Biodegradable polymeric nanoparticles as drug delivery devices

Journal of Controlled Release 70(2001)1–20

https://www.360docs.net/doc/aa5215004.html,/locate/jconrel

Review

Biodegradable polymeric nanoparticles as drug delivery devices

a a ,a *Kumaresh S.Soppimath ,Tejraj M.Aminabhavi ,Anandrao R.Kulkarni ,

Walter E.Rudzinski a

Department of Chemistry ,Polymer Research Group ,Karnatak University ,Dharwad 580003,India

Department of Chemistry ,Southwest Texas State University ,San Marcos ,TX 78666,USA

Received 12June 2000;accepted 28September 2000

Abstract

This review presents the most outstanding contributions in the ?eld of biodegradable polymeric nanoparticles used as drug delivery systems.Methods of preparation,drug loading and drug release are covered.The most important ?ndings on surface modi?cation methods as well as surface characterization are covered from 1990through mid-2000.?2001Elsevier Science B.V .All rights reserved.

Keywords :Nanoparticle;Method of preparation;Surface modi?cation;Drug delivery;Drug targeting

1.Introduction

and reduce the toxicity or side effects [2].However,developmental work on liposomes has been limited Over the past few decades,there has been consid-due to inherent problems such as low encapsulation erable interest in developing biodegradable ef?ciency,rapid leakage of water-soluble drug in the nanoparticles (NPs)as effective drug delivery de-presence of blood components and poor storage vices.Various polymers have been used in drug stability.On the other hand,polymeric NPs offer delivery research as they can effectively deliver the some speci?c advantages over liposomes.For in-drug to a target site and thus increase the therapeutic stance,NPs help to increase the stability of drugs/bene?t,while minimizing side effects [1].The proteins and possess useful CR properties.

controlled release (CR)of pharmacologically active Nanoparticles generally vary in size from 10to agents to the speci?c site of action at the therapeu-1000The drug is dissolved,entrapped,encapsu-tically optimal rate and dose regimen has been a lated or attached to a NP matrix and depending upon major goal in designing such devices.Liposomes the method of preparation,nanoparticles,nanos-have been used as potential drug carriers instead of pheres or nanocapsules can be obtained.Nanocap-conventional dosage forms because of their unique sules are vesicular systems in which the drug is advantages which include ability to protect drugs con?ned to a cavity surrounded by a unique polymer from degradation,target the drug to the site of action

membrane,while nanospheres are matrix systems in which the drug is physically and uniformly dis-persed.In recent years,biodegradable polymeric NPs *Corresponding author.Fax:191-836-747-884.

E -mail address :rrist@https://www.360docs.net/doc/aa5215004.html,.in (T.M.Aminabhavi).have attracted considerable attention as potential

2K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

drug delivery devices in view of their applications in 2.1.1.Solvent evaporation method

the CR of drugs,their ability to target particular In this method,the polymer is dissolved in an organs/tissues,as carriers of DNA in gene therapy,organic solvent like dichloromethane,chloroform or and in their ability to deliver proteins,peptides and ethyl acetate.The drug is dissolved or dispersed into genes through a peroral route of administration[3,4].the preformed polymer solution,and this mixture is Some general aspects on micro-and nanoparticles then emulsi?ed into an aqueous solution to make an have been reviewed earlier[1,5–11].A majority of oil(O)in water(W)i.e.,O/W emulsion by using a these reviews have dealt with the NPs of poly(D,L-surfactant/emulsifying agent like gelatin,poly(vinyl lactide),poly(lactic acid)PLA,poly(D,L-glycolide)alcohol),polysorbate-80,poloxamer-188,etc.After PLG,poly(lactide-co-glycolide),PLGA,and poly-the formation of a stable emulsion,the organic (cyanoacrylate)PCA.The present review details the solvent is evaporated either by increasing the tem-latest developments on the above mentioned poly-perature/under pressure or by continuous stirring. mers as well as NPs based on chitosan,gelatin,The effect of process variables on the properties of sodium alginate and other hydrophilic/biodegradable NPs was discussed earlier[26].The W/O/W method polymers.Surface modi?cation aspects are also has also been used to prepare the water-soluble covered in more detail.The PLA,PLG and PLGA drug-loaded NPs[27].Both the above methods use a polymers being tissue-compatible have been used high-speed homogenization or sonication.However, earlier as CR formulations in parentral and implanta-these procedures are good for a laboratory-scale tion drug delivery applications[12–14].In addition,operation,but for a large-scale pilot production, poly(e-caprolactone),PCL,which was?rst reported alternative methods using low-energy emulsi?cation by Pitt et al.[15,16]for the CR of steroids and are required.In this pursuit,following approaches narcotic antagonists as well as to deliver opthalmic have been attempted.

drugs[17],and poly(alkylcyanoacrylate),PACA,are

now being developed as NPs.In addition,less 2.1.2.Spontaneous emulsi?cation/solvent diffusion frequently used polymers like poly(methylidene method

malonate)[18],gelatin[19],chitosan[20]and so-In a modi?ed version of the solvent evaporation dium alginate[21]will also be included in this method[28–30]the water-soluble solvent like ace-review.The important published literature within the tone or methanol along with the water insoluble period1990–2000is critically reviewed.The review organic solvent like dichloromethane or chloroform does not cover the entire literature within this period,were used as an oil phase.Due to the spontaneous but the reader is advised to go to the original diffusion of water-soluble solvent(acetone or metha-literature in order to get more details.nol),an interfacial turbulence is created between two

phases leading to the formation of smaller particles.

As the concentration of water-soluble solvent(ace-

tone)increases,a considerable decrease in particle 2.Preparation of nanoparticles size can be achieved.

Conventionally,NPs have been prepared mainly 2.1.3.Salting out/emulsi?cation–diffusion method by two methods:(i)dispersion of the preformed The methods discussed above require the use of polymers;and(ii)polymerization of https://www.360docs.net/doc/aa5215004.html,anic solvents,which are hazardous to the environ-

ment as well as to the physiological system[31].The

US FDA has speci?ed the residual amount of organic 2.1.Dispersion of preformed polymers solvents in injectable colloidal systems[32,33].In

order to meet these requirements,Allemann and Several methods have been suggested to prepare co-workers have developed two methods of prepar-biodegradable NPs from PLA,PLG,PLGA and ing NPs.The?rst one is a salting-out method[34,35] poly(e-caprolactone)by dispersing the preformed while the second one is the emulsi?cation–solvent polymers[22–25].diffusion technique[36,37].

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–203 2.1.4.Production of NPs using supercritical?uid[44],the solution is charged with the supercritical technology?uid in the precipitation vessel containing solute of Production of NPs with the desired physicochemi-interest in an organic solvent.At high pressures, cal properties to facilitate the targeted drug delivery enough anti-solvent will enter into the liquid phase has been a topic of renewed interest in pharma-so that the solvent power will be lowered and the ceutical industries.Conventional methods like sol-solute precipitates.After precipitation,when the?nal vent evaporation,coacervation and in situ polymeri-operating pressure is reached,the anti-solvent?ows zation often require the use of toxic solvents and/or through the vessel so as to strip the residual solvent. surfactants.Therefore,research efforts have been When the solvent content has been reduced to the directed to develop the environmentally safer en-desired level,the vessel is depressurized and the capsulation methods to produce the drug-loaded solid product is collected.A schematic of the SAS micron and submicron size particles.If solvent method is shown in Fig.1.In a modi?ed version of impurities remain in the drug-loaded NPs,then these the SAS technique[39],the solid of interest is?rst become toxic and may degrade the pharmaceuticals dissolved in a suitable solvent and then this solution within the polymer matrix.Supercritical?uids have is rapidly introduced into the supercritical?uid now became the attractive alternatives because these through a narrow nozzle.The supercritical?uid are environmentally friendly solvents and the method completely extracts the solvent,causing the super-can be pro?tably used to process particles in high critical?uid insoluble solid to precipitate as?ne purity and without any trace amount of the organic particles.This method,also called as gas anti-solvent solvent.Literature on the production of drug-loaded(GAS)technique,has been successfully used to microparticles using supercritical?uids is enormous produce microparticles as well as NPs.

