Biodegradable Nanoparticles for Drug Delivery and Targeting

Current Opinion in Solid State and Materials Science 6 (2002) 319–327

B iodegradable nanoparticles for drug delivery and targeting*M.L. Hans, A.M. Lowman

Biomaterials and Drug Delivery Laboratory, Department of Chemical Engineering, Drexel University, Philadelphia, PA 19104,USA

Received 24 July 2002; accepted 4 September 2002

Abstract

Throughout the world today, numerous researchers are exploring the potential use of polymeric nanoparticles as carriers for a widerange of drugs for therapeutic applications. Because of their versatility and wide range of properties, biodegradable polymericnanoparticles are being used as novel drug delivery systems. In particular, this class of carrier holds tremendous promise in the areas ofcancer therapy and controlled delivery of vaccines. 2002 Elsevier Science Ltd. All rights reserved.

Keywords: Nanoparticles; PLGA; Drug delivery; Surface modifications

1 . Introduction particles to cross the intestinal lumen into the lymphaticsystem following oral delivery. Likewise, the therapeutic

Polymer nanoparticles are particles of less than 1mm effect of drug-loaded nanoparticles was relatively poor duediameter that are prepared from natural or synthetic rapid clearance of the particles by phagocytosis postpolymers. Nanoparticles have become an important area of intravenous administration. In recent years this problemresearch in the field of drug delivery because they have the has been solved by the addition of surface modifications toability to deliver a wide range of drugs to varying areas of nanoparticles.the body for sustained periods of time. Natural polymers Another promising class of nano-sized vehicles that(i.e. proteins or polysaccharides) have not been widely have been considered in drug delivery applications isused for this purpose since they vary in purity, and often liposomes. These vesicles prepared from lipids have beenrequire crosslinking that could denature the embedded used as potential drug carriers because of the protectiondrug. Consequently, synthetic polymers have received they can offer drugs contained in their core. However,significantly more attention in this area. The most widely liposomes have shown a low encapsulation efficiency, poorused polymers for nanoparticles have been poly(lactic storage stability, and rapid leakage of water-soluble drugsacid) (PLA), poly(glycolic acid) (PGA), and their co- in the blood [2]. As such, their ability to control the releasepolymers, poly(lactide-co-glycolide) (PLGA). These poly- of many drugs may not be good. Solid, biodegradablemers are known for both their biocompatibility and nanoparticles have shown their advantage over liposomesresorbability through natural pathways. Additionally, the by their increased stability and the unique ability to createdegradation rate and accordingly the drug release rate can a controlled release.be manipulated by varying the ratio of PLA, increased In recent years, significant research has been done usinghydrophobicity, to PGA, increased hydrophilicity. nanoparticles as oral drug delivery vehicles. In this appli-

During the 1980s and 1990s several drug delivery cation, the major interest is in lymphatic uptake of thesystems were developed to improve the efficiency of drugs nanoparticles by the Peyer’s patches in the GALT (gutand minimize toxic side effects [1]. The early nanoparticles associated lymphoid tissue). Peyer’s patches are character-and microparticles were mainly formulated from poly- ized by M cells that overlie the lymphoid tissue and are(alkylcyanoacrylate). Initial promise for microparticles was specialized for endocytosis and transport into intraepitheli-dampened by the fact that there was a size limit for the al spaces and adjacent lymphoid tissue. Nanoparticles bind

the apical membrane of the M cells, followed by a rapidinternalization and a ‘shuttling’ to the lymphocytes [3,4].*Corresponding author. Tel.:11-215-895-2228.

