18 54 Pharmacy - Discovery JournalsREVIEW Balasubramanian et al. Emerging polymers and Chemistry of Camptothecin Derivatives in Nanoparticle Drug delivery system, Discovery Pharmacy,

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Balasubramanian et al.Emerging polymers and Chemistry of Camptothecin Derivatives in Nanoparticle Drug delivery system,Discovery Pharmacy, 2012, 1(1), 3-14, www.discovery.org.inwww.discovery.org.in/dp.htm © 2012 discovery publication. All rights reserved

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Balasubramanian J1,*, Narayanan N2, Shahul Hameed Maraicar K2, Magendran R2, Muruganand R2

1. Shield Healthcare Pvt. Ltd, Maduravoyal, Chennai-600 095,Tamilnadu, India, E-mail: [email protected]. Periyar Maniammai University, Thanjavur-613403, Tamilnadu, India

*Corresponding author: Balasubramanian J, Shield Healthcare Pvt. Ltd, Maduravoyal, Chennai-600 095, Tamilnadu, India, Email:[email protected]

Received 21 April; accepted 15 May; published online 25 June; printed 29 June 2012

ABSTRACTThe purpose of the study is to investigate various polymers used along with camptothecin and its derivatives in which itexamines the engineered polymers used along with the camptothecin derivatives. Polymers have been utilized for developingnanoparticle drug delivery systems combination with camptothecin derivatives. The development of such polymers has causedadvances in nanotechnology based drug delivery system, which, in turn, has resulted in smart polymers based chemotherapy incancer treatment that can respond to changes in environmental condition such as temperature, pH, and biomolecules. Theresponses vary widely from swelling or deswelling to degradation. Drug-polymer conjugates and drug-containing nanoparticlehave been used for drug targeting. Engineered polymers and polymeric systems have also been used in new areas, such asmolecular imaging as well as in nanotechnology. This review examines the engineered polymers that have been used astraditional drug delivery systems and as more recent applications in nanotechnology. Camptothecin have emerged as promisingeffective anti-chemotherapeutic agent. But the toxicities were in greater level to be used in a clinical setting.

Key words: Nanotechnology; Chemotherapy; Champtothecin; Polymers.

Abbreviations: MX-1 - Human breast carcinoma cell line; LXFL529 - One large cell lung cancer line; CXF280 -Colorectal lines;HT29 - Human colon adenocarcinoma grade II cell line; C50-Inhibitory concentration; MAPK P38 - Mitogen-activated proteinkinases; MDR - 1-Multidrug resistance protein 1; AUC - Area under curve ; OSI-211 - liposomal lurtotecan.

1. INTRODUCTIONNanotechnology has enabled significant advancesin the areas of cancer diagnosis and therapy. Thefield of drug delivery is a sterling example, withnanoparticles being increasingly used forgenerating therapeutic formulations of poorlywater-soluble, yet potent anticancer drugs.Whereas a number of nanoparticle-drugcombinations are at various stages of preclinicalor clinical assessment, the overwhelmingmajorities of such systems are injectableformulations and are incapable of being partakenorally. The development of an oral nano-deliverysystem would have distinct advantages for cancerchemotherapy. The use of polymers andpolymeric structures in the treatment, diagnosis,and monitoring of biological systems is continuingto increase in sophistication. Research exploringthe use of nanoparticles for drug deliveryapplications has included the exploration anddevelopment of nanocolloids, liposomes, micelles,nanogels, polymer drug conjugates, and a varietyof other polymeric nanoparticles that arecomposed of organic polymers with specific

physical or chemical properties that make themrelevant delivery vehicles. Polymers have playedan integral role in the advancement of drugdelivery technology by providing controlledrelease of therapeutic agents in constant dosesover long periods, cyclic dosage, and tunablerelease of both hydrophilic and hydrophobicdrugs. From early beginnings using off-the-shelfmaterials, the field has grown tremendously,driven in part by the innovations of chemicalengineers. Modern advances in drug delivery arenow predicated upon the rational design ofpolymers tailored for specific cargo andengineered to exert distinct biological functions.

Drugs that target deoxyribonucleic acid (DNA)are among the most effective chemotherapeuticagents used clinically but treatment related toxicityand the development of drug resistance limit theireffectiveness. The cellular responses to DNAdamage include damage recognition, repair andinduction of signaling cascades leading to cellcycle checkpoint activation, apoptosis and stress

REVIEW Discovery Pharmacy, Volume 1, Number 1, July 2012

PharmacyEmerging polymers and chemistry of Camptothecinderivatives in nanoparticle drug delivery system

Chemotherapy:primarily refers tothe treatment ofcancer with anantineoplasticdrug or with acombination ofsuch drugs into astandardizedtreatment regimen

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related responses. Cells typically are arrested atmultiple cell cycle checkpoints, at which cellsattempt to repair damaged DNA beforeprogressing into mitosis, and numerous keymolecules have been identified includingdamaged sensor proteins, transducer kinases andeffectors. One of the most important pathways ofsuch checkpoints in mammalian cells is that ofdouble-strand break repair. Camptothecin (CPT)derivatives emerged as a promising group ofchemotherapeutic agents in the 1960’s because oftheir inhibition of topoisomerase I leading to DNAdamage (Yau et al., 2003). Topoisomerase I is aubiquitous enzyme involved in the regulation ofDNA topology during replication, recombinationand transcription. Topoisomerase I forms aphosphotyrosine bond with DNA, catalyzing aforward reaction in which DNA is cleaved to allowunwinding, and a reverse reaction, in which DNAis re-ligated. CPT interferes with the re-ligationstep of this process by reversibly binding to andstabilizing the enzyme DNA complex. Once theCPT molecule has intercalated with thetopoisomerase I-DNA complex, the collisionbetween the complex and the replication forkduring the S-phase is thought to result in DNAdouble-strand breaks. Additionally, anticancerproperties of CPT that are S-phase independenthave been elucidated, including rapid cessation ofRNA synthesis and interference with the cell cyclecheckpoint network by inhibiting checkpoint kinase1 . With respect to antitumor activity, the lactone Ering in the CPT molecular structure has beenidentified as the most critical structural feature.

