the particles,anchoring of stabilizer onto/into surface, ability of preservative to re-duce zeta potential, nature of the particle stabilizer and interaction ofpreservative with stabilizer layer [319]. Recently, tocotrienol loadedNLCs were developed and evaluated for their antiproliferative effectagainst +SA epithelium cell lines and were found to be about 2-foldmore effective as compared to free tocotrienol [320]. Furthermore,NLCs have also been implemented for oral delivery of etoposide andabout 3.5-fold increase in the oral bioavailability was observed ascompared to free drug [321]. Increased permeation across, decreasedclearance and specialized uptake of nanoparticles were attributed forthe probable reasons for increased oral bioavailability. Furthermore,the developed formulation posed about 5-fold increase in the in vitrocytotoxicity against A549 cell lines as compared to free drug, suggestiveof potential of NLCs based drug delivery system for improving the oraldeliverability of various anticancer drugs.

their oral bioavailability.

Outcome Ref

2.23-Fold increase in bioavailability [291]About 2000-fold increase in the solubility of curcumin [292]7.6-Fold increase in the oral bioavailability as compared tofree drug.

[293]

35.8-Fold increase in the oral bioavailability as compared tocontrol

[294]

12-Fold increase in the oral bioavailability as compared tofree drug.

[295]

onoethyloter

8.77-Fold increase in the total AUC [283]

60-Fold increase in bioavailability [296]

About 2.8-fold increase in the oral bioavailability as comparedto free drug

[297]

About 3.4-fold increase in oral bioavailability as compared toclinical formulation

[298]

200 About 2-fold increase in the intestinal permeability across therat intestine as compared to plain drug

[299]

ophor RH 40 1.2–1.5-Fold increase in bioavailability [300]rsaturation 5-Fold higher bioavailability [301]

3-Fold increase in the solubility of Paclitaxel [302]

e glycol 1000 succinate; PEG: Polyethylene glycol;HPMC: Hydroxypropylmethyl cellulose.




T

F

1288

1289

1290

1291

1292

1293

1294

1295

1296

1297

1298

1299

1300

1301

1302

1303

1304

1305

1306

1307

1308

1309

1310

1311

1312

1313

1314

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1339

1340

1341

1342

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1344

1345

1346

1347

1348

1349

1350

1351

1352

1353

1354

1355

1356

1357

1358

1359

1360

1361

1362

1363

1364

1365

1366

1367

1368

1369

1370

1371

1372

1373

1374

1375

1376

1377

1378

1379

Table 7t7:1

t7:2 List of anticancer drugs benefited from solid lipid nanoparticles for improvement in oral bioavailability.

t7:3 Drug Ingredients Outcomes Ref

t7:4 5-Flurouracil Dynasan, soya lecithin, polyvinyl alcohol Sustained release of drug till 48 h [309]t7:5 Camptothecin Stearic acid, Soya lecithin, poloxamer 188 About 1.4-fold increase in the oral bioavailability as compared to free drug was observed [305]t7:6 Doxorubicin Emulsifyingwax, Brij 78 and Vitamin E TPGS About 9-fold increase in the in vitro cytotoxicity against P388/ADR cancer cell lines as compared to free drug [310]t7:7 Emodin Stearic acid, poloxamer 188 and Tween 80 Significantly higher in vitro cytotoxicity against MCF-7 and MDA-MB-231 cancer cell lines as compared to

free drug.[311]

t7:8 Methotrexate Stearic acid, Soya lecithin and sodiumtaurodeoxy-cholate

Significant improvement in the half life and mean residence time of formulation as compared to free drug.The life span of Ehrlich Ascites Carcinoma bearing mice was increased upon treatment with formulation ascompared to free drug

[312]

t7:9 Tamoxifencitrate

Glycerol behenate, sodiumtauroglycocholate

About 3.5-fold increase in the mean residence time of formulation as compared to free drug [313]

t7:10 Paclitaxel Stearic acid, lecithin and poloxamer 188 Significant improvement in the in vitro cytotoxicity of paclitaxel as compared to free drug [304]t7:11 Paclitaxel Folate-(PEG)-phosphatidyl-ethanolamine Significant improvement in in vivo antitumor efficacy of formulation as compared to free drug [314]t7:12 Paclitaxel Glyceryl palmitostearate nanoparticles Retention of the in vitro cytotoxicity of paclitaxel against B16F10 cell lines [315]t7:13 Paclitaxel Folate modified monostearin About 11-fold increase in the in vitro cytotoxicity against A549 cell lines as compared to free drug [316]t7:14 Vinorelbine PEG2000-stearic acid About 27-fold and 25-fold increase in the in vitro cytotoxicity of vinorelbine in developed formulation

against MCF-7 and A549 cell lines, respectively was observed as compared to free drug.[317]