E-mail address: [email protected](A.M. Lowman). The size and surface charge of the nanoparticles are crucial

1359-0286/02/$ – see front matter 2002 Elsevier Science Ltd. All rights reserved.PI I : S1359-0286( 02 )00117-1

mailto:[email protected]

320 M.L. Hans, A.M. Lowman / Current Opinion in Solid State and Materials Science 6 (2002) 319–327

for their uptake. There have been many reports as to the out by dissolving the polymer and the compound in anoptimum size for Peyer’s Patch uptake ranging from less organic solvent. Frequently, dichloromethane or methylenethan 1mm to less than 5mm [5,6]. It has been shown that chloride is used for PLGA copolymers. The emulsion ismicroparticles remain in the Peyer’s patches while prepared by adding water and a surfactant to the polymernanoparticles are disseminated systemically [7]. This appli- solution. In many cases, the nanosized polymer dropletscation of nanoparticles in oral delivery holds tremendous are induced by sonication or homogenization. The organicpromise for the development of oral vaccines and in cancer solvent is then evaporated and the nanoparticles are usuallytherapy. collected by centrifugation and lyophilization [5,8–11].

Nanoparticles have a further advantage over larger A modification on this procedure has led to the protocolmicroparticles, because they are better suited for intraven- favored for encapsulating hydrophilic compounds andous (i.v.) delivery. The smallest capillaries in the body are proteins, the double or multiple emulsion technique. First,5–6mm in diameter. The size of particles being distributed a hydrophilic drug and a stabilizer are dissolved in water.into the bloodstream must be significantly smaller than 5 The primary emulsion is prepared by dispersing themm, without forming aggregates, to ensure that the par- aqueous phase into an organic solvent containing a dis-ticles do not form an embolism. solved polymer. This is then reemulsified in an outer

Clearly, a wide variety of drugs can be delivered using aqueous phase also containing stabilizer [6,7,9,12–14].nanoparticulate carriers via a number of routes. Nanoparti- From here, the procedure for obtaining the nanoparticles iscles can be used to deliver hydrophilic drugs, hydrophobic similar to the single emulsion technique for solventdrugs, proteins, vaccines, biological macromolecules, etc. removal. The main problem with trying to encapsulate aThey can be formulated for targeted delivery to the hydrophilic molecule like a protein or peptide-drug is thelymphatic system, brain, arterial walls, lungs, liver, spleen, rapid diffusion of the molecule into the outer aqueousor made for long-term systemic circulation. Therefore, phase during the emulsification. This can result in poornumerous protocols exist for synthesizing nanoparticles encapsulation efficiency, i.e. drug loading. Therefore, it isbased on the type of drug used and the desired delivery critical to have an immediate deposit of a polymerroute. Once a protocol is chosen, the parameters must be membrane during the first water-in-oil emulsion. Song ettailored to create the best possible characteristics for the al. [9] was able to accomplish this by dissolving a highnanoparticles. Four of the most important characteristics of concentration of high molecular weight PLGA into a thenanoparticles are their size, encapsulation efficiency, zeta oil phase consisting of 80:20% weight dichloromethane/potential (surface charge), and release characteristics. In acetone solution. Additionally, the viscosity of the innerthis review, we intend to summarize many of the tech- aqueous phase was increased by increasing the concen-niques used for preparing polymeric nanoparticles, includ- tration of stabilizer, bovine serum albumin (BSA). Theing the types of polymers and stabilizers used, and how primary emulsion was then emulsified with Pluronic F68these techniques affect the structure and properties of the resulting in drug-loaded particles of approximately 100 nmnanoparticles. Additionally, we will discuss advances in [9].surface modifications, drug encapsulation and targeted Another method that has been used to encapsulatedrug delivery applications. insulin for oral delivery is phase inversion nanoencapsula-

tion (PIN). Zn-insulin is dissolved in Tris–HCl and aportion of that is recrystallized by the addition of 10%

2 . Synthesis and characterization ZnSO . The precipitate is added to a polymer solution of4

PLGA in methylene chloride. This mixture is emulsifiedAs stated previously, there are several different methods and dispersed in 1 l of petroleum ether, which results in the

for preparing nanoparticles. Additionally, numerous meth- spontaneous formation of nanoparticles [15].ods exist for incorporating drugs into the particles. For All of the previously mentioned techniques use toxic,example, drugs can be entrapped in the polymer matrix, chlorinated solvents that could degrade certain drugs andencapsulated in a nanoparticle core, surrounded by a shell- proteins if they come into contact during the process.like polymer membrane, chemically conjugated to the Consequently, an effort has been made to develop otherpolymer, or bound to the particle’s surface by adsorption. techniques in order to increase drug stability during theA summary of these methods including the types of synthesis. One such technique is the emulsification–diffu-polymer, solvent, stabilizer and drugs used is given in sion method. This method uses a partially water-solubleTables 1 and 2. solvent like acetone or propylene carbonate. The polymer