Camptothecin have emerged as promisingeffective anti-chemotherapeutic agent. But thetoxicities were in greater level to be used in aclinical setting. Camptothecin is a cytotoxicquinolone alkaloid derived from the bark, wood,fruit of the Asian (china) tree camptothecaacuminata (family: nyssaceae), Camptothecin hasbeen found in Ervatamia heyneana (family:Apocynaceae), Ophiorrhiza pumila (family:Rubiaceae), and also in Indian plantNothapodytes foetia (family: Icacinaceae). Anumber of attempts have been made not only toreduce the toxicity but, also to improve theefficacy. Derivatives of original Camptothecinmolecule have been created by modified one ormore rings in an effort to improve thepharmacokinetics and toxicity profiles of parentcompound.

An alkylating Camptothecin derivative, 7-chloromethyl-10, 11-methylenedioxy-camptothecin(7-CM-MDO-CPT) was recently shown to produceirreversible topoisomerase I cleavage complexesby binding to the +1 base of the scissile strand ofa top1 cleavage site. We demonstrate that 7-CM-EDO-CPT (7-chloromethyl-10, 11-ethylenedioxy-camptothecin) also induces irreversible top1-DNAcomplexes. 7-CM-MDO-CPT, 7-CM-EDO-CPT,and the no alkylating derivative 7-ethyl-10, 11-methylenedioxy-camptothecin (7-E-MDO-CPT)

also induced reversible top1 cleavable complexes,which were markedly more stable to salt-inducedreversal than those induced by 7-ethyl-10-hyroxy-CPT, the active metabolite of Irinotecan. Thisgreater stability of the top1 cleavable complexeswas contributed by the 7-alkyl and the 10, 11-methylene- (or ethylene-) dioxy substitutions.Studies in SW620 cells showed that 7-E-MDO-CPT, 7-CM-MDO-CPT, and 7-CM-EDO-CPT aremore potent inducers of cleavable complexes andmore cytotoxic than Camptothecin.

We recently reported that 7-CM-MDO-CPT isunique among Camptothecin’s because itproduces irreversible cleavable complexes. Analkylation (at position N3 of the purine in the DNAminor groove) blocks top1 relegation. Anotherdifference between 7-CM-MDO-CPT andCamptothecin is that both substitutions (7-chloromethyl and 10, 11-methylenedioxy) havepreviously been shown to enhance the top1inhibitory activity.

Water soluble 20(S)-glycinate esters of twohighly potent 10, 11-methylenedioxy’ analogues ofCamptothecin have been synthesized andevaluated for their ability to eradicate humanbreast cancer tumor xenografts (Hu et al., 2003).The glycinate ester moiety increases the watersolubility of the 10, 11-methylenedioxy analogues4-16-fold. The glycinate esters are also 20-40-foldless potent than Irinotecan in inhibiting humanacetyl cholinesterase. Our results indicate thatwater soluble 20(S)-glycinate esters of highlypotent Camptothecin analogues providecompounds that maintain biological activity. Anumber of other 7- and 10-substituted and 10, 11-disubstitiued Camptothecin’s have beendeveloped these include the highly potent MDCPTand CMMD.

Topotecan and Irinotecan, the first analoguesapproved by the FDA, are now widely used aschemotherapeutic agents. Topotecan has beenapproved as a second-line agent for ovarian andsmall cell lung cancer, while Irinotecan has beenapproved for metastatic colorectal carcinoma.Irinotecan is a prodrug that is converted to theactive metabolite form 10-hydroxy-7-ethylcamptothecin (SN38).

1.1. Camptothecin

Figure 1Camptothecin

Camptothecin(CPT): It is acytotoxic quinolinealkaloid whichinhibits the DNAenzymetopoisomerase I(topo I).

Topoisomers:These aremolecules with thesame chemicalformula andstereochemicalbond connectivitiesbut differenttopologies.

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Camptothecin has a planar pentacyclic ringstructure, that includes a pyrrolo[3,4-β]-quinolinemoiety (rings A, B and C), conjugated pyridonemoiety (ring D) and one chiral center at position20 within the alpha-hydroxy lactone ring with (S)configuration (the E-ring), (Fig.1). Its planarstructure is thought to be one of the mostimportant factors in topoisomerase inhibition.Camptothecin binds to the topo I and DNAcomplex resulting in a ternary complex, andthereby stabilizing it (Wall et al., 1996). Thisprevents DNA relegation and therefore causesDNA damage which results in apoptosis.Camptothecin binds both to the enzyme and DNAwith hydrogen bonds. The most important part ofthe structure is the E-ring which interacts fromthree different positions with the enzyme (Hsianget al., 1985). The hydroxyl group in position 20forms hydrogen bond to the side chain on asparticacid. It’s critical that the configuration of the chiralcarbon is (S) because (R) is inactive. The lactoneis bonded with two hydrogen bonds to the aminogroups on arginine. The D-ring interacts with the+1 cytosine on non-cleaved strand and stabilizesthe topo I-DNA covalent complex by forminghydrogen bond. This hydrogen bond is betweencarbonyl group in position 17 on the D-ring andamino group on the pyrimidine ring of +1 cytosine.Toxicity of Camptothecin is primarily a result ofconversion of single-strand breaks into double-strand breaks during the S-phase when thereplication fork collides with the cleavagecomplexes formed by DNA and .The lactone ringin Camptothecin is highly susceptible to hydrolysis(Hsiang et al., 1989; Muggia et al., 1972). Theopen ring form is inactive and it must therefore beclosed to inhibit topo I. The closed form is favoredin acidic condition, as it is in many cancer cellsmicroenvironment. Camptothecin is transported into the cell by passive diffusion. Cellular uptake isfavored by Lipophilicity, which enhancesintracellular accumulation. Lipophilicity makesmore stable compounds because of improvedlactone partitioning into red blood cells andconsequently less hydrolysis of the lactone.Camptothecin has affinity for Human serumalbumin (HSA), especially the carboxylate form ofCamptothecin.