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3.2.3.5. Lipid nanocapsules. Lipid nanocapsules are the novel colloidalnanocarriers having typical core shell arrangement of the constituentswith liquid reservoir (usually oils) as core coated by protective mem-brane. The protectivemembrane generally comprises of polymer chainspresent in the surfactant which is aligned as exterior coat during thepreparation of lipid nanocapsules [322]. Similar to nanoemulsions,various methods have been proposed for formulation of lipid nano-capsules, out of which phase inversion temperature is most commonlyadapted [323]. Briefly, the method relies on the properties of thenon-ionic surfactants such as PEG hydroxystearates, having tendencyto pose temperature dependent solubility. The lipid nanocapsules areprincipally known for their biocompatibility, biodegradability, superiorencapsulation of drug molecules, very high drug payloads, specific ab-sorption mechanism across the gastrointestinal tract, sustained release,membrane efflux transporter inhibition, targeting potential (active andpassive) and most importantly oral deliverability [322]. Furthermore,the aqueous-core lipid nanocapsules have also been proposed that arecapable of incorporating both hydrophilic and lipophilic drugmolecules[324].

Recently, the stability of the paclitaxel loaded lipid nanocapsuleswas established in the gastrointestinal tract. The stability of these sys-tems was attributed to the presence of the surface PEG coating, whichspecifically protected the aggregation of internal lipid constituentsdue to acidic pH in the stomach and against pancreatin activity in in-testine. However, weaker protection was exhibited in the presence ofbile salts and hence pre-prandial administration of lipid nanocapsulesfor better stability profile along the gastrointestinal tract could besought [325]. With these promising results, the uptake of the lipidnanoparticles across the in vitro Caco-2 cell monolayer model wasevaluated. About 3.5-fold increase in the apparent permeability ofpaclitaxel upon its loading in lipid nanocapsules was observed ascompared to free drug; vesicle mediated transcytosis being the pro-posed mechanism for improved permeability [172]. These resultsare in correlation with pharmacokinetic studies conducted by anothergroup which posed about 3-fold increase in the oral bioavailability ofpaclitaxel when loaded in lipid nanocapsules as compared to freedrug [12]. Similarly, about 18-fold increase in the apparent perme-ability of SN-38 in Caco-2 cell monolayer model was observed whenloaded in lipid nanocapsules as compared to free drug [326].

3.2.3.6. Liposomes. Liposomes are the most sophisticated class of lipidbased drug delivery systems known for improving the deliverabilityof various difficult-to-deliver drugs. These are vesicular structuresprepared from phospholipids and are capable of accommodatingboth hydrophilic and lipophilic drug substances within them. Theseare reported to have huge potential in delivery of various anticanceragents especially in targeted drug delivery [327–329]. However, they


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are not stable in harsh gastrointestinal environment. The principal rea-sons for their instability comprises of acidic environment in the stom-ach (that leads to aggregation of constituent phospholipids) andpresence of degrading enzymes in intestine (such as pancreatic lipase).Henceforth various attempts have been made in this direction to im-prove their oral stability. The classical approach includes surface modi-fication such as PEGylation [330], transphosphatidylation [331], mucincoating (mucin liposomes) [332], polymer coatings (polymerized lipo-somes) [333], polyelectrolyte coatings (nanocapsules) [334] and chito-san coating [335]. Recently, exemestane loaded proliposomes wereprepared using distearoyl phosphatidylcholine (DSPC), cholesteroland dimyristoyl-phosphatidylglycerol (DMPG). These proliposomesare in the free flowing powder form which upon exposure to aqueousenvironment results in to formation of multilamellar liposomes thatmay be optionally sonicated for generation of desired sized liposomes.The developed formulation was found to exhibit about 3-fold increasein the permeability across the rat intestine as compared to the plaindrug [336]. The probable mechanisms for increased oral bioavailabilityinclude higher accumulation at the brush bordermembrane thereby in-creasing the concentration gradient across the intestinal epithelium, in-creased paracellular absorption, receptor mediated endocytosis andpredominantly byM-cells present over Peyer's patches along the intes-tine [337]. Although both hydrophilic and lipophilic drugs could beloaded in to liposomes, the concerns on drug loading, entrapment effi-ciency, cost incurred, and long term stability should be considered be-fore developing a particular drug compound in liposome based drugdelivery system.