The most common method used for the preparation of and bioactive compound is dissolved in the solvent andsolid, polymeric nanoparticles is the emulsification–sol- emulsified in the aqueous phase containing the stabilizer.vent evaporation technique. This technique has been The stabilizer prevents the aggregation of emulsion drop-successful for encapsulating hydrophobic drugs, but has lets by adsorbing of the surface of the droplets. Water ishad poor results incorporating bioactive agents of a added to the emulsion, to allow for the diffusion of thehydrophilic nature. Briefly, solvent evaporation is carried solvent into the water. The solution is stirred leading to the

M.L. Hans, A.M. Lowman / Current Opinion in Solid State and Materials Science 6 (2002) 319–327 321

Table 1Summary of methods used for preparation used for preparation of polymeric nanoparticles

Method Polymer Solvent Stabilizer Size (nm) Reference

Solvent diffusion PLGA Acetone Pluronic F-127 200 [33]PLGA Acetone/DCM PVA 200–300 [19]PLA-PEG MC PVA/PVP |130 [45]PHDCA THF – 150 [38]PLGA Acetone Sodium cholate 161 [36]PLGA Propylene carbonate PVA or DMAB |100 [16]

Solvent displacement PLA Acetone/MC Pluronic F68 123623 [41]SB-PVA-g-PLGA Acetone/ethyl Poloxamer |110 [32]

acetate 188

Nanoprecipitation PLGA/PLA/PCL Acetone Pluronic F68 110–208 [20]PLGA Acetonitrile – 157.161.9 [18]

Solvent evaporation PLA-PEG-PLA DCM – 193–335 [48]PLGA DCM PVA 800 [10]PEO-PLGA MC PVA 150625 [8]

Multiple emulsion PLGA Ethyl acetate – .200 [37]PLGA Ethyl acetate/MC PVA/PVP |280 [45]PLGA Ethyl acetate/MC PVA 335–743 [34]PLGA-mPEG DCM – 133.563.7–163.363.6 [49]PLGA DCM PVA 70–160 [42]PLGA DCM PVA 213.8610.9 [14]PLGA DCM/acetone PVA 100 [9]PLGA DCM PVA |250 [6]PLGA Ethyl acetate PVA 192612 [12]PLGA Ethyl acetate PVA |300 [7]PLGA DCM PVA 380640–17206110 [13]

Salting out PLA Acetone PVA 300–700 [21]

Ionic gelation Chitosan TPP – 278603 [41]

Interfacial deposition PLGA Acetone – 135 [40]

Phase inversion PLGA MC – .5 mm [15]nanoencapsulation

Polymerization CS-PAA – – 206622 [25]PECA – Pluronic F68 320612 [31,26]PE-2-CA – – 3806120 [30]

Size is in nm, unless otherwise indicated. DCM, dichloromethane; MC, methylene chloride; PVP, polyvinylpyrrolidone; PHDCA, poly(hexade-cylcyanoacrylate); THF, tetrahydrofuran; SB-PVA-g-PLGA, sulfobutylated PVA, graft, PLGA; PCL, poly(epsilon-caprolactone); TPP, sodium tripoly-phosphate; PAA, poly(acrylic acid); PECA, polyethylcyanoacrylate; PE-2-CA, polyethyl-2-cyanoacrylate.

nanoprecipitation of the particles. They can then be effecting the particle size, morphology, or yield. Murakamicollected by centrifugation, or the solvent can be removed et al. [19] effectively modified the solvent diffusionby dialysis [16,17]. technique by using two water-miscible solvents, one with