Hexacyclic Camptothecin analogues haveshown great potency. For examplemethylenedioxy or ethylenedioxy group connectedbetween 10 and 11 form a 5 or 6 membered ringwhich leads to more water-soluble derivate andincreased potency. Researches have shown thatethylenedioxy analogues are less potent thanmethylenedioxy.

Adding amino or chloro group at 9th position orchloromethyl group at 7th position to these 10, 11-methylenedioxy or ethylenedioxy analoguesresults in compounds with even greatercytotoxicity but weaker solubility in water(Masubuchi, 2004). To yield 10, 11-methylenedioxy or ethylenedioxy analogues withgood water solubility a good way is to introduce a

water solubilizing substituent at position 7.Lurtotecan meets those requirements; it’s a 10,11-ethylenedioxy analogue with a 4-methylpiperazino-methylene at position 7 and hasshown a great potency in clinical researches.

A ring can also be formed between position 7and 9, like position 10 and 11. That gives newopportunities to make water-soluble derivatives.These hexacyclic Camptothecin become moreactive when electron-withdrawing groups are putin position 11 and methyl or amino groups at 10.Exatecan is an example of hexacyclicCamptothecin that has a 6 membered ring overposition 7 and 9, and is 10-methyl, 11-fluorosubstituted. It is water-soluble and more potentthan Topotecan.

The water soluble Camptothecin derivativesare synthesized. And some of the names areExatecan, DX-8951f, CKD-602, Irinotecan,Topotecan are the novel synthetic Camptothecinderivatives. Namitecan, Elomotecan are the newlyfound semi-synthetic derivatives.

1.2. Afeletecan (BAY 38-3441)

Another prodrug, BAY 38-3441, was created byconjugating Camptothecin to a carbohydratemoiety with a peptide spacer (Fig.2). The purposeof the conjugate was to stabilize the lactone ringallowing for prolonged exposure of cells to theactive form. In preclinical studies, BAY 38- 3441was found to inhibit tumor growth in xenograftmodels of MX-1 breast, LXFL529 lung, CXF280and HT29 colon cancer cell lines. A phase I trialtesting a variety of dose schedules concluded that320 mg/m2/day as 30-minute infusions given dailyfor 3 days every 3 weeks would be the bestschedule to use in phase II trials.

1.3. BelotecanBelotecan, or CKD-602, is a novel water solublecamptothecin analogue with the molecular name(7-[2-(Nisopropylamino) ethyl]-(20S)-amptothecin)(Fig.3). The stability of the molecule has beenconfirmed in both plasma and methanol for atleast 3 months. Conversion from the lactone tocarboxylate form occurs and is dependent on pH.In a phase I trial, CKD-602 was found to beeffective against gastric and ovarian tumors at aMTD of 0.7mg/m2/day. Two phase II trials werecompleted testing CKD-602 at a starting dose of0.5mg/m2/day for 5 days every 3

Figure 2Afeletecan (BAY 38-3441)

Pyrimidine: It isa heterocyclicaromatic organiccompoundsimilar tobenzene andpyridine,containing twonitrogen atomsat positions 1and 3 of the six-member ring

Nanomedicine: Itis the medicalapplication ofnanotechnology.Nanomedicineranges from themedicalapplications ofnanomaterials, tonanoelectronicbiosensors, andeven possiblefutureapplications ofmolecularnanotechnology.

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weeks, one in patients with ovarian cancer andthe other in patients with small cell lung cancer(SCLC). The overall response rate in the ovariancancer patients was 45% (9/20) with 4 patientsexperiencing partial response and 5 patientsexperiencing a CA125 response. Another 5patients had stable disease.

1.4.DE-310DE-310 was created by covalently linking acarrier, carboxymethydextran polyalcohol, toexatecan. This modification was made in an effortto improve the bio distribution and reduce thetoxicity of exatecan. One study showed that, intumor-bearing mice, the concentration of releasedDX-8951 from the conjugated form (DE-310) was30 times greater in tumor tissue than in plasma.This suggests there may be some tumorselectivity of the carrier form. In a phase I trialtesting the efficacy in a range of adult solidtumors, DE-310 stabilized disease in five patientsand produced no complete or partial responses.Toxicities included grade 3/4 myelosuppression,transient elevations in liver transaminases, andmild nausea, vomiting and anorexia. Thepharmacokinetics and clinical efficacy of DE-310seem promising in these early trials. The results ofongoing clinical trials will provide more informationabout this analogue.

1.5. Diflomotecan

Diflomotecan (BN 80915) is a member of a groupcalled the homocamptothecins (Fig.4). It isdistinguished from other homocamptothecinsbecause it is fluorinated at the 9 and 10 positionsof the A-ring. Homocamptothecins have anethylene spacer between the alcohol moiety andthe Carboxyl group on the E-ring of camptothecin,creating a 7-membered lactone ring that is morestable in the plasma compared to other

camptothecin analogues. The six memberedrings, characteristic of most Camptothecinanalogues, undergo an equilibrium reactionthrough hydrolysis which results in an inactivecarboxylate form in the serum. Acidicenvironments reverse this process thus activatingthe six-member ring, which can lead tohemorrhagic cystitis. In the seven-member ringanalogues, the hydrolysis is irreversible evenunder acidic conditions.

1.6. DRF-1042

DRF-1042 [5(RS)-(2-hydroxyethoxy)-20(S)-CPT]is somewhat water soluble and has an affinity forprotein (Fig.5). The analogue is susceptible toreversible pH-dependent hydrolysis converting thelactone ring into the inactive carboxylate form.Preclinical studies confirmed good oralbioavailability and stability in human plasma. Aphase I trial using the analogue in patients with avariety of solid tumors demonstrated a therapeuticresponse in 67% (8/12) patients, 2 with a CR, 2with a PR and 4 with stabilized disease. Thetumors that responded included osteosarcoma,renal cell carcinoma and breast carcinoma.