[38–44].However,comparatively much less have

been investigated to produce NPs[39,40].It is 2.1.5.Polymerization methods

beyond the scope of the present review to give an Nanoparticles can also be prepared by polymeri-entire coverage on supercritical?uid technology;we zation of monomers.Poly(alkylcyanoacrylate)s, will discuss only two of the most commonly used PACA,being biodegradable,have been used as tissue methods of producing micro-or nanoparticles.adhesives in surgery since these are well tolerated in In the rapid expansion of supercritical solution vivo[45,46].This has prompted intense research (RESS)method the solute of interest is solubilized in activity to study polymerization reactions.Couvreur a supercritical?uid and the solution is expanded et al.[47,48]reported the production of NPs(|200 through a nozzle.Thus,the solvent power of super-nm diameter)by polymerizing mechanically the critical?uid dramatically decreases and the solute

eventually precipitates.This technique is clean be-

cause the precipitated solute is completely solvent-

free.Unfortunately,most polymers exhibit little or

no solubility in supercritical?uids,thus making the

technique less of practical interest.RESS was very

popular in the late80s and early90s for particle

production of bioerodible drug-loaded polymers like

PLA.A uniform distribution of drug inside the

polymer matrix can be achieved by this method for

low molecular mass(,10000)polymers.However,

the RESS method cannot be used for high molecular

mass polymers due to their limited solubility in

supercritical?uids.For these reasons,much less

information is found in the literature over the past

Fig.1.Schematic diagram of the SAS method:PV1and PV2are 6–7years on this technique[41,43].two volumetric pumps,N is nozzle,P is precipitation vessel,MV In the supercritical anti-solvent(SAS)method is micrometric valve and EV is expansion vessel.

4K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

dispersed methyl or ethyl cyanoacrylate in aqueous

acidic medium in the presence of polysorbate-20as a

surfactant without irradiation or an initiator.Here,

the cyanoacrylic monomer is added to an aqueous

solution of a surface-active agent(polymerization

medium)under vigorous mechanical stirring to poly-

merize alkylcyanoacrylate at ambient temperature.

Drug is dissolved in the polymerization medium

either before the addition of the monomer or at the

end of the polymerization reaction.The NP suspen-

sion is then puri?ed by ultracentrifugation or by

resuspending the particles in an isotonic surfactant-

free medium.The mechanism of polymerization of

PACA monomer is given below.

Polymerization follows the anionic mechanism,Fig. 2.Schematic representation for the production of poly-

(alkylcyanoacrylate)nanoparticles by anion polymerization. since it is initiated in the presence of nucleophilic

222

initiators like OH,CH O and CH COO leading

to the formation of NPs of low molecular mass due[49],but NP production is not possible above a pH to rapid polymerization.Such NPs are degraded very of3.0,probably due to the aggregation and stepwise fast.In order to circumvent this problem and to molecular mass increase at lower pH.Other factors produce higher molecular mass as well as stable that in?uence the formation of NPs include the NPs,polymerization must be carried out in an acidic concentration of monomer and the speed of stirring. medium(pH1.0–3.5).After dispersing the monomer The NPs of PACA have gained wide popularity in in an aqueous acidic medium containing surfactant recent years despite some major drawbacks such as and stabilizer,polymerization is continued for3–4h use of low pH(around2)and cytotoxicity[50].This by increasing the pH of the medium to obtain the has lead to the synthesis of new dialkyl-methylidene desired products.malonic acid ester monomers[51]and the NPs of During polymerization,various stabilizers like poly(methylidenemalonate),PDEMM were prepared, dextran-70,dextran-40,dextran-10,and these were found to be non-biodegradable both -184,etc are added.In addition,some surfac-in vitro and in vivo[52,53].To overcome this tants like polysorbate-20,-40or-80are also used.problem,new derivatives of PDEMM were prepared Particle size and molecular mass of NPs depend i.e.,ethyl-2-ethoxycarbonylmethylenoxycarbonyl upon the type and concentration of the stabilizer acrylate.NPs from these monomers were prepared and/or surfactant used.A schematic representation by the same methods as those adopted for the for the production of poly(alkylcyanoacrylate)NPs is preparation of PACA NPs by anionic polymerization shown in Fig.2.The size and molecular mass of NPs[54].The pH of the polymerization medium critically depend upon the pH of the polymerization medium in?uenced the physicochemical properties of NPs,

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–205 but the minimum sized NPs were produced in the pH preparation method involves ionic gelation,with a range of5.5–6.0when compared to pH2.0and pH mixture of two aqueous phases,of which one 7.6for the PBCA and PDEMM,respectively[55].contains chitosan and a diblock copolymer of ethyl-The reaction scheme for the synthesis of PMM NPs ene oxide(EO),and the other contains a polyanion is given below.sodium tripolyphosphate(TPP).In this method,the

positively charged amino group of chitosan interacts

with the negatively charged TPP.The size(200–

1000nm)and zeta potential(120mv and160mv)

of the NPs produced were modulated by varying the

composition of chitosan with the PEO–PPO diblock

polymer.These NPs have shown good association

with proteins,such as bovine serum albumin,tetanus

toxoid and diptaheria toxoid[63,64],insulin[65]as

well as oligonucleotide[66].

Mao and co-workers[67,68]prepared the DNA–

chitosan NPs by a complex coacervation technique

and used for the oral gene delivery.The complex

coacervation technique was also used to prepare the An attempt was also made to reduce the formation

DNA–gelatin NPs[69].The chitosan NPs are proved of oligomer and to increase the yield of PMM2.1.2.

to be better carriers than the gelatin-based NPs for [56].The process variables like pH,concentration of

loading the immunological and antineoplastic pro-surfactant and monomer concentration have been

teins[70].The chitosan NPs were also produced by monitored to produce NPs with higher molecular

the emulsion coacervation method[71].In this mass[57].Recently,the preparation of ethyl-2

method,chitosan and the drug to be loaded were (ethoxycarbonyl)ethyl methylene malonoate-co-

dissolved in water and water-in-oil emulsion pre-ethylene oxide have been reported[58];these poly-

pared in liquid paraf?n using an emulsifying agent. mers are associated with both the hydrophilic and

To this stable emulsion,another emulsion of NaOH hydrophobic functionalities and they may be better

in liquid paraf?n was added.When in contact with polymers to prepare the long-circulating NPs.The

NaOH,chitosan NPs were produced by the coacerva-hydrophilic NPs,100nm and narrow size dis-

tion of the polymer.Alginate-based NPs were also tribution were prepared by using the aqueous core of

developed and used for the delivery of oligonucleo-the reverse micellar droplets as nanoreactors[59,60].

tides[21,72].

Other polymerization methods were also reported in

Novel biodegradable polyesters,consisting of the literature for the development of acrylic based

short poly(lactone)chains grafted onto poly(vinyl NPs but these are not discussed since they are not

alcohol)(PV A)or charge-modi?ed sulfobutyl-PV A biodegradable.