One problem with this technique is that water-soluble more affinity for PLGA and one with more affinity for thedrugs tend to leak out of the polymer phase during the stabilizer, PVA, such as acetone and ethanol.solvent diffusion step. To improve this process for water- Nanoparticles can also be synthesized by the nanop-soluble drugs, Takeuchi et al. [17] changed the dispersing recipitation method. Briefly, the polymer and drug aremedium from an aqueous solution to a medium chain dissolved in acetone and added to an aqueous solution

triglyceride and added a surfactant, Span 80, to the containing Pluronic F68. The acetone is evaporated underpolymer phase. The nanoparticles are collected from the reduced pressure and the nanoparticles remain in theoily suspension by centrifugation. Several parameters can suspension resulting in particles from 110 to 208 nm [20].also be changed to benefit the encapsulation of hydrophilic The salting-out process is another method that does not usemolecules. Govender et al. [18] found that increasing the chlorinated solvents. Using this technique, a water-in-oilaqueous phase pH to 9.3 and incorporating pH-responsive emulsion is formed containing polymer, acetone, mag-excipients such as poly(methyl methacrylate-co- nesium acetate tetrahydrate, stabilizer, and the activemethacrylic acid) (PMMA-MAA), and lauric and caprylic compound. Subsequently water is added until the volumeacid increased hydrophilic drug encapsulation without is sufficient to allow for diffusion of the acetone into the


Table 2Comparison of particle diameter for polymeric nanoparticles

Polymer Drug Size (nm) Reference

PLGA Doxorubicin 200 [33]PLGA/PLA/PCL Isradipine 110–208 [20]PLGA U-86983 144637–88641 [9]PLGA Rose Bengal 150 [40]PLGA Triptorelin 335–743 [34]PLGA Procaine hydrochloride 16461.1–209.562.7 [18]PLGA-mPEG Cisplatin 133.563.7–163.363.6 [49]PLGA U-86983 70–160 [42]PLGA Insulin .1 mm [15]PLGA Hemagglutinin |250 [6]PLGA Haloperidol 800 [10]PLGA Estrogen |100 [16]PEO-PLGA Paclitaxel 150625 [8]PLA Tetanus toxoid .200 [37]PLA Savoxepine |300–700 [21]PLA PDGFRb tyrphostin inhibitor 123623 [41]PLA-PEG-PLA Progesterone 193–335 [48]PECA Amoxicillin 320612 [31]Poly(butyl cyanoacrylate) Dalargin 250 [29]Chitosan Cyclosporin A 283624–281605 [47]

Size is in nm, unless otherwise indicated.

water, which results in the formation of nanoparticles. This different study conducted by Kwon et al. [16], PLGAsuspension is purified by cross-flow filtration and lyophili- nanoparticles prepared using didodecyl dimethyl ammo-zation [21]. However, one disadvantage to this procedure nium bromide (DMAB) were smaller than particles pre-is that it uses salts that are incompatible with many pared with PVA [16]. Lemoine et al. [6] found that thebioactive compounds. presence of PVA in the inner aqueous phase produced

In most published techniques, nanoparticles are syn- smaller particles than Span 40 [6]. When Pluronic hasthesized from the biocompatible polymers. However, it is been used a stabilizer, the grade used can have a distinctpossible to make biodegradable nanoparticles from mono- effect on the size of the nanoparticles. For example,mers or macromonomers by polycondensation reactions particles prepared with Pluronic F68 were smaller than[22,23]. These processes also result in sizes ranging from particles prepared with Pluronic F108 [26].200 to 300 nm. Nanoparticles can also be made from The amount of stabilizer used will also have an effect onhydrophilic polysaccharides like chitosan (CS). CS- the properties of the nanoparticles. Most importantly, if thenanoparticles can be formed by the spontaneous ionic concentration of the stabilizer is too low, aggregation ofgelatin process [12,24]. CS-poly(acrylic acid) nanoparticles the polymer droplets will occur and little if any nanoparti-have also been made by polymerization of acrylic acid and cles will be recovered. Alternatively, if too much of thethe ‘dropping method’ [25]. The resulting nanoparticles stabilizer is used, the drug incorporation could be reducedhave small sizes and positive surface potentials. This due to interaction between the drug and stabilizer. How-technique is promising as the particles can be prepared ever, when the stabilizer concentration is between theunder mild conditions without using harmful organic ‘limits’, adjusting the concentration can be a means ofsolvents controlling nanoparticle size. For example, using the