1.7. Exatecan

Exatecan (DX-8951f) is a totally synthetic, watersoluble analogue that does not require enzymaticactivation like some of the other prodrugs such asIrinotecan (Fig.6). It has modifications at both theA-ring and B-ring as indicated by the molecularname 7-(4-methylpiperazinomethylene) - 10, 11-ethylenedioxy-20(S)-Camptothecin. It is a morepotent Inhibitor of topoisomerase I thanCamptothecin, Topotecan and SN38. The IC50 in

Figure 3Belotecan

Figure 4Diflomotecan

Figure 5DRF-1042

Figure 6

Exatecan

CA-125: It is(cancer antigen125 orcarbohydrateantigen 125) alsoknown as mucin16 or MUC16 is aprotein that inhumans isencoded by theMUC16 gene.MUC16 is amember of themucin familyglycoproteins

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murine p388 leukemia cells of DX- 8951f was0.975 Ig/ml, which was superior to SN38 (2.71Ig/ml), topotecan (9.52 Ig/ml) and Camptothecin(23.5Ig/ml). Exatecan has broad activity in multiplecell lines and/or xenografts including humanbreast, gastric, renal, colon, ovarian, cervical andlung. Part of the effectiveness may come from thefact that the efflux pump P-glycoprotein multidrugtransporter does not recognize Exatecan as asubstrate.

1.8. Gimatecan

Gimatecan is a lipophilic analogue also known asST1481, which has an oxyiminomethyl at positionseven of the B-ring (Fig.7). Several features ofgimatecan make it superior to camptothecin andtopotecan in laboratory studies (Croce et al.,2004; Pratesi et al., 2004). The lipophilicproperties of the molecule allow for oraladministration and increase cellular accumulation,but at the same time give it a higher affinity foralbumin. Experimental data using non-small celllung cancer NCIH460 and ovarian A2780/DX cellslines showed that the concentration required for50% cell growth inhibition (IC50) of gimatecan(0.01 ±0.006 IM ) is less than Camptothecin (0.33± 0.05 IM), topotecan (1.38 ± 0.19 IM) and SN38(0.21+ 01 IM). In the presence of albumin thepotency is less (0.063 ± 0.004 IM), but was stillsuperior to the other drugs. The lipophilic naturealso helps to stabilize the bond between theanalogue and topoisomerase I complex. AfterNaCl disruption of the complex the DNA remainscleaved, indicating that the bond formed bygimatecan is more stable compared to othercamptothecin. In addition to inhibitingtopoisomerase I, gimatecan may also haveantiangiogenic effects. Another beneficial propertyof gimatecan is the ability of the drug to overcomeresistance. In several studies, there was a lack ofrecognition of the novel analogue by both theMDR-1 and BCRP transport systems. The novelanalogue not only has improved efficacy, but alsohas a lower toxicity. After oral administration inmice the highest concentrations were seen in theliver, but it can also be isolated from the brain,indicating a possible clinical role for livermetastasis and CNS tumors. Phase I trialsconfirmed that, in humans, gimatecan maintainedits properties of rapid absorption and slowelimination. These trials indicate that the analogue

has some activity in recurrent malignant glioma,melanoma and metastatic colorectal cancer.

1.9. Irinotecan

Irinotecan is a drug used for the treatment ofcancer (Fig.8). Chemical name (4S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl,1,4'-bipiperidine-1'-carboxylate-Irinotecan preventsDNA from unwinding by inhibition oftopoisomerase 1. In chemical terms, it is asemisynthetic analogue of the natural alkaloidcamptothecin. Its main use is in colon cancer, inparticular, in combination with other chemotherapyagents. It received accelerated approval by theU.S. Food and Drug Administration (FDA) in 1996and full approval in 1998. It is an antineoplasticenzyme inhibitor primarily used in the treatment ofcolorectal cancer. It is a derivative of camptothecinthat inhibits the action of topoisomerase I.Irinotecan prevents relegation of the DNA strandby binding to topoisomerase I-DNA complex, andcauses double-strand DNA breakage and celldeath.

1.10. Karenitecin

This analogue, also known as BNP1350, is amodification of the 7 position of the B-ring with themolecular name (7-[(2-trimethylsilyl) ethyl]-20(S)-camptothecin (Fig.9). Karenitecin and thesilatecan class of derivatives are highly lipophilic,remain in the lactone form under physiologicalconditions, and do not require hepatic conversion.The drug can be administered intravenously ororally with good oral bioavailability seen in mice.Penetration into the central nervous system ofnon-human primates was found to be low with theratio of cerebral spinal fluid area under the curveto the plasma AUC being less than 5% (0.4%-3.0%). In preliminary trials, karenitecin was foundto be cytotoxic to pediatric cell lines as well asadult lung, prostate, pancreatic, breast, colon,ovarian and head and neck cell lines. Theantiproliferative effects of karenitecin on humanovarian and colon cancer cell lines were superior

Figure 7Gimatecan

Figure 8Irinotecan

Figure 9Karenitecin

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to SN-38 and topotecan. Treatment of coloncancer xenograft models with karenitecin resultedin ≥50% growth inhibition. Other phase II trials arecurrently underway to define the role ofkarenitecin in other tumor types.

1.11. Lamellarin

LAM-D is a hexacyclic marine alkaloid (Fig.10).More than 30 lamellarins have been isolated, andinterestingly, some of them, including LAM-D,show equally potent cytotoxic activities againstboth multidrug-resistant tumor cell lines and theircorresponding parental cell lines. LAM-D displaysa pronounced selective cytotoxicity for tumortypes, but its mechanism of action was totallyunknown. On the basis of its chemical structure,we postulated that LAM-D can bind to DNA andinterfere with the catalytic activities of humantopoisomerases. A molecular modeling analysissuggested that the 6H-[1]benzopyrano[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-one planar chromophore of LAM-D can intercalatebetween DNA bp and that the appendedmethoxyphenol substituent oriented at a rightangle with respect to the main chromophore mayserve as a hook to trap proteins. Cytotoxicitymeasurements in two pairs of leukemia cell linessensitive or resistant to CPT indicate thattopoisomerase I plays a role in the antiproliferativeactivity of LAM-D. The synthetic analogue LAM-501 was found to be inactive againsttopoisomerase I and considerably less cytotoxicthan the natural product, indicating that theplanarity of the hexacyclic chromophore isessential for DNA binding and topoisomerase Iinhibition.