3.2.3.7. Layersomes. Layersomes, by definition, are composed of thelayer by layer (LbL) coating of the polyelectrolytes over liposomesto increase stability of the formulation in the biological milieu andlong term storage. Our group has pioneered the multiple polyelectro-lyte stabilized polymeric nanocapsules for oral delivery of therapeuticagents. Recently, this patented approach has been successfullyimplemented for design and development of oral delivery of variousdifficult-to-deliver anticancer agents [338]. About 5.89-fold increasein the oral bioavailability of doxorubicin as compared to the freedrug and comparable therapeutic efficacy and toxicity profile wereobserved as compared to i.v. LipoDox® [339]. Similar results werealso observed in case of paclitaxel with about 4.07 fold increase inthe oral bioavailability, superior therapeutic efficacy and safety pro-file as compared to i.v. Taxol [340]. Recently, doxorubicin loadedpoly(L-glutamic acid) microcapsules have also been prepared usingLbL approach and was evaluated on multi-drug-resistant (MDR) celllines [341]. A significant level of accumulation was found in the celllines and internalization of the prepared polyelectrolyte polymer cap-sules was attributed to macropinocytosis [342].




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3.2.3.8. Liquid crystalline nanoparticles (LCNPs). LCNPs are consideredas sophisticated lipid based nanocarriers prepared from polar lipids,having capability to encapsulate both hydrophilic and lipophilicdrugs [343]. The different types of lipids/surfactants which could beemployed for preparation of LCNPs include Glyceryl monooleate,selachyl alcohol, glyceryl dioleate, phytantriol, oleyl glycerate,phytanyl glycerate, Brij 30/Brij 35 combination, monopalmitolein,ethoxylated fatty alcohols, monoolein/phosphatidyl choline combina-tion, etc. [344]. Our group has recently employed LCNPs for improvingthe antitumor efficacy of various anticancer agents such as doxorubi-cin, tamoxifen, docetaxel, CoQ10, curcumin etc. About 5.34-foldincrease Cmax and 17.74-fold increase in area under curve was ob-served upon incorporation of doxorubicin in to LCNPs as comparedto free drug (unpublished data). Further an insignificant differencein tumor inhibition of LCNPs (oral) vs. LipoDox® (i.v.) was observedin DMBA induced breast cancer model in rats till 20 days. Additional-ly, the developed formulation posed negligible cardiotoxicity incontrast to clinical formulation. The prophylactic and therapeuticantitumor efficacy of CoQ10 was significantly increased upon incor-poration in to LCNPs as compared to free drug (unpublished data).Mechanistically, LCNPs are known to increase the oral bioavailabilityby virtue of bioadhesiveness, membrane fusing properties, clathrin/caveolae/lipid raft-mediated endocytosis, superior encapsulation, sol-ubilization, etc. [345].

3.2.3.9. Lipid–drug conjugates. Lipid–drug conjugate approach is one ofthe most advanced versions of the lipid based drug delivery systemsin which the concerned drug is covalently linked to lipids thereby im-proving the drug payload into the system up to as high as 40–50% w/w [318]. The lipids that can be used for formulation of lipid–drug con-jugates include phospholipids, fatty acids such as docosahexaenoicacid, stearic acid, oleic acid, etc. and lipoamino acids. Methotrexateconjugated dihexanoylphosphatidylethanolamine was synthesizedfor improving its impaired transport across cell membranes, fre-quently leading to resistance. The developed system was found~120-fold more effective against methotrexate resistant humanT-lymphoblastic leukemia cell line as compared to free methotrexate[346]. Furthermore, methotrexate conjugated with lipoamino acidswas found ~150-fold more effective than free methotrexate undersimilar set of conditions [347]. In another set of conditions, paclitaxelconjugated docosahexaenoic acid showed about 61-fold higher accu-mulation of conjugated form at tumor site as compared to free drug atequitoxic doses whereas about 8-fold increase was observed at equi-molar doses [348]. Furthermore, stearic acid conjugated methotrex-ate has been designed and developed which showed significantimprovement in the oral bioavailability of methotrexate as comparedto free drug [349]. Recently, phytanyl pro-drug analogue of capecitabinehas been synthesized and evaluatedwhich revealed significantly higherantitumor efficacy as compared to parent compound [350]. Important-ly, the resulting lipid–drug conjugate is amphiphilic in nature and iscapable of self assembling with definite structure which could furtherassist in the stabilization and superior absorption of drug in the gastro-intestinal tract. Again here also the principal concerns as applicableto polymer–drug conjugates equally stands well and should beconsidered.