(SB-PV A)were prepared by bulk melt polymeri-

zation of lactide and glycolide in the presence of 2.1.6.NPs prepared from hydrophilic polymers different core polyols.The modi?ed backbones were Other than the commonly-used synthetic hydro-obtained by reacting the activated PV A with the phobic polymers,active research is now focused on sulfobutyl groups.By carefully adjusting the poly-the preparation of NPs using hydrophilic polymers mer composition,novel class of water-soluble comb-like chitosan,sodium alginate,gelatin,etc.Different like polyesters were prepared.These polymers un-methods have been adopted to prepare NPs from the dergo spontaneous self-assembling to produce NPs, hydrophilic polymers.Several hydrophobic–hydro-which form the stable complexes with a number of philic carriers having limited protein-loading capaci-proteins such as human serum albumin,titanous ty have been prepared by using organic solvents toxoid and cytocrome C.However,the development [61,62].Calvo and coworkers[63–66]have reported of NPs from such polymers does not require the use a method to prepare hydrophilic chitosan NPs.The of solvents or surfactants[73–75].

6K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

3.Drug loading when compared to chromatographic methods,which

require ultracentrifugation.

A successful NP system may be the one,which In addition to adsorption and incorporation,a new has a high loading capacity to reduce the quantity of method of drug loading for the water-soluble drugs the carrier required for administration.Drug loading was proposed by Yoo et al.[85].In this method,drug into the NPs is achieved by two methods:one,by was chemically conjugated into NPs.The conjugated incorporating the drug at the time of NP production doxorubicin–PLGA and doxorubicin-loaded PLGA or secondly,by adsorbing the drug after the forma-NPs were prepared by the spontaneous emulsion–tion of NPs by incubating them in the drug solution.solvent diffusion method.The encapsulation ef-It is thus evident that a large amount of drug can be?ciency of96.6%and3.5%loading of doxorubicin–entrapped by the incorporation method when com-PLGA conjugate have been achieved.For the un-pared to the adsorption[76,77].Adsorption iso-conjugated doxorubicin,these values were,respec-therms for the NP/drug delivery system give vital tively6.7%and0.3%(w/w).

information on the best possible formulation,the

drug binding capacity onto the surface of NPs and

the amount of drug adsorbed.For instance,Couvreur 4.Drug release

et al.[78]reported the adsorption of two antineoplas-

tic drugs viz,dactinimycin and methotrexate onto Drug release from NPs and subsequent biodegra-poly(methylcyanoacrylate)and poly-dation are important for developing the successful (ethylcyanoacrylate).It was observed that methotrex-formulations.The release rates of NPs depend upon: ate was bound to the NPs to a lesser extent than(i)desorption of the surface-bound/adsorbed drug; dactinimycin.Generally,in the case of PACA,it is(ii)diffusion through the NP matrix;(iii)diffusion observed that longer the alkyl chain length higher the(in case of nanocapsules)through the polymer wall; af?nity for the drugs.The capacity of adsorption is(iv)NP matrix erosion;and(v)a combined erosion/ thus related to the hydrophobicity of the polymer and diffusion process.Thus,diffusion and biodegradation the speci?c area of the NPs.In case of entrapment govern the process of drug release.

method,an increase in concentration of the mono-Methods to study the in vitro release are:(i) mer,increases the association of drug,but a reverse side-by-side diffusion cells with arti?cial or bio-trend is observed with the drug concentration in the logical membranes;(ii)dialysis bag diffusion tech-dispersed solution.This observation was further nique;(iii)reverse dialysis sac technique;(iv)ultra-substantiated by Radwan[79]who studied the effect centrifugation;(v)ultra?ltration;or(vi)centrifugal of monomer concentration on%drug loading.These ultra?ltration technique.Despite the continuous ef-results indicate that there is a need to optimize the forts in this direction,there are still some technical amount of monomer available for the drug entrap-dif?culties to study in vitro drug release from NPs ment.[86,87].These are attributed to the separation of NPs The type of surface-active materials and stabilizers from the release media.In order to separate NPs and has an effect on drug loading[80].Chukwu et al.to avoid the tedious and time-consuming separation [81]studied the adsorption of different psycho-techniques,dialysis has been used;here,the suspen-pharmacological agents onto NPs of poly-sion of NPs is added to the dialysis bags/tubes of (isobutylcyanoacrylate),PIBCA,in the pH range different molecular mass cut-off.These bags are then between2.0and7.4.Adsorption of drugs onto NPs incubated in the dissolution medium[88–90]. followed the Langmuir mechanism[82,83].In Another technique involves the use of a diffusion another study[84],a dielectric method was used to cell consisting of donor and acceptor compartments; investigate the adsorption of b-blockers onto PIBCA this technique was used to separate through the NPs.In this method,the NP suspensions were taken arti?cial/biological membranes[91].In this method, into a capacitance cell,exposed to a high-frequency kinetic study was not performed under the perfect ?eld(10MHz)and the complex impedance was sink conditions,because the NPs were not directly measured.This technique is rapid and inexpensive diluted in the release media,but were separated from

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–207 the release media through the membrane.Thus,the drug from the core across the polymeric barrier amount of drug in the release media did not re?ect layer.Hence,theoretically,the drug release should the real amount released.In order to avoid the follow the zero-order kinetics.Calvo et al.[17] enclosure of NPs in the dialysis bag,Leavy and obtained almost the similar release pro?les for Benita[92]used a reverse dialysis technique for the indomethacin from both NPs and nanocapsules.This O/W emulsion.In this method,NPs were added indicated that the polymer coating does not show any directly into the dissolution medium.The same barrier properties for the drug release.The drug technique was adopted by Calvo et al.[17]for the release from the nanocapsule takes place mainly by evaluation of NPs,nanocapsules and nanoemulsions.the partitioning of the drug;however,the main factor However,the method is not very sensitive for controlling the release is the volume of the aqueous studying the rapid release formulations;but can only medium.For instance,with higher dilution of the be used for the release of formulations having the dissolution media,a faster and complete release of release time longer than1h[93].the drug takes place.However,Lu et al.[97] Release pro?les of the drugs from NPs depend reported that the release of bovine serum albumin upon the nature of the delivery system.In the case of from PLA nanocapsule depends upon the molecular a matrix device,drug is uniformly distributed/dis-mass of the polymer,which indicates that the release solved in the matrix and the release occurs by may not occur by partitioning of the drug,but may diffusion or erosion of the matrix.If the diffusion of be due to diffusion across the polymer coating.

the drug is faster than matrix degradation,then the The method of drug incorporation into NPs has mechanism of drug release occurs mainly by diffu-also shown an effect on drug release.Fresta et al. sion,otherwise it depends upon degradation[28].[90]reported a higher burst up to60–70%for the Rapid initial release is attributed to the fraction of NPs loaded with drug by adsorption;here,the burst the drug which is adsorbed or weakly bound to the effect is less and the remaining drug release is quite large surface area of the NPs,than to the drug slow.This study demonstrated that the incorporation incorporated in NPs.Following the dilution of the method has shown better sustained release charac-dissolution media under perfect sink conditions the teristics.When the drug is chemically conjugated drug partition showed an increase due to the immedi-with PLGA NPs,the release took place over25days, ate release https://www.360docs.net/doc/aa5215004.html,ter,an exponential delayed whereas with those NPs containing unconjugated release rate is observed probably due to the drug free drug,a rapid release in about5days occurred diffusion from the matrix[94,95,35,17,28].Release[85].Here,the CR properties have been attributed to in the matrix type of NPs follows the?rst-order chemical degradation of the conjugated PLGA, kinetics[90,79].which permitted water solubilization and subsequent Recently,Polakovic et al.[96]theoretically release of the drug-conjugated PLGA oligomers into studied the release of PLA NPs loaded with varying the medium.In case of drug release from hydrogel amounts(7–32%w/w)of lidocane.Two models NPs,release occurs mainly due to swelling,which were used to study the drug release:(i)by crystal can be controlled by either adding the hydrophilic dissolution and(ii)by diffusion through the polymer functional groups or by monitoring cross-linking of matrix.When the drug loading is,10%(w/w)(the the matrix.