1.12. Lurtotecan

Lurtotecan (GI-147211) was created by theaddition of an N-methyl piperazinomethylenegroup at the C7 position of the B-ring and an

ethylenedioxy group to the A-ring (Fig.11). Themodification does not protect against thehydrolysis of the lactone ring into its inactive formin the serum. Given as an oral medication thebioavailability was found to be low, thusintravenous administration was recommended. Inpreclinical studies, lurtotecan was found to be

more water soluble and have ahigher affinity for topoisomerasethan topotecan. It also had superiorpotency to topotecan in melanoma,colon cancer, breast cancer andovarian cancer cell lines. In phase Itrials, responses were seen inpatients with breast, ovarian, colonand liver neoplasms. In a phase IItrial, lurtotecan administered as 1.2mg/m2/day for 5 days every 3weeks produced 3 partial responsesin patients with breast cancer and 2partial responses in patients with

non-small cell carcinoma. The response rate was16.6% in the refractory group and 21.1% in thechemosensitive group. The major toxicitiesincluded neutropenia, thrombocytopenia, nausea,vomiting, fatigue and anorexia. Modifications ofthe original lurtotecan molecule produced aliposomal form called OSI-211 with the hope ofimproving the therapeutic index by decreasingclearance and allowing for accumulation of thedrug in tumor cells. This hypothesis wassupported by a KB xenograft model that showedthat the therapeutic index of NX211, lurtotecanand Topotecan was 0.5, 1 and 2.9, respectively.The maximum plasma concentration (Cmax) ofNX211 was 20.1 Ig/ml, which was 122-fold higherthan the Cmax of lurtotecan. The area under thecurve (AUC) was 127 IgOh/ml for NX211 and0.0672 for lurtotecan. A phase I trial showed apartial response in one patient with breast cancerand in one patient with ovarian cancer. In humansrenal clearance was low, as the main route ofelimination is biliary. In one study the DLTs wereneutropenia and thrombocytopenia; however, inanother study the DLTs were stomatitis, sophagitisand diarrhea.

1.13. MAG-CPTCamptothecin (CPT) can be covalently conjugatedto methacryloylglycinamide (MAG) with an aminoacid spacer at the C-20 position to make it watersoluble (Fig.12). Camptothecin is released into theplasma through an enzyme- and pH-dependentprocess. In one study, 10 patients with colorectalcancer received 60 mg/m2 of MAG-CPT for 24hours, 3 days or 1 week prior to surgery. At thetime of surgery, tumor, plasma and adjacentnormal tissue samples were collectedsimultaneously. Contrary to previous xenograftsstudies, which showed preferential delivery ofCamptothecin into tumor tissue, the results of thisstudy showed that the ratios of MAG-CPT toCamptothecin were equal in plasma and in tumortissue from 24 hours to 7 days after dosing. In aphase I trial, MAG-CPT was given as a 30-minute

Figure 10Lamellarin

Figure 11Lurtotecan

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infusion over 3 days every 4 weeks in patientswith solid tumors and showed no activity in thesmall number of evaluable patients. Adding acarrier molecule to Camptothecin does appear toimprove the pharmacokinetic properties, but thebladder toxicity remains severe.

1.14. Prothecan

Prothecan or Pegamotecan is a water soluble,stable prodrug which was developed through theconjugation of camptothecin-(20) O-glycinate withpolyethylene glycol (PEG) (Fig.13).PEGcamptothecin (CPT) is released when it ishydrolyzed to Camptothecin in human tissues. It isthought that the high molecular weight of thismolecule may allow for better vascularpermeation, intravascular retention and, possibly,selective tumor distribution. PEG-alpha-CPT hasbeen tested in a colorectal xenograft model andwas found to reduce tumor burden by 90% withoutsevere toxicity. Toxicities includedmyelosuppression, with neutropenia being thedose-limiting toxicity, cystitis, nausea, vomiting,diarrhea and alopecia. Cystitis occurred in 35% ofpatients and was mild in the majority of cases,consisting of isolated microscopic hematuria. Thestudy did not show a relationship between theseverity of side effects and dose of PEG-CPT or

exposure to CPT, thus there may be variability inthe lactone ring opening. This would be a down-side to this analog compared to some of theothers.

1.15. Rubitecan

Rubitecan (RFS2000) was created by adding anitro group in the nine position of the A-ring of theparent Camptothecin molecule (Fig.14). LikeCamptothecin, this analogue continues todemonstrate lactone ring instability. The drug canbe administered orally or intravenously. OralBioavailability is influenced by food intake, thusthe drug needs to be taken under fastingconditions. The metabolic conversion from thelipophilic prodrug, 9-nitrocamptothecin (9-NC), into9-aminocamptothecin (9-AC), is not well definedor quantified. The cytotoxicity of 9-NC and 9-AC isnot affected by P-glycoprotein, MDR 1, or MDR 2.However, 9-AC but not 9-NC is susceptible tocellular efflux and resistance associated withBCRP. Despite some susceptibility to resistance,phase I studies indicated growth inhibition inhuman tumor xenografts including lung,colorectal, breast, pancreatic, ovarian, prostate,stomach, melanoma and leukemia treated withRubitecan. The maximum tolerated dose in micewas determined to be 1mg/m2/day. This has ledto the development of an aerosolized liposomalformulation of Rubitecan, known asdilauroylphosphatidylcholine-9-nitro-20(S)-Camptothecin (DLPC-9-NC). Preliminary datashowed equivalent tumor response at lower dosescompared to other routes of administration. Therecommended dose was 13.3 Ig/kg/day on a 60-minute exposure 5 days a week for 8 weeks at aconcentration of 0.4 mg/ml in the nebulizer. Out ofthe 25 patients treated in the study, 2 patients withuterine cancer had a partial response and 3patients with primary lung cancer had stabilizeddisease. The dose-limiting toxicity was chemicalpharyngitis. Other side-effects included cough,sore throat, nausea, vomiting, anorexia,dysgeusia, fatigue and neutropenia. A decrease inpulmonary function tests while on treatment wasobserved, but the end of treatment FEV1 valuewas not significantly different from baseline.