3.2.4. DendrimersDendrimers are the hyper branched and uniformly distributed

macromolecules that possess definite molecular weight, shape, sizeand specific chemical and physical properties including host–guestentrapment properties [351]. The tailor made design makes these so-phisticated systems eligible for incorporation of wide variety of drugsthat otherwise pose potential delivery challenges. The drug moleculescan be either physically entrapped or chemically conjugated to thedendritic structures during or after synthesis of macromolecularsystems. Furthermore, encapsulation of drug molecules within the


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dendritic structures selectively eliminates solubility and permeabilityrelated issues. Henceforth, these systems can be exploited to accom-plish the oral delivery of anticancer agents. The applicability ofdendrimers in cancer therapeutics has been exhaustively reviewedrecently [352]. However, very few reports are available on utilizationof these systems for oral delivery.

The principal reason for intuitions on dendrimers having potentialfor oral delivery of drugmolecules includes their high solubilization ca-pacity [353], increased permeation capability across the gastrointestinaltract via paracellular or transcellular (preferentially via clathrin-dependent endocytosis) pathway [354], encapsulation of the drugmol-ecules, thereby protection fromharsh gastrointestinal environment andhigh drug payload (in contrast to other nanocarriers in race) [355]. Theproperties of dendrimers such as size, conformation and surface chargehave been found to significantly affect the absorption of these systemsacross the GIT [351]. Dendrimers with particle size ≤ 3 nm werefound to permeate via transcellular or paracellular pathway whereashigher sized permeated through nonspecific adsorptive endocytosis[356]. Concomitantly, anionic dendrimers showed relatively higherserosal transfer as compared to anionic dendrimers, which could be at-tributed to the higher interaction of these systems with negativelycharged intestinal epithelium. Furthermore, cationic dendrimers alsoshowed some evidence of toxicity in glucose-active transport assay athigher concentrations. Cumulatively, anionic dendrimers posed greaterpotential for oral drug delivery in compassion to its cationic counterpart[357].

The permeability studies of various dendrimer generations againstCaco-2 cell monolayers revealed significant reduction in thetransepithelial electrical resistance values and increase in the [14C]mannitol permeability as a function of donor concentration, incuba-tion time and generation number, thereby confirming the potentialof these systems for oral delivery of drug molecules. In addition, thelower generations in the order of G2 were found nontoxic to theCaco-2 cells, which further paved the way for subsequent studies[358]. The hypothesis was confirmed when doxorubicin complexedpoly(amido amine) (PAMAM) dendrimers were developed and eval-uated. The developed complex showed about 200-fold higher oralbioavailability as compared to free doxorubicin [359]. Similar resultshave also been observed for an active metabolite of irinotecan(SN-38) loaded PAMAM dendrimer, which showed pH dependent re-lease profile (no release at physiological pH 7.4 and significantlyhigher drug release at tumor pH 5.5) with about 10-fold increase inthe permeability across and about 100-fold increase in cellular uptakeby Caco-2 cells [360]. The permeation enhancer effect of PAMAMdendrimers has also been proven recently, which revealed reversalof permeation irrespective of the time, even within 10 min of pre-treatment. This was further confirmed by absence of any membranetoxicity in intestinal epithelia of rats measured as a function of re-leased lactate dehydrogenase (LDH) and protein post treatment[361].