drug is molecularly dispersed),the release kinetics

shows a better?t to the diffusion model.The

existence of lidocane crystals at higher concentration 5.Surface properties of NPs

(.10%)is observed.Since the drug should dissolve

?rst from the crystals and then diffuse from the 5.1.Protein adsorption and phagocytosis of NPs matrix,the overall release mechanism could be

described by the dissolution model.Plasma protein adsorption and phagocytosis of In the case of nanocapsules(reservoir-type drug-NPs is a subject that has been widely studied in delivery systems)the drug core is coated with the recent years.When the NPs are administered in-polymer and the release occurs by diffusion of the travenously they are easily recognized by the body

8K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

immune systems,which are then cleared from the of poly(oxyethylene)in the polymer has drastically circulation.Apart from the size of NPs,their surface decreased the protein adsorption when compared to hydrophobicity determines the amount of adsorbed the pure polyesters.

blood components,mainly proteins(opsonins).These In another study by the same group of researchers will determine the in-vivo fate of NPs[98,99].[105],an attempt was made to correlate the ad-Binding of these opsonins onto the surface of NPs,sorption results with the in-vivo circulation of NPs. called opsonization,acts as a bridge between NPs The di-block and multi-block copolymers of PEG and phagocytes.Hence,for a qualitative and quan-were used as model polymers to show the decrease titative understanding of the interaction of blood in adsorption of proteins;these NPs have shown proteins with NPs,it is necessary to design long-long-circulating properties.The reduced liver uptake circulating NPs by surface modi?cation.of NPs was dependent on the molecular mass and In a study by Allemann et al.[100],it was surface density of PEG.The in-vitro protein rejection reported that when the PLA NPs are incubated in properties of the PEG-coated poly-human plasma and serum,the IgG was found to be(alkylcyanoacrylate)NPs were investigated after the major protein along with albumin,apolipopro-when the freeze fracture of NPs were pre-incubated tein-E,which were adsorbed on the https://www.360docs.net/doc/aa5215004.html,pli-with?brinogen as model blood protein[106].The ment C components(part of immune system used decrease in protein adsorption onto PEG-coated NPs 3

for the recognition of foreign surfaces)were also was evident by2-DPAGE after incubating them in adsorbed onto the surface of NPs after incubation in human serum.The NPs were also long-circulating as the serum reaching the level of antibody IgG.Blunk proved from in-vivo tests.

et al.[101]studied the kinetics of protein adsorption

onto polystyrene NPs and con?rmed that albumin 5.2.Surface characterization methods

and?brinogen were adsorbed in a highly diluted

plasma(0.08and0.8%).However,in the plasma of Many techniques have been developed and used to high concentration(80%),proteins were displaced study the surface modi?cation of NPs.The ef?ciency within seconds or even fractions of a second.The of surface modi?cation can be measured either by study indicated that apolipoproteins A-I,C-III,E and estimating the surface charge,density of the func-J were the major proteins adsorbed onto NPs.tional groups or an increase in surface hydrophilicity.

A two-dimensional polyacrylamide gel electropho-One method used to measure the surface modi-resis(2-DPAGE)was used to estimate quantitatively?cation is to determine zeta potential(j)of the the interaction of plasma proteins with iron oxide aqueous suspension containing NPs.In this method, NPs in the presence of plasma proteins stabilized by the mobility of charged particles is monitored by polysaccharide.Particles incubated in the plasma applying an electrical potential.The zeta potential were separated and were then washed with different values may be positive or negative depending upon washing media.The protein adsorbed on NPs was the nature of the polymer or the material used for then estimated by2-DPAGE.By this,it was found surface modi?cation.The extent of surface hydro-that?brinogen,IgG and albumin were the major philicity can then be predicted from the values of j. plasma proteins adsorbed onto NP surface[102,103].This is a widely used technique to understand the In another study by Luck et al.[104],the interaction surface charges of NPs.

of proteins with NPs was shown to depend upon the Another commonly used technique is electron method of NP preparation.For example,the amount spectroscopy for chemical analysis,ESCA,also of several apolipoproteins in plasma protein adsorp-called X-ray photoelectron spectroscopy(XPS).This tion patterns of the spray-dried PLGA and PLA NPs technique is based on the emission of electrons from were distinctly higher than when compared to the materials,in response to irradiation by photons of adsorption patterns of the particles produced by W/suf?cient energy,to cause ionization of the core-O/W emulsion technique.Some adsorbed proteins level electrons.These electrons are emitted at ener-were found to be speci?c for particles produced by gies characteristic of the atoms from which they are the same method.The presence of hydrophilic chain emitted.Since photons have low penetration energy,

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–209 only those electrons pertaining to atoms at or near action with the surface even at lower concentrations ?

the surface(up to100A)escape and these can be of the protecting polymeric layer.The biological counted.For each atom type,the number of electrons consequences of steric protection of drug carriers emitted is related to the number of atoms of a with the surface-grafted polymers have been dis-particular type of https://www.360docs.net/doc/aa5215004.html,ing this technique,surface cussed and clinical applications of the long-circulat-elemental analysis was performed[107].ing NPs have been studied[10].A theoretical model In another technique,the surface hydrophobicity of repulsion of proteins from the solid substrate was of NPs can be directly measured by hydrophobic proposed by Joen et al.[110].The steric repulsion, interaction chromatography.This technique involves van der Waals attractions and hydrophobic inter-the column chromatography,which is able to sepa-action free energy have been correlated.The model rate materials based on the interaction with a hydro-provides a basis for the prevention of opsonin phobic gel matrix[108].The nanoparticle and the gel deposition.High surface density and long chain-interaction is a function of surface hydrophobicity of lengths of PEG are necessary for low protein ad-NPs.Propyl agarose gel is used as a stationary phase sorption.However,surface density has a greater and elution of NPs can be achieved by using the effect than the chain-length on steric repulsion and phosphate buffer.Eluent samples can be collected van der Waals attraction.

and the optical density measured spectrophotomet-Bazile et al.[111]developed the NPs based on rically at400nm.The gel matrix can then be washed methoxy PEG–PLA i.e.,Me-PEG–PLA and blends to remove the NPs.of PLA with Me-PEG–PLA.These NPs,labeled by

introducing C-labeled PLA in the formulation were 5.3.Methods of surface modi?cation more slowly captured by the cultured THP-1mono-

cytes when compared to pluronic F68-coated PLA Surface modi?cation of biodegradable and long-NPs.The half-life of Me-PEG–PLA NPs was im-circulating polymeric NPs has been achieved mainly proved by a factor of180(360min)when compared by two methods:(i)surface coating with hydrophilic to the uncoated and F68-coated NPs.Even though,a polymers/surfactants;and(ii)development of bio-high amount of radioactivity was located in the heart degradable copolymers with hydrophilic segments.and blood vessels due to particle circulation,in other Some of the widely used surface-coating materials phagocytic organs,radioactivity was found even are:polyethylene glycol(PEG),polyethylene oxide after6h of i.v.administration indicating a delay in (PEO),poloxamer,poloxamine,polysorbate(Tween-phagocytosis.Tobio et al.[112]observed much 80)and lauryl ethers(Brij-35).greater penetration of tetanus toxoid(TT)encapsu-

lated PEG–PLA NPs than PLA NPs after nasal 5.3.1.PEG and PEO-coated NPs administration.A high persisting radioactivity was PEG-coated NPs have received a lot of attention.found in body compartments up to8h after the

125

Gref et al.[109]described the one step method to introduction of I TT-loaded NPs.