The production of nanoparticles has several independent solvent evaporation technique, increasing the PVA con-variables. One key parameter is type of surfactant /stabi- centration will decrease the particle size [6,9]. However,lizer to use. A wide range of synthetic and natural when using the emulsification diffusion method, Kwon etmolecules with varying properties has been proposed to al. [16] found a that a PVA concentration from 2 to 4%prepare nanoparticles. Feng et al. [11] has investigated the was ideal for creating smaller nanoparticles,|100 nm inuse of phospholipids as a natural emulsifier. In their study, diameter.dipalmitoyl-phosphatidylcholine (DPPC) improved flow Another factor that can affect the nanoparticles prop-and phagocytal properties due to a denser packing of erties is the final freeze-drying process. It has beenDPPC molecules on the surface of the nanoparticles reported that additives such as saccharides are necessaryleading to a smoother surface than particles made with the for cryoprotection of the nanoparticles in the freeze-dryingsynthetic polymer, poly(vinyl alcohol) (PVA). DPPC also process [27]. These saccharides may act as a spacingimproved the encapsulation efficiency compared to PVA matrix to prevent particles aggregation. Because of theusing the emulsification solvent evaporation method. In a possibility of aggregation, freeze-drying procedure can


affect the ‘effective’ nanoparticle size and consequently what the goal of the nanoparticle delivery system is beforetheir release behavior and accordingly the drug phar- determining the size desired. For example if the goal ismacokinetics [28]. rapid dissolution in the body or arterial uptake then the

The polymer used to formulate the nanoparticles will size of the nanoparticles should be approximately 100 nmalso strongly affect the structure, properties and applica- or less. If prolonged dissolution is required, or targetingtions of the particles. As previously stated, PLGA has been the mononuclear phagocytic system (MPS), larger particlesthe most common polymer used to make biodegradable around 800 nm would be preferable. A comparison ofnanoparticles, however, these are clearly not the optimal various drugs encapsulated and the resulting sizes of thecarrier for all drug delivery applications. For each applica- particles are summarized in Table 2. From examination oftion and drug, one must evaluate the properties of the these data, it appears that the encapsulation efficiencysystem (drug and particle) and determine whether or not it increases with the diameter of the nanoparticles. In oneis the optimal formulation for a given drug delivery study, the encapsulation efficiency was maximized in theapplication. For example, poly(butyl cyanoacrylate) double emulsion solvent evaporation technique when thenanoparticles have been successful in delivering drugs to pH of the internal and the external aqueous phases werethe brain [29]. Other cyanoacrylate-based nanoparticles brought to the isoelectric point of the peptide beingsuch as polyalkylcyanoacrylate (PACA) and poly- encapsulated, methylene chloride was used as a solvent,ethylcyanoacrylate (PECA), have also been prepared. They and the PLGA was rich in free carboxylic end groups [34].are considered to be promising drug delivery systems due Another characteristic of polymeric nanoparticles that isto their mucoadhesive properties and ability to entrap a of extreme interest is zeta potential. The zeta potential is avariety of biologically active compounds. These polymers measure of the charge of the particle, as such the larger theare biodegradable, biocompatible, as well as compatible absolute value of the zeta potential the larger the amountwith a wide range of compatible drugs [26,30]. Further- of charge of the surface. In a sense, the zeta potentialmore, these polymers have a faster degradation rate than represents an index for particle stability. For the case ofPLGA, which in some cases may be more desirable. PECA charged particles, as the zeta potential increases, thenanoparticles have been prepared by emulsion polymeri- repulsive interactions will be larger leading to the forma-zation in the presence and absence of different molecular tion of more stable particles with a more uniform sizeweight poly(ethylene glycol) (PEG), using Pluronic F68 as distribution. A physically stable nanosuspension solelythe stabilizer [31]. stabilized by electrostatic repulsion will have a minimum