1.16. SilatecanSilatecan (formerly AR-67) is a synthetic, highlylipophilic derivative of camptothecin, with potentialantineoplastic and radiosensitizing activities. AR-67; DB-67, 7-t-Butyldimethylsilyl-10-hydroxycamptothecin; Silatecan. IUPAC/Chemical

Figure 12MAG-CPT

Figure 13Prothecan

Figure 14Rubiteca

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name:(S)-11-(tert-butyldimethylsilyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-,14(4H,12H)- dione (Fig.15). SilatecanDB-67 binds to and stabilizes the topoisomerase I-DNA covalent complex, inhibiting the religation oftopoisomerase I-mediated single-stranded DNAbreaks and producing lethal double-stranded DNAbreaks when encountered by the DNA replicationmachinery; inhibition of DNA replication andapoptosis follow. Camptothecin readily undergoeshydrolysis at physiological pH, changing itsconformation from the active lactone structure toan inactive carboxylate form. Modifications on theE ring of camptothecin prevent binding of humanserum albumin, which prefers the inactivecarboxylate form, thereby enhancing the stabilityof the active lactone structure and resulting inprolonged agent activity. In addition, this agentmay radiosensitize tumor cells.

1.17. Topotecan

Topotecan hydrochloride (trade name Hycamtin)is a chemotherapy agent that is a topoisomerase-Iinhibitor. (IUPAC) name(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H) –dionemonohydrochloride. It is thewater-soluble derivative of camptothecin. It is usedto treat ovarian cancer and lung cancer, as well asother cancer types (Fig.16). Topotecan is the firsttopoisomerase inhibitor for oral use. Hycamtin ortopotecan is a semi-synthetic derivative ofCamptothecin. Topoisomerase-I is a nuclearenzyme that relieves torsional strain in DNA byopening single strand breaks. Oncetopoisomerase-I creates a single strand break, theDNA can rotate in front of the advancingreplication fork. Topotecan intercalates between

DNA bases. This intercalation disrupts the DNAduplication machinery when it reaches a sitewhere topotecan is intercalated. This disruptionprevents DNA replication, and ultimately leads tocell death. Mammalian cells cannot efficientlyrepair these double strand breaks. This processleads to breaks in the DNA strand resulting inapoptosis.

1.18. T-0128T-0128 is another analogue created by theaddition of a carrier molecule linked by aminoacids to Camptothecin. One study showed that therelease of the carboxymethyl dextran carrier fromT2513 (7-ethyl-10-aminopropyloxy-CPT) may bedependent on the macrophage concentrationsince the efficacy of T-0128 was improved in thepresence of macrophages.

1.19. Oxyalkanoic Acid EstersOnly preclinical studies have been done on noveloxyalkanoic acid esters of camptothecin. Thehypothesis behind this modification on the E-ringwas that it would stabilize the lactone ring, therebydecreasing toxicity and increasing tumor celldeath. Several of these derivatives were tested inmultiple cancer cell lines and the results werecompared to camptothecin, irinotecan and taxol.The results indicated the antitumor activity wasimproved in the derivatives that had shortercarbon chains between the carbonyl and oxygen.The antitumor effects were similar tocamptothecin, but superior to irinotecan and taxol,even in MDR1-expressing cells. Further trials arecurrently underway to confirm the properties ofthese novel agents.

1.20. PolyesterRecently, biodegradable polyesters such as poly(lactic acid), poly (glycolic acid) and thecopolymers of lactic and glycolic acid, i.e., poly(lactide-co- glycolic acid). (PLGA) have been usedextensively for biomedical application. they protectthe entrapped drug against degradation andcontrol its site specific delivery .They aresynthesized through ring opening polymerizationof cyclic lactone .these copolymer are amorphousand easily dissolve in organic solvent such asdichloromethane weight and the lactide :glycolideratio. Higher glycolide content and lowermolecular weight increase the degradation rate.As they are all strongly hydrophobic they are moreefficient for encapsulation of hydrophobic drugthan hydrophilic drug. The drug release fromPLGA micro particles often has a tri phasic patternin-vitro as well as in-vivo. A fast initial releasephase (burst )followed by a second slow releasephase lasting days or weeks and a third rapidrelease phase is seen in particular with peptideand protein drugs. The burst release isundesirable in most of the sustained drug deliveryapplications, since the dosage of the potent drugencapsulated is required to be released over along period of time.

Figure 15Silatecan

Figure 16Topotecan

Hydrophobic: It isthe physicalproperty of amolecule that isrepelled from amass of water.Hydrophobicmolecules tend tobe non-polar and,thus, prefer otherneutral moleculesand non-polarsolvents.

Polyester: It is acategory ofpolymers whichcontain the esterfunctional groupin their mainchain. Althoughthere are manypolyesters, theterm "polyester"as a specificmaterial mostcommonly refersto polyethyleneterephthalate(PET)

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1.21. Poly (ethylene glycol) based blockco-polymers

The nature of the surface of the nanoparticleslargely influences their biodistribution following in-vivo administrations (Conover et al., 1999).Hydrophobic nanoparticles are rapidly clearedfrom the systemic circulation by MPS, ending inthe Liver or in the spleen. The hydrophobic natureof the most biodegradable particles could limit theapplicability of these carriers in many drug deliveryapplications (Sarapa et al., 2003). In order toovercome concerns of clearance by the MPS,Surface modification techniques have beenutilized. These modification techniques ultimatelyproduced a particle that is not recognized by theMPS by rendering the surface of the particlehydrophilic. Several types of surface modifiednanoparticles have been described in recentliterature. The most common moiety used forsurface modification Poly (ethylene glycol). PEG isa hydrophilic, non-ion polymer that has beenshown to exhibit excellent biocompatibility. PEGmolecules can be added to the particles viacovalent bonding or surface adsorbents. Thepresence of PEG brush on the surface of thenanoparticle besides increasing residence time inthe systemic circulation can also reduce proteinand enzyme adsorption on the surface and thuscan retard particle degradation. The degree ofprotein adsorption can be minimized by alteringthe density and molecular weight of PEG on thesurface. The stability of PLA particles has beenshown to increase in stimulated gastric fluid withthe addition of PEG on the particle surface. PEGcoated (statically stabilized) nanoparticles canavoid sequestration by the MononuclearPhagocyte system (MPS) and hence shoeincreased circulation time in the body.Biodegradable and biocompatibility polymer suchas poly (lactide) (PLA) poly (ɛ-carprolactone)(PCL), poly (benzyl aspartate) (PLBA) and poly(ẞ-benzyl L- glutamate) (PLBG) have beencommonly used for the core material of micelleswhile PEO and PEG are used as hydrophilicblock. Studies on polymers micelles comprised of

PEO as hydrophilic block and PLC, PLA, PLBA,as hydrophobic block have been have beencarried out by many group.