prepare the PEG-coated NPs using amphiphilic Gref et al.[113]reported the preparation of blend PEG–polyester diblock copolymer as the starting NPs of PLA with monomethoxy polyoxyethylene material and showed that the protective coating(MPOE)by solvent evaporation method using so-affecting against the phagocytes depends upon den-dium cholate surfactant.The zeta potentials mea-sity and molecular mass of PEG.They also studied sured at various concentrations of NaCl varied from the biodistribution of covalently-attached PEG–255mV for PLA to0mV for blends depending PLGA NPs.The protective effect of PEG on carriers upon the composition of MPOE in the NPs.The zeta like liposomes,NPs and micelles was studied by potential increased with an increasing amount of Torchilin[11]in terms of the statistical behavior of MPOE suggesting that the MPOE chains that are polymers.A mechanism was proposed which as-present on the surface of NPs mask the ionized

sumes that the surface-grafted chains of?exible and COO end-group of PLA.These results are sup-hydrophilic polymers form dense conformational ported by a phagocytosis study on the monocytes. clouds thus preventing other polymers from inter-When MPOE content in the blend is greater than

10K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

2–3%,the MPOE chain adopts a brush-like con?gu-the PEG coated NPs.Peracchia et al.[121]also ration forming a sterically-uncharged barrier,thereby prepared the methoxy PEG cyanoacrylate–hexadecyl reducing the zeta potential and phagocytosis.cyanoacrylate amphiphilic NPs by polymer precipi-Govender et al.[114]examined the drug-encapsu-tation or by solvent evaporation method;the PEG lation characteristics of PLA–PLA NPs using coating was con?rmed by XPS.The particles ex-procaine hydrochloride,a water-soluble drug.The hibited a reduced cytotoxicity and enhanced degra-PLA–PEG NPs were produced by the nano-precipi-dation.NPs prepared in the presence of PEGs have tation technique.The drug-entrapment ef?ciencies of shown some advantages in preventing opsonization these NPs were compared with those of PLGA NPs.and thereby avoiding the MPS uptake[122].This Kim et al.[115]used the ESCA method to evaluate mechanism is explained in Fig.3.

the presence of PEG on the surface of indomethacin-PEO-surface modi?ed systems have received an loaded Me-PEG–PLA NPs.The in-vitro cytotoxicity increased attention in recent years.Jaeghere et al. of these NPs did not show any remarkable cytotox-[123]studied the freeze-dried PEO-surface modi?ed icity against the normal human?broblast cells.NPs as a function of PEO chain length and surface The optimum surface density of PEG on NPs density to avoid the MPS uptake.NPs were produced plays an important role in steric repulsion.These by salting-out method using the blends of PLA and NPs have shown a lower accumulation in the liver,PLA–PEO copolymers.In an effort to study the but the observed high spleen uptake is due to the effect of surface density of PEO on the compliment removal of PEG coating from the surface of NPs,an consumption,Vittaz et al.[124]used the diblock important property in spleen targeting[116].In polymer of PLA and polyethylene oxide(PLA–addition,the distance between PEG chains on the PEO).It was found that as the PEO density on the surface of NPs is critical to avoid the adsorption of surface of the NPs increases,a decrease in compli-plasma proteins.For instance,a decrease in the ment consumption is observed due to steric repulsion distance between PEG chains on the surface from6.2of the surface to proteins.A preliminary study was to 5.1nm drastically decreases the adsorption of made on the synthesis of amphiphilic PEO–PPO–apolipoproteins up to90%.This further con?rms that

the density of hydrophilic segment on the surface of

NPs is important in opsonization.However,any

further decrease in this distance did not show

signi?cant effects on the adsorption of plasma pro-

teins[117].

Peracchia et al.[118]used the emulsi?cation and

solvent evaporation method to prepare the diblock

Me-PEG–PLA copolymeric NPs containing20and

33%of lidocaine.They con?rmed high-density of

the surface PEG by ESCA.However,the size of NPs

produced by the block copolymer was twice as high

as those of PLGA NPs.This was attributed to an

increase in the chain length of PEG.Peracchia et al.

[119,120]reported the chemical coupling of PEG

with PBCA NPs prepared by emulsion polymeri-

zation in the presence of PEG,Me-PEG and(Me)-

PEG.Polymerization was possible only in the pres-

ence of PEG and Me-PEG as hydroxyl group was

Fig.3.Effect of surface PEG density and its conformation on the necessary for polymerization and association of PEG

opsonization process:(A)opsonization takes place when the on the surface of NPs.Higher PEG density was

density is low,(B)opsonization is not possible at higher surface observed on the surface of NPs when Me-PEG was density and(C)when both the end groups of PEG participate in used.A decrease in hydrophobicity was observed for surface modi?cation.

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–2011 PEO block copolymers(Plunoric)and poly(e-cap-uptake pathways are observed for NPs depending rolactone)by bulk polymerization[125].The size of upon their surface characteristics and the rodent the NPs prepared varied from116to196nm,species.Coating was effective in stimulating the depending upon the type of copolymer used.spleen uptake in rats and mice.Spleen uptake of

Fluoresbrite NPs was higher than Estapor NPs, 5.3.2.Poloxamine and poloxamer coated NPs probably due to differences in the surface charac-Poloxamer and poloxamine have been widely used teristics of NPs.

in surface coating studies.Storm et al.[126]pre-Polystyrene-latex nanospheres(PSL-NS,mean sented an overview of the advances made up to1995diameter,85nm)were coated with lactosyl-poly-on the surface modi?cation of NPs to oppose the styrene(LPS,high af?nity to hepatocytes)to evalu-MPS uptake.In a study by Illum and Davis ate their targeting characteristics to hepatocytes and [127,128],poloxamer and poloxamine were used as PSL-NS surfaces[133].Hepatocytes were adhered the coating materials to prepare the long-circulating speci?cally with the LPS-coated dishes made of the NPs of polystyrene and poly(methyl methacrylate).A same materials as PSL-NS.Flow cytometry inves-prolonged circulation time and reduction in liver tigations showed that the LPS-coated?uorescein-uptake in rabbits was found for the poloxamine-isothiocyanate(FITC)–PSL-NS were taken up by coated polystyrene NPs(60nm size)when compared hepatocytes when compared to the noncoated FITC–to the uncoated NPs of the same size.A decrease in PSL-NS as a control.These?ndings indicated that hepatic uptake of about20%for the NPs prepared LPS–PSL-NS could target to hepatocytes.The sur-with poloxamer-188and about40%for the NPs face of LPS on PSL-NS showed higher hydrophil-coated with poloxamer-338was observed.Rabbit icity than PEG-6000,Tween-80,poloxamer-407and 131

experiments with I-labelled polystyrene poloxamer-908,which indicated that LPS–PSL-NS poloxamer-407coated NPs showed the superior may avoid the reticuloendothelial system capture and performance over that of poloxamer-338to avoid the have a long plasma duration after the in-vivo i.v. hepatospleenic uptake.adminstration.Plasma coagulation can be prevented Rudt and Muller[129]studied the uptake of by the addition of0.1%of PV A in LPS–PSL-NS surface modi?ed poloxamine-coated polystyrene NPs solution when LPS–PSL-NS were injected.The and found extremely low levels of uptake for100nm LPS–PSL-NS were the potential hepatocyte targeting size https://www.360docs.net/doc/aa5215004.html,pared to poloxamer,poloxamine was carriers for the injectable formulations.

more effective as a coating material to avoid the liver

capture of rabbits[130].Moghimi and Gray[131]

developed the long-circulating poloxamine-908 5.3.3.Cyclodextrin/carbohydrate coated NPs coated polystyrene NPs(60nm)that are resistant to Carbohydrates were also found to avoid the MPS MPS uptake.The time interval of administration was uptake when coated on the surface of NPs.To avoid important in maintaining the long circulation time.the MPS uptake the coated NPs with carbohydrate Spleen-capture study of the?uorescent-labeled was reported by Cho et al.[134].The NPs of PLA polystyrene NPs coated with poloxamer407or and poly(L-lysine)-grafted-polysaccharide were also poloxamine908was made[132]on two rodent developed for the delivery of DNA[135]and these species viz.,mouse and rat in order to assess the were found to be resistant against self-aggregation effect of coating on their intraspleenic distribution.and nonspeci?c adsorption of the serum proteins. Two?uorescent polystyrene NPs used were:Recently,Duchene et al.[136]used amphiphilic ?