Other groups have successfully prepared nanoparticles zeta potential of630 mV [35]. This stability is importantfrom functionalized PLGA polymers. In one study, Jung et in preventing aggregation. When a surface modification isal. [32] synthesized nanoparticles made of a branched, added like PEG the negative zeta potential is lowered,biodegradable polymer, poly(2-sulfobutyl-vinyl alcohol)-g- increasing the nanoparticles stability [12].LGA [32]. The purpose of using sulfobutyl groups at-tached to the hydrophilic backbone was to provide a higheraffinity to proteins by electrostatic interactions that would 3 . Surface modificationfavor adsorptive protein loading. Adjustments can be madeto the characteristics nanoparticles by differing degrees of Before deciding which of the techniques to use forsubstitution of sulfobutyl groups. In another case, a synthesizing nanoparticles, one must consider what thecarboxylic end group of PLGA was conjugated to a nature of the drug used as well as the means and durationhydroxyl group of doxorubicin and formulated into desired for the delivery. That will determine not only hownanoparticles. This modification produced a sustained the particles are synthesized but also what the nature of therelease of the drug that was approximately six times longer particles should be. In particular, the body recognizesthan with unconjugated drug [33]. hydrophobic particles as foreign and thus they are rapidly

The molecular weight and concentration of the polymer taken up by the MPS. However, if sustained systemicused will also affect the nanoparticles. The molecular circulation is required than the surface of the hydrophobicweight of the polymer has opposite effects on nanoparticle nanoparticles must be modified in order prevent phago-size and encapsulation efficiency. Smaller size nanoparti- cytosis.cles, approximately 100 nm, can be prepared with lower Following intravenous administration, hydrophobicmolecular weight polymer, however, at the expense of nanoparticles are rapidly cleared from the systemic circula-reduced drug encapsulation efficiency. On the other hand, tion by the MPS, ending in the liver or the spleen. If thean increase in polymer concentration increases encapsula- goal is to treat a condition in the liver, then the propertion efficiency and the size of the nanoparticles [7,9,16]. choice for the application would be a hydrophobic

When considering a particular polymeric nanoparticle nanoparticle. While it would appear that the hydrophobicfor a given drug delivery application, particle size and nature of most biodegradable particle would limit theencapsulation efficiency are two of the most important applicability of these carriers in many drug deliverycharacteristics of nanoparticles. One should determine applications, one may overcome concerns of clearance by


the MPS through surface modification techniques. The cles was associated with less interaction with the MPS, andgoal of these modification techniques is to produce a longer systemic circulation. Also, PEG-containing PLGAparticle that is not recognized by the MPS due to the nanoparticles synthesized by Li et al. [14] were able tohydrophilic nature of the surface. extend the half life of BSA in a rat model to 4.5 h from