1.22. Polycaprolactones (PLC)Poly (ɛ-carprolactone) (PCL) obtained by ringopening polymerization of ɛ-carprolactone wasreported initially for the controlled release ofsteroids and narcotic antagonists as well as todeliver ophthalmic agent under certaincircumstances, it is possible to enzymaticallydegrade cross-linked PLC (termed enzymaticsurface erosion). Low molecular fragments of PLCare also reportedly absorbed by macrophagesintracellularly the rate of biodegradation for PLC isslower than other biodegradable materials thusmaking it suitable for design of long termimplantable systems.

1.23. Poly (alkyl cyanoacrylate)Their delayed degradation characteristics thus donot generate an acidic environment during drugrelease. This has prompted intense research fortheir use in many nanoparticle formulations.Couvreure reported the production of NPs bymechanically polymerizing the dispersed or aninitiator in the presence of polysorbate 20 as asurfactant. The in vitro release studies under sinkcondition in water or in rat plasma showed a fastrelease in the first 10 min followed by a slowerone over 6 hrs. The potential of polyalkycyanoacrylate (PACANPs) is to overcomemultidrug resistance problem at cellular level andin relation to drug bio-distribution. Poly alkyl(cyanoacrylate) nanoparticles have been identifiedas to be fulfilling these requirements to overcomethe resistance caused by the P-glycoproteincomplex. lipid nanocapsules prepared usingpoly(alkyl cyanoacrylate ) were between 25 to 100nm in size and showed fast initials release of 60 to75% in the first 48 hours . However the majorlimitations associated with use of this of thispolymer are the particles size high cell uptake andtoxicity.

NANOPARTICLES IN CHEMOTHERAPYNanoparticle exerts its site-specific drug delivery by avoiding the reticuloendothelial system, utilizing enhancedpermeability and retention effect and tumor-specific targeting. These carriers are designed in such a way that they areindependent in the environments and selective at the pharmacological site. The formation of nanoparticle andphysiochemical parameters such as pH, monomer concentration, ionic strength as well as surface charge, particle sizeand molecular weight are important for drug delivery. Further, these nanoparticles have the capability to reverse multidrugresistance a major problem in chemotherapy. A single cancerous cell surrounded by other tissues will replicate at a higherrate the healing tissues will not be able to compete with the cancer cells for the inadequate supply of nutrients. Tumorinterstitium is characterized by a high interstitial pressure, leading an outward convective interstitial fluid flow as well asabsence of an anatomically well-defined functioning lymphatic network. Hence, the transport of an anticancer drug ininterstitium will be governed by the physiological (i.e., pressure) and physiochemical properties of the molecule itself (i.e.,size, composition, and structure), properties of investigation and by the physiochemical properties of the molecule itself(i.e., size configuration, charge, and hydrophobicity), poorly vascularized tumor regions, acidic environment high interstitialpressure, and low micro vascular pressure. Colloidal nanoparticle incorporating anticancer agents can overcome suchresistance to drug circulation, therapy increasing selectivity of drug towards cancer cells, and reducing toxicity towardsnormal cells controlled release of drug can be achieved by controlling the nanoparticulate structure, polymer used and theway by which the drug is associated with the carriers.

Pyrimidine: It is aheterocyclicaromatic organiccompound similarto benzene andpyridine,containing twonitrogen atoms atpositions 1 and 3of the six-memberring

Polymerization:It is a process ofreactingmonomermoleculestogether in achemicalreaction to formpolymer chainsor three-dimensionalnetworks.

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1.24. Poly (orth-ester) (POE)Poly (orth-esters) in another important group ofhydrophobic polymer with drug deliveryapplication and are synthesized by the addition ofpolyols to diketene acetals. POES possess acidsensitive orthoester linkage that under so rapidhydrolysis at physiological pH and an even fasterrate in an acidic pH .therefore, incorporation of asmall amount of acidic excipients may help tocontrol the hydrolysis rate. One the hand,incorporation of basic excipients stabilizes thebulk of the matrix but facilitates erosion at thesurface. wang et al., (1936) has studied poly(phosphoester) ionomers as tissue engineeringscaffolds. The polymers conjugated with N-hydroxsuccimide were hydrolyzed in biphasicmode, with a fast initial phase occurring in the firstfew hours, followed by a slower phase in the nextfew days. These ionomers represent a novel classof biomaterials with readily controlled physical andchemical attributes for tissue engineering.

1.25. PolyanhydridePolyanhydride are hydrophobic and contain watersensitive linkages that may undergo hydrolyticbond cleavage to generate water solubledegradation products. Surface erosion takes placedue to water sensitive linkage. The majority ofpolyanhydrides studies are based on sebacic acid(SA), p (carboxphenoxy) propane (CPP) and p-(carboxyphenoxy) hexane (CPH). The sebacicacid component of biodegradable Pas is utilizedas surface eroding drug delivery device.

1.26. PolyamidePolyamides form another important class ofpolymer particularly as drug delivery matrices.Polyamides with a structural resemblance topolypeptide are used as matrices for the transportof drug. Example include different type of poly(amino acid) such as poly (L-glutamic acid), poly(aspartic acid) are derived from the correspondingnatural amino acids. It circulated in the blood for along time evaded RES uptake due to thehydrophilic polyethylene glycol the EPR effect. Liand co- workers have synthesized a novelbiodegradable poly (ester amide) derived from 3-morpholine and ɛ-carprolactone. Increase inmorpholine content enhanced water absorption ofthe polymers. In vitro degradation data andrelease profile.