Estapor(FX-010,185nm,Prolabo,France)and cyclodextrin NPs to increase the loading of water-?

Fluoresbrite(Plain YG,260nm,Polysciences,soluble drugs and bioavailability of the poorly water-UK).A?uorimetric investigation indicated that the soluble drugs intended for targeted delivery by the ?

Fluoresbrite NPs were more ef?ciently trapped by oral or parenteral route.In order to further increase ?

the spleen than the Estapor-based NPs in mice and the loading capacity,PIBCA NPs were loaded with rats.Results indicate an increase in the size of NPs the natural or hydroxypropyl cyclodextrins.The ?

after coating the Estapor NPs.Different spleen loading capacity increased with an increase in stabili-

12K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

ty constant of the inclusion drug/parent g-cyclo-biological membrane was studied and an increase in dextrin and with a decrease in water solubility.the permeation of polysorbate-80coated NPs The PIBCA NPs were prepared by the anionic occurred[91].A schematic representation of the polymerization of isobutylcyanoacrylate in0.01M increased drug permeation from the polysorbate-80 HCl containing1%poloxamer-188and in the pres-coated NPs through the biological membrane is ence of cyclodextrins.The size,zeta potential and shown in Fig.4.

cyclodextrin content were in?uenced by the nature of Borchardt et al.[142]studied the uptake of cyclodextrin.The smallest size particles were ob-polysorbate-80coated poly(methyl methacrylate) tained from hydroxypropyl b-cyclodextrin,but the(PMMA)NPs by bovine brain microvessel endo-highest cyclodextrin content was obtained for b-thelial cell monolayers.These NPs showed an in-cyclodextrin.The cyclodextrin NPs or the polymeric creased uptake by the endothelial cells of the BBB. NPs containing cyclodextrin were useful in targeting Troster et al.[143]demonstrated a nine-fold increase the water-insoluble drugs through oral or parentral in the accumulation of radioactivity in the brain area route.The presence of cyclodexrins in these NPs has after i.v.administration of polysorbate-80coated

drastically reduced the surface negativity probably C-PMMA NPs.A recent study by Steiniger et al. due to their hydrophilicity;hence,the cyclodextrin[144]suggested that polysorbate-80coated poly-coated NPs may help in avoiding the MPS.

5.3.4.Polysorbate-coated NPs to penetrate the

blood–brain barrier

Targeting drugs to the brain by crossing the

blood–brain barrier(BBB)has been a challenge.In

this pursuit,many attempts have been made to

develop novel drug delivery systems.BBB is formed

by the tight endothelial cell junctions of the capil-

laries within the brain,which limits the ability of

many drugs to penetrate through the brain tissue in

order to enter the central nervous system(CNS).It is

known that many regulators of the brain functions

such as cytokines,transferrin,enkephalins,endor-

phins or delta sleep inducing peptides pass through

BBB from the vessels into brain[137,138]as well as

some excitatory and depressant amino acids,pene-

trate poorly through BBB.The poor BBB penetration

of such substances makes the problem of drug

targeting to the brain highly pertinent.However,the

surface modi?ed NPs have been used to deliver the

anti-in?ammatory drugs acting on the CNS because

these can pass through BBB[139,140].

The mechanism of enhancement of drug transport

from the coated NPs through BBB is due to the

number of mechanisms:(i)by binding the NPs to the

inner endothelial lining of the brain capillaries and

subsequently,particles deliver drugs to the brain by

providing a large concentration gradient,thus en-

hancing the passive diffusion;(ii)brain endothelial

Fig.4.The schematic representation of the drug uptake through uptake by phagocytosis[141].The effect of surfac-biological membrane from(A)free drug and(B)polysorbate-80 tant coated NPs on drug permeation across the coated nanoparticle bound drug[91,141].

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–2013 (alkylcyanoacrylate)NPs are superior over the un-also reported an increased analgesic activity of coated NPs to transport drugs across BBB.dalargin-loaded PBCA NPs coated with polysorbate-Recently,investigations have been carried out80when administered in mice.In a further study, [145]with PBCA NPs as well as with the non-Alyautdin et al.[148]found that BBB crossing was biodegradable polystyrene(PS)NPs(200nm in observed for low molecular mass and polar hydro-diameter)to study the transport of analgesic peptide,philic drug like tuborcurarin after loading it into dalargin to the brain.Its entry into the CNS of the polysorbate-80coated PBCA NPs.An in-vivo per-mice was evaluated using the tail-?ick procedure.fused rat brain was used along with the simultaneous Locomotor activity measurements were performed to recording of an electroencephalogram(EEG)since compare the toxicity of NPs.BBB permeability of the drug induces epileptic form seizures.An i.v. PBCA NPs was studied in-vitro using a co-culture of injection of the NPs demonstrated the appearance of bovine brain capillary endothelial cells and rat EEG seizures5min after the administration. astrocytes.Dalargin associated with PBCA NPs and Schroeder et al.[149]studied the transport of polysorbate-80induced a potent and prolonged anal-dalargin,kytorphin(centrally-acting analgesics)and gesia,which was not observed by using polystyrene amitriptyline(antidipressant)-loaded PBCA NPs NPs,but not using the PBCA NPs.Locomotor coated with polysorbate-80across the BBB.In-vivo activity dramatically decreased in the mice dosed analgesic activity carried out in mice showed a with PBCA NPs,but not with the polystyrene NPs.drastic enhancement of analgesia for the drug-loaded The in-vitro and in-vivo results suggested that the NPs coated with polysorbate-80.The amitriptylin PBCA NPs induce a nonspeci?c opening of the BBB concentration in the brain increased,but the con-in the presence of polysorbate-80allowing the centration in serum decreased for dextran-stabilized transport of dalargin into the CNS.Although polysorbate-80coated NPs.These results indicate polysorbate-80coated PBCA NPs are useful in that the surface modi?cation of NPs by coating with increasing the penetration of drugs into the CNS,polysorbate-80is effective in drug delivery through potential therapeutic applications are limited because BBB.

of the high systemic NP concentration needed to

deliver drugs to the CNS.