Several types of surface modified nanoparticles that 13.6 min [14]. Another study compared the dosages ofhave been described in recent literature are summarized in PLGA nanoparticles versus PEG-PLGA nanoparticles. TheTable 3. The most common moiety used for surface PLGA nanoparticles pharmacokinetics seemed to dependmodification is poly(ethylene glycol) (PEG). PEG is a on MPS saturation. However, the pharmacokinetics ofhydrophilic, nonionic polymer that has been shown to PEG-PLGA dosages did not exhibit the same dependenceexhibit excellent biocompatibility. PEG molecules can be on dosage/MPS saturation due to their stealth nature [39].added to the particles via a number of different routes Poloxamer and poloxamines have also been shown toincluding covalent bonding, mixing in during nanoparticle reduce capture by macrophages and increase the time forpreparation, or surface adsorption. The presence of a PEG- systemic circulation. Similarly PLGA particles coated withbrush on the surface of nanoparticles can serve other poloxamer 407 and poloxamine 908 extended the half lifefunctions besides increasing residence time in the systemic of rose bengal, a hydrophilic model drug, with|30% leftcirculation. For one, PEG tethers on the particle surface in the bloodstream after 1 h post nanoparticle administra-can reduce protein and enzyme adsorption on the surface, tion, as opposed to 8% present after 5 min post free drugwhich for PLGA based particles will retard degradation. administration [40].The degree of protein adsorption can be minimized by Another polymer used for surface modification isaltering the density and molecular weight of PEG on the chitosan. The addition of CS to the surface of PLGAsurface [36]. The stability of PLA particles has been shown nanoparticles, resulted in increased penetration of macro-to increase in simulated gastric fluid (SGF) with the molecules in mucosal surfaces [24]. CS coated PLGAaddition of PEG on the particle surface. After 4 h in SGF, particles were able to increase the positive zeta potential of9% of the PLA nanoparticles converted to lactate versus the particles and increase the efficiency of tetanus toxoid3% conversion for PEG-PLA particles [37]. PEG is also protein encapsulation. Radiolabelled tetanus toxoid wasbelieved to facilitate transport through the Peyer’s patches used to show the enhanced transport across nasal andof the GALT [12]. intestinal epithelium using CS coated particles versus

125As stated previously though, the primary reason for uncoated particles, with a higher percentage of I presentinterest in preparing PEG functionalized particles is to in the lymph nodes for CS coated particles [12].improve the long-term systemic circulation of thenanoparticles. The PEG functionalized particles are notseen as a foreign body and are therefore not taken up by4 . Targeted drug delivery using nanoparticlesthe body, allowing them to circulate longer providing for asustained systemic drug release. Because of their behavior Another exciting application of surface modified par-these PEG functionalized nanoparticles are often called ticles is targeted drug delivery to tumors or organs. Kreuter‘stealth nanoparticles’ [38]. Furthermore, it has been et al. [29] were able to deliver several drugs successfullydetermined that PEG MW is important with respect to through the blood brain barrier using polysorbate 80 coatedMPS uptake. For example, Leroux et al. [21] showed that poly(butylcyanoacrylate) nanoparticles [29]. It is thoughtan increase in PEG molecular weight in PLGA nanoparti- that after administration of the polysorbate 80-coated

Table 3Comparison of nanoparticles modified with the addition of polymers to the surface

Polymer Surface modification Size (nm) Reference

PLGA Poloxamine 908 |160 [40]PLGA Poloxamer 407 |160 [40]PLGA Chitosan 500629 [12]PLGA-mPEG mPEG 133.563.7–163.363.6 [49]PLGA-mPEG mPEG 113.5614.3 [39]PLGA-PEG PEG 198.1611.1 [14]PLA PEG 164–270 [36]PLA PEG 6000 295 [21]PLA-PEG PEG .200 [37]PLA-PEG PEG |130 [45]PHDCA PEG |150 [38]PECA PEG 220610–28068 [31]PBCA Polysorbate 80 250 [29]


particles, apolipoprotein E (ApoE) adsorbs onto the surface cles could be effective in treating these pathogens withcoating. The ApoE protein mimics low density lipoprotein lower doses of drugs.(LDL) causing the particles to be transported via the LDL The lungs are another target area for nanoparticles duereceptors into the brain. to their large surface area, good mucosal permeation,