1.27. CyclodextrinsCyclodextrins or cycloamyloses are a family ofcompounds made up of sugar molecules boundtogether in a ring (cyclic oligosaccharides).Cyclodextrins are different types based on theirstructure it is classified as α, β and γ–cyclodextrins. Cyclodextrins are produced fromstarch by means of enzymatic conversion.Cyclodextrins have been widely applied to thepharmaceutical field due to their ability to includehydrophobic molecules in their cavity and to maskcertain physicochemical characteristics of theincluded molecule such as poor water solubility,

stability problems, unwanted side effects, taste,odor, and incompatibility of drugs and excipients.As a result of the increasing interest in andsuccessful licensing and commercialization ofnanoparticulate pharmaceutical products,cyclodextrins have also been incorporated intonanoparticulate drug delivery systems for severalpurposes. This can be achieved by twoapproaches; either by complexion of activeingredient with an appropriate cyclodextrinderivative and entrapment into polymericnanoparticles to solve problems arising from thedrug's physicochemical properties or bymodification of cyclodextrins to render anamphiphilic character to these molecules whichallow cyclodextrins to self-align into nanoparticlesin the form of nanospheres, nanocapsules, solidlipid nanoparticles, nanosize liposomes andnanosize vesicles with or without the presence ofsurfactants. This review will deal with the currentliterature concerning the applications ofcyclodextrins and derivatives as nanomaterials fordrug delivery focusing on nanoparticles preparedfrom novel cyclodextrin derivatives namelyamphiphilic cyclodextrins and their in vitrocharacterization, efficacy and safety drug-loadingvalues were significantly higher for amphiphiliccyclodextrin nanoparticles when compared withthose for PLGA and PCL nanoparticles.Nanoparticle formulations showed a significantcontrolled release profile extended up to 12 daysfor amphiphilic cyclodextrin nanoparticles and48 h for polymeric nanoparticles.

2. CONCLUSIONThe use of biodegradable polymeric nanoparticles(NPs) for controlled drug delivery has shownsignificant therapeutic potential. Concurrently,targeted delivery technologies are becomingincreasingly important as a scientific area ofinvestigation. In cancer, targeted polymeric NPscan be used to deliver chemotherapies to tumorcells with greater efficacy and reduced cytotoxicityon peripheral healthy tissues. The camptothecinanalogues are chemotherapeutic agents. Theanalogues were created by modifying the differentrings of the original camptothecin molecule, givingeach analogue unique property. Thesemodifications which gives the variousimprovements in the parent molecule, includingchanges in bioavailability, stabilization of thelactone ring, and/or a decrease in the substraterecognition by drug-resistant proteins. Thesetypes of modifications that have translated intogreater tumoricidal effects with improvements inthe toxicity profile in preclinical studies. Thedifferent Polymers like Acrylate polymers,Polyethylene Glycol, poly (methylidene malonate),Poly (lactic acid), Polycaprolactone, Polyglycolicacid and Cyclodextrins are also used to improvethe effectiveness of the camptothecin analoguedrugs. As a better understanding of theseanalogues develops through these clinical trials,progress is being made towards creating more

Glycoproteins:Glycoproteins areproteins thatcontainoligosaccharidechains (glycans)covalentlyattached topolypeptide side-chains.

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effective and less toxic chemotherapeutic agents.Over the next decade, the benefits of solubilityand stability enhancement will be more greatlyappreciated, as will the implications for patentlandscape. The use of the platform technology inthe discovery arena may also prove a fertilepathway and will aid in the speedy development ofthis technology, as complex solubility andbioavailability aspects will be addressed at the

early screening stage. Another potentialapplication–biologically active nanoparticles forboth disease detection and therapy–may not justbe a dream, and may well see the light of day inthe future.

SUMMARY OF REVIEW1. The field of drug delivery is a sterling example, with nanoparticles being increasingly used for generating therapeutic

formulation of poorly water-soluble drugs. Advances in polymer science have led to the development of novel drug deliverysystem.

2. Some polymers are obtained from natural resources and the chemically modified for various application, while other arechemically synthesized and used. A large number and synthetic polymer are available.

3. United States Patents Granted for Amphiphilic Block Copolymers as Anti-cancer Drug-Encapsulated Nanoparticles arepoly(alkylene), poly(alkyleneglycol, PEG), poly(ethylene oxide), PVP(Hydrophilic block), PLA, poly(p-dioxaanone) PLA, PGA,PLGA, PCL, poly (hydroxyester), poly(akylene oxide), polyester, poly (alkyleneoxide), polyester, polyorthoester,polyanhydride(Major Hydrophobic block).

4. The nanoparticle exhibited a good anti-tumer activity and prolonged the retention of CPT-11 in bloobstream. CPT-loadedPLA/PEG-PPG-PEG nanoparticles have been investigated in attempt to overcome the drawbacks of the high dose andfrequent dosing.

FUTURE ISSUSESThe advancements in the nanotechnology are widely penetrating to biomedical sciences and technology. Since the discovery ofthe enhanced permeation and retention effect in 1986, a great variety of nanosized dosage forms have been developing. Amongtumorcidal agent classified in the cytotoxic chemotherapeutic, camptothecin (CPT) was proved to be effective in preclinical trials.Therefore it is a great opportunity to overcome the current limitation of camptothecin and its derivatives. CPT-liposomeformulations are known to stabilize active lactone form that hydrolyze to inactive carboxyl ate form at physiological pH andincrease the residence time in the bloodstream.

DISCLOUSURE STATEMENTThere is no financial support has been provided.

ACKNOWLEDGMENTSWe thank the professors and colleague for the enormous support to carry out the review work.

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18 54 Pharmacy - Discovery JournalsREVIEW Balasubramanian et al. Emerging polymers and Chemistry of Camptothecin Derivatives in Nanoparticle Drug delivery system, Discovery Pharmacy,