In an effort to deliver anticancer drugs to the brain 6.Delivery of proteins and peptides using NPs using NPs,Gulyaev et al.[146]demonstrated that

the brain concentration of systemically administered Peptide drugs are attracting,as their role in doxorubicin was enhanced by more than60-fold by physiopathology is better understood and because of binding it to polysorbate-80coated PBCA NPs.the progress made in biotechnology and bioengineer-Doxorubicin was selected as a model drug due to its ing.Particularly,the development of DNA-recombi-potent antitumor activity and because the drug is not nant technology has made these compounds available able to cross the BBB by i.v.injection.Polysorbate-on large scale than in the past.However,the use of 80coated NPs reached the brain intact and released peptide in medicine is partly limited by their rapid the drug after endocytosis by the brain blood vessel degradation by proteolytic enzymes in the gastroin-endothelial cells.High brain concentrations achieved testinal tract;thus,they need to be administered in this study suggested a signi?cant improvement in through the parentral route.The biological half-life the treatment of brain tumors.of peptides is short and needs frequent administra-Alyautdin et al.[147]studied the ef?ciency of tions.On the other hand,their transport across polysorbate-80coated PBCA NPs in crossing BBB biological barriers is poor due to poor diffusivity and to deliver the water-insoluble analgesic drug,loper-lower partition coef?cients.In this pursuit,the mide,in mice.Intravenous injection of the particulate biodegradable delivery systems have been polysorbate-80coated NPs resulted in a long and proposed for the safe and controlled parentral ad-signi?cant analgesic effect,which was measured by ministration of peptides[150].

the tail?ick method,while the uncoated NPs were Proteins and peptides are unstable in PLGA unable to produce analgesia.Alyautdin et al.[141]because of the hydrophobicity and acidity of PLGA

14K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

[151].Another problem is the fast burst release of release insulin from the nanospheres over a span of6 protein drugs from the PLGA matrices.In order to h.The 1.6%zinc insulin in PLGA with fumaric circumvent these problems,different approaches anhydride oligomer and iron oxide additives was have been explored to modify the properties of shown to be active orally and was able to control the PLGA matrices by using the hydrogel NPs plasma glucose levels.A number of properties of this [152,153].This has prompted the development of formulation,including size,release kinetics,bioadhe-novel protein delivery systems.In these studies,siveness and ability to traverse the gastrointestinal bovine serum albumin(BSA)was encapsulated?rst epithelium have contributed to its oral ef?cacy.

in PV A NPs,which were then loaded into PLGA In recent years,greater advances have been made microspheres using the phase separation method.The particularly by the research group of Professor protein loaded PLGA–PV A composite NPs were Robert Langer at MIT(USA)on the development of then characterized and were having the nonporous gene delivery systems.However,a discussion on surface to release BSA for over2months.In a recent these systems is beyond the scope of this review. study by Gasper et al.[154],it was shown that the

presence of end carboxyl group in PLGA resulted in

a high protein loading of up to4.86mass%and the7.Conclusions

release continued for about20days.On the other

hand,the presence of esteri?ed carboxyl end groups The use of biodegradable polymers for the CR of in PLGA led to a lower loading(2.65mass%)of therapeutic agents is now well established.Although proteins and a release of up to14days.currently there are only a small number of commer-The release kinetics and in-vivo effects of NPs cially available products that utilize this technology

containing PGDF-Receptor b(PDGFR b)tyrphostin(e.g.,Lupron Depot),these polymers have great inhibitor,AG-1295,AG-1295-loaded PLA NPs were utility for the CR of several drugs like vaccines, prepared by the spontaneous emulsi?cation/solvent human growth hormone,insulin,anti-tumor agents, displacement technique[155].The in-vitro release contraceptives and also vaccines.Long circulation of rate and the impact of drug/polymer ratio on the size drugs in the body is the key in successful drug of NPs were determined.It was shown that by delivery and drug targeting to the site of action. modulating the formulation variables,release kinet-Many polymeric NPs have been developed for this ics and particle size were tailor-made to address the purpose.Certainly,surface modi?cation is useful in clinical needs.A novel pulmonary delivery system of achieving these goals.From the polymer chemistry PLGA nanosphere(400nm size)encapsulating the viewpoint,it is important to synthesize newer poly-physiologically active peptide was developed by mers and copolymers to match the hydrophilic and Kawashima et al.[156].These were prepared by hydrophobic properties.Production of NPs using the using the modi?ed emulsion solvent diffusion meth-environmentally friendly processes like supercritical od in water.The aqueous dispersions of PLGA?uids is quite a promising area of research to nanospheres administered pulmonarily to guinea pig develop the products that are free from the unwanted via nebulization reduced signi?cantly the blood toxic residual solvents.Although many important glucose level for over48h when compared to the goals have been reached in achieving stabilization of nebulized aqueous solution of insulin as a reference.drugs in circulation,yet more investigations are About85%of the drug was released from the needed to develop the newer materials in this area. nanospheres during the initial burst,followed by a

prolonged release of the remaining drug for few

hours in saline solution at378C.Acknowledgements

Zinc insulin was successfully encapsulated in

various polyester and polyanhydride nanosphere We immensely thank the Council of Scienti?c and formulations using the phase inversion nanoencapsu-Industrial Research,New Delhi,India[Grant[ lation technique[157].The encapsulated insulin80(0025)97/EMR-II]for a major?nancial support maintained its biological activity and was able to of this study.Dr.Walter E.Rudzinski thanks the

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–2015

[17]P.Calvo,J.L.Vila-Jato,M.J.Alonso,Comparative in vitro Southwest Texas State University,San Marcos for a

evaluation of several colloidal systems,nanoparticles, research enhancement grant.We also thank Dr.M.I.

nanocapsules and nanoemulsions as ocular drug carriers,J. Aralaguppi for his assistance.Pharm.Sci.85(1996)530–536.

[18]F.Lescure,C.Seguin,P.Breon,P.Bourrinet,D.Roy,P.

Couvreur,Preparation and characterization of novel poly-

(methylidene malonate 2.1.2.)-made nanoparticles,Pharm. References

Res.9(1994)1270–1277.

[19]C.A.Farrugia,M.J.Grover,Gelatin behavior in dilute [1]J.Kreuter,Nanoparticles,in:J.Kreuter(Ed.),Colloidal Drug aqueous solutions:Designing a nanoparticulate formulations,

Delivery Systems,Marcel Dekker,New York,1994,pp.J.Pharm.Pharmacol.51(1999)643–649.

219–342.[20]R.Fernandez-Urrusuno,P.Calvo,C.Remunan-Lopez,J.L.

[2]C.G.Knight(Ed.),Liposomes From Physical Structure To Villa-Jato,M.J.Alonso,Enhancement of nasal absorption of

Therapeutic Applications,Elsevier,Amsterdam,1981.insulin using chitosan nanopartilces,Pharm.Res.16(1999) [3]https://www.360docs.net/doc/aa5215004.html,nger,Biomaterials in drug delivery and tissue engineer-1576–1581.

ing:One laboratory’s experience,Acc.Chem.Res.33(2000)[21]I.C.Aynie,C.Vauthier,E.Fattal,M.Foulquier,P.Couvreur, 94–101.Alginate nanoparticles as a novel carrier for antisense [4]https://www.360docs.net/doc/aa5215004.html,nza,https://www.360docs.net/doc/aa5215004.html,nger,W.L.Chick,Principles of Tissue oligonucleotide,in:J.E.Diederichs,R.Muler(Eds.),Future

Engineering,in:Academic Press,Austin,TX,1997,pp.Strategies of Drug Delivery With Particulate Systems,Med-405–427.pharm Scienti?c Publisher,Stuttgart,1998,pp.5–10. [5]L.B,Peppas,Recent advances on the use of biodegradable[22]C.Vauthier,S.Beanabbou,G.Spenlehauer,M.Veillard,P.

microparticles and nanoparticles in the controlled drug Couvreur,Methodology of ultradispersed polymer system, delivery,Int.J.Pharm.116(1995)1–9.S.T.P.Pharm.Sci.1(1991)109–116.

[6]A.Zimmer,J.Kreuter,Microspheres and nanoparticles used[23]E.Allemann,R.Gurnay,E.Doelker,Drug-loaded nanopar-

in ocular drug delivery systems,Adv.Drug.Deliv.Rev.16ticles-Preparation methods and drug targeting issues,Eur.J.

(1995)61–73.Pharm.39(1993)173–191.