The properties of these dendrimer systems can be further enhancedupon surface functionalization such as PEGylation, polyamine func-tionalization, acetylation or lipid anchoring. The PEGylation of theanionic dendrimers altered their transport mechanism across the gas-trointestinal tract and in fact decreased transport was observed in alltested cases of G3 and G4 dendrimers. However, the decrease in thetransport of these dendrimers was marginal and comparable to othermacromolecules. Therefore, authors concluded that this decrease canbe afforded to avail the advantages offered by PEGylation such as facil-itated conjugation and improved biodistribution post absorption [362].On the contrary, the surface modification of PAMAM dendrimers withpolyamines such as arginine and ornithine significantly improvedthe apparent permeability of modified dendrimers as compared tounmodified dendrimers when tested in Caco-2 cell model. The authorsproposed polyamine transported system for improved permeability.However, the toxicity of argininemodified dendrimerswas significantly




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higher at all tested concentrations as compared to unmodified and orni-thine conjugated dendrimers [363]. In yet another set of studies the tox-icity of the cationic PAMAM dendrimers was reduced by about 10-foldby acetylation of their terminal amine groups. No compromise on thepermeability was observed rather permeability was increased due toavoidance of any non specific binding to highly reactive amine groups[364]. Furthermore, about 8–10-fold increase in the apparent perme-ability of [14C]mannitol and significant reduction in toxicity wereobserved upon surface engineering of cationic PAMAM dendrimerswith lauroyl chloride as compared to unmodified cationic PAMAMdendrimers [365]. The probable reason for this increment in perme-ation by surface lipid functionalization could be attributed to the exploi-tation of phospholipase-C (PLC)-dependent pathway and transcellularpathway (via perturbation and change of fluidity of the cellmembrane).Similar results were also observed upon conjugating lipid (C12 chains)with polylysine dendrimers revealing the potential of these lipidfunctionalizations on dendrimers for oral delivery [366].

4. Conclusion

Although the newer generations of anticancer agents which can bedelivered orally are at priority in developmental pipeline, the classicaldrug substances can also bedelivered efficiently via specific formulationdesign approach. The poor physicochemical and biopharmaceuticalproperties associated with the various anticancer drugs hinderingtheir oral deliverability can be effectively circumvented by utilizationof absorption enhancers (P-gp inhibitors and functional excipients)and pharmaceutical approaches such as nanocrystals and nanocarriers.These novel drug delivery systems owing to their special properties areable to bypass various barriers of drug delivery across the gastrointesti-nal tract. Furthermore, the targeting potential of these systems is of spe-cial interest in the cancer therapy. Passive targeting via enhancedpermeation and retention is one of the common and important advan-tages offered by almost all types of nanocarriers. The oral delivery ofanticancer agents via such drug delivery systems is of great interestfor improving the quality of life of patients suffering cancer. In addition,the pharmacoeconomic advantage with oral delivery of ‘injection only’drugs will fetch significant attraction of health care agencies by reduc-ing the overall cost incurred in health care management.

5. Future prospects

With the advent of nanotechnology in the drug delivery applica-tions for improving the deliverability of various difficult-to-deliverdrugs, there arises obvious concerns that need to be addressed. Theprincipal concern is the safety profile of these nanocarriers for chronictreatment which is already under consideration and dedicated effortsare being made by scientific community and health care agencies. Theresults so far seems to be promising which is evident from the factthat there are numerous nanotechnology based products approvedby regulatory agencies and are in clinical use. The increasing numberof such products under clinical trials clearly reflects the thrust in thescientific community in this area. Sincere efforts are made in thefield of understanding the mechanism of cellular trafficking of thesenanocarriers and its correlation with the efficacy and toxicity profileis one of the priority research areas. The insight of these will lead todevelopment in the newer technologies that would be able to exploitthe physiological principles for drug delivery purposes withoutcompromising the safety profile. Furthermore, more attempts canbe made for translation of the laboratory developments in to productdevelopment. This could be achieved by efforts in the area of improv-ing the drug payload within the nanocarriers, simple manufacturingsteps, usage of inexpensive excipients and robust formulation design.Furthermore, attempts can also be made to further exploit thetargeting potential of nanocarriers so as to increase their uptakefrom gastrointestinal tract to an extent comparable to that of


parenteral administration. In addition, the utilization of the functionalexcipients within the carrier systems can also be exploited to greaterextent so as to design and develop rationalized drug delivery systemsfor various difficult to treat diseases such as cancer.

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Oral delivery of anticancer drugs: Challenges and opportunities