There are other specific areas where nanoparticle ad- well-developed vascular system, thin alveolar walls, andministration may have an advantage over microparticulate- low activity of drug metabolizing enzymes. When CSbased drug delivery systems. One area that has been of coated nanoparticles were administered via the lungs, thererecent interest is in prevention of restenosis. Restenosis is a were detectable blood levels of the drug 24 h aftermajor postoperative concern following arterial surgery. In administration, as opposed to 8 h for the noncoatedorder to inhibit vascular smooth muscle cell proliferation, particles [17].drugs must be delivered at a high concentration over a long Nanoparticles have been used to target mucosal sur-period of time. Nanoparticles offer an advantage because faces. Long-term extraocular (cornea and conjunctiva) drugthe medication would not have to be delivered systemically delivery with nanoparticles provides an improvement inas they are small enough for cellular internalization, and conventional drug delivery in this region. It was possibleconnective tissue permeation. Several types of drugs to deliver drug loaded CS-nanoparticles to the extraocularincluding antiproliferative agents have been used to test structures over the course of 48 h at higher levels than withthis method of delivery. PLA nanoparticles were loaded free drug, without exposing the inner ocular structures (iriswith platelet-derived growth factor receptorb tyrphostin and aqueous humour) to the drug [47].inhibitor and delivered intraluminally to an injured ratcarotid artery [41]. The drug had the desired effect ofpreventing restenosis, but of significance was the absence5 . Release characteristicsof drug in other areas of the arteries and systemiccirculation. Song et al. [42] found that specific additive The release characteristics of polymeric nanoparticlesafter nanoparticles formation, such as heparin, DMAB, or are one of the most important features of the drug/polymerfibrinogen, could enhance arterial retention of the particles. formulations because of the proposed application in sus-Suh et al. [8] created poly(ethylene oxide)-PLGA tained drug delivery. There are several factors that affectnanoparticles which had an initial burst release of 40% of the release rate of the entrapped drug. Larger particles havethe antiproliferative drug in the first 3 days [8]. However, a a smaller initial burst release and longer sustained releasetotal of 85% of the drug was released after 4 weeks. This than smaller particles. In addition, the greater the drugshows that nanoparticles have a great potential for long loading the greater the burst and the faster the release rate.term arterial drug delivery. For example, PLA nanoparticles containing 16.7% savox-

Much attention has also been given to lymphatic target- epine released 90% of their drug load in 24 h, as opposeding using nanoparticles. The lymphatic absorption of a to particles containing 7.1% savoxepine, which releaseddrug via the GALT has an advantage over a portal blood their content over 3 weeks [21]. The initial burst release isroute since it avoids any liver pre-systemic metabolism, thought to be caused by poorly entrapped drug, or drugknown as the first pass effect. This could be beneficial for adsorbed onto the outside of the particles. When usinganticancer treatment, mucosal immunity, as well as the polymers, which interact with a drug, like PLGA with apotential for staining the lymph nodes prior to surgery free COOH group and proteins, the burst release is lower[43]. Nanoparticles can also be used to carry antisense and in some cases absent, and drug release is prolongedoligonucleotides and plasmid DNA that can be used to [7,34].treat some forms of cancer and viral infections, as well as a The addition of other polymers to PLA based polymersnew vaccination approach. Antisense oligonucleotides can also be used to control drug release. For example, PEGnormally have poor stability and cannot easily penetrate has been polymerized into a PLA homopolymer creating acells, but are easily encapsulated in nanoparticles [44,45]. PLA-PEG-PLA copolymer [48]. The amount of the drug,

Nanoparticles have also had some success as a new in this case progesterone, released increased with the PEGdelivery vehicle for vaccines. CS-nanoparticles have been content and the molecular weight of the copolymers. Thesuccessful as a nasal vaccine in some animal studies drug release continued to increase as the total molecularproducing significant IgG serum responses and superior weight of the copolymers decreased. The initial burst wasIgA secretory responses when using influenza, pertussis, decreased in the absence of lower molecular weightand diphtheria vaccines [46]. polymers. The content of PEG in the copolymer affected

Attention has been given to the absorption via the the size of the particles as well as the degradation of theintestinal tract because of its availability to the lymphatic polymers. Similar effects were seen with PLGA-mPEGsystem. However, high doses of antibiotics and an- nanoparticles loaded with cisplatin [49]. Consequently ittiparasitics are given to treat gastrointestinal bacteria and would be possible to alter the release rate of the drug byparasites because only 10–15% of the drug administered is changing the amount of PEG in the copolymer as well asabsorbed [35]. The increased mucoadhesivity of nanoparti- the molecular weights of the polymers.


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Biodegradable Nanoparticles for Drug Delivery and Targeting