[7]P.Couvreur,L.Grislain,V.Lenaerts,F.Brasseur,P.Guiot,[24]P.Couvreur, C.Dubernet, F.Puisieux,Controlled drug

in:P.Guiot,P.Couvreur(Eds.),Polymeric Nanoparticles and delivery with nanoparticles:Current possibilities and future Microspheres,CRC Press,Boca Raton,Florida,1986.trends,Eur.J.Pharm.41(1995)2–13.

[8]D.F.Raney,Biomimetic transport,rational drug delivery,[25]M.J.Alonso,Nanoparticulate drug carrier technology,in:C.

Biochem.Pharmacol.59(2000)105–114.Cohen,H.Bernstein(Eds.),Microparticulte Systems For the [9]K.E.Uhrich,S.M.Cannizzaro,https://www.360docs.net/doc/aa5215004.html,nger,K.M.Shakes-Delivery of Proteins and Vaccines,Marcel Dekker,New

sheff,Polymeric systems for controlled drug release,Chem.York,1996,pp.203–242.

Rev.99(1999)3181–3198.[26]P.D.Scholes,A.G.A.Coombes,L.Illum,S.S.Davis,M.Vert, [10]C.Monfardini,F.M.Veronese,Stabilization of substances in M.C.Davies,The preparation of sub-500nm poly(lactide-

circulation,Bioconjug.Chem.9(1998)418–450.co-glycolide)microspheres for site-speci?c drug delivery,J.

[11]V.P.Torchilin,Polymer-coated long-circulating microparticu-Control.Rel.25(1993)145–153.

late pharmaceuticals,J.Microencapsul.15(1998)1–19.[27]M.F.Zambaux, F.Bonneaux,R.Gref,P.Maincent, E.

[12]D.L.Wise,T.D.Fellman,J.E.Sanderson,R.L.Wentworth,Dellacherie,M.J.Alonso,https://www.360docs.net/doc/aa5215004.html,brude,C.Vigneron,In?uence

Lactide/glycolide acid polymers,in:G.Geregoriadis(Ed.),of experimental parameters on the characteristics of poly(lac-Drug Carriers in Biology and Medicine,Academic,London,tic acid)nanoparticles prepared by double emulsion method, 1979,pp.237–270.J.Control.Rel.50(1998)31–40.

[13]T.M.Jackanicz,H.A.Nash,D.L.Wise,J.B.Gregory,Poly[28]T.Niwa,H.Takeuchi,T.Hino,N.Kunou,Y.Kawashima,

lactic acid as a biodegradable carrier for contraceptive Preparations of biodegradable nanospheres of water-soluble steroids,Contraception8(1973)227–234.and insoluble drugs with D,L-lactide/glycolide copolymer by [14]L.C.Andersson, D.L.Wise,J.F.Howes,An injectable a novel spontaneous emulsi?cation solvent diffusion method

sustained release fertility control system,Contraception13and the drug release behavior,J.Control.Rel.25(1993) (1976)375–384.89–98.

[15]C.G.Pitt,M.M.Gratzi, A.R.Jeffcot,R.Zweidinger, A.[29]P.Wehrle, B.Magenheim,S.Benita,The In?uence of

Schindler,Sustained release drug delivery systems II:factors process parameters on the PLA nanoparticle size distribution affecting release rate for poly(e-caprolactone)and related evaluated by means of factorial design,J.Pharm.Biopharm.

biodegradable polyesters,J.Pharm.Sci.68(1979)1534–41(1995)19–26.

1538.[30]H.Murakami,H.Yoshino,M.Mizobe,M.Kobayashi,H.

[16]C.G.Pitt,T.A.Marks, A.Schindler,Biodegradable drug Takeuchi,Y.Kawashima,Preparation of poly(D,L-lactide-co-

delivery systems based on aliphatic polyesters:application to glycolide)latex for surface modifying material by a double contraceptives and narcotic antagonists,in:R.Baker(Ed.),coacervation method,Proced.Intern.Symp.Control.Rel.

Controlled Release of Bioactive Materials,Academic,New Bioact.Mater.23(1996)361–362.

York,1980,pp.19–43.[31]D.T.Birnbaum,J.D.Kosmala,D.B.Henthorn,L.B.Peppas,

16K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

Controlled release of b-estradiol from PLAGA microparti-in:R.S.Manly(Ed.),Adhesion in Biological Systems, cles:The effect of organic phase solvent on encapsulation Academic,New York,1970,pp.185–199.

and release,J.Control.Rel.65(2000)375–387.[47]P.Couvreur,B.Kante,M.Roland,Les perspectives d’utilisa-[32]R.Bodmeier,J.W.McGinity,Solvent selection in the prepa-′

tion des formes microdisperses comme vecteurs intracel-ration of poly(D,L-lactide)microspheres prepared by the lulaires,Pharm.Acta Helv.53(1978)341–347.

solvent evaporation method,Int.J.Pharm.43(1988)179–[48]P.Couvreur,B.Kante,M.Roland,P.Goit,P.Bauduin,P.

186.Speiser,Polycyanoacrylate nanocapsules as potential [33]R.Arshaday,Preparation of porous and nonporous bio-lysosomotropic carriers:preparation,morphology and sorp-

degradable polymeric hollow microspheres,J.Control.Rel.tive properties,J.Pharm.Pharmacol.31(1979)331–332.

17(1991)1–22.

[49]N.Behan,C.Birkinshaw,N.Clarke,A study of the factors [34]E.Allemann,R.Gurnay,E.Doelker,Preparation of aqueous

affecting the formation of poly(n-butylcyanoacrylate) polymeric nanodispersions by a reversible salting-out pro-

nanoparticles,Proced.Intern.Symp.Control.Rel.Bioact.

cess:in?uence of process parameters on particle size,Int.J.

Mater.26(1999)1134–1135.

Pharm.87(1992)247–253.

[50]C.Lherm,R.H.Muller, F.Puiseux,P.Couvreur, [35]E.Allemann,J.C.Leroux,R.Gurnay,E.Doelker,Invitro

Alkylcynoacrylate drug carriers:II.Cytotoxicity of extended-release properties of drug-loaded poly(D,L-lactic)

cyanoacrylate nanoparticles with different alkyl chain length, acid nanoparticles produced by a salting-out procedure,

Int.J.Pharm.84(1992)13–22.

Pharm.Res.10(1993)1732–1737.

[51]J.-L.De Keyser,C.J.C.De Cock,J.H.Poupaert,P.Dumont, [36]J.C.Leroux, E.Allemann, E.Doelker,R.Gurnay,New

1414

Synthesis of C labeled acrylic derivatives:diethyl[3-C] approach for the preparation of nanoparticles by an emulsi?-

methylidenemalonate and isobutyl[3-C]cyanoacrylate,J.

cation–diffusion method,Eur.J.Pharm.Biopharm.41

https://www.360docs.net/doc/aa5215004.html,p.Radiopharm.27(1989)909–916.

(1995)14–18.

[52]J.-L.De Keyser,J.H.Poupaert,P.Dumont,Poly(diethyl [37]G.D.Quintanar,Q.A.Ganem, E.Allemann,H.Fessi, E.

methylidenemalonate)nanoparticles as a potential drug car-Doelker,In?uence of the stabilizer coating layer on the

rier:preparation,distribution and elimination after intraven-puri?cation and freeze drying of poly(DL-lactic acid)

nanoparticles prepared by emulsi?cation-diffusion technique,ous and peroral administration to mice,J.Pharm.Sci.80 J.Microencapsulation15(1998)107–119.(1991)67–70.

[38]J.W.Tom,P.G.Debenedetti,Particle formation with super-[53]T.K.M.Mabela,J.H.Poupaert,P.Dumont, A.Haemers,

critical?uids—a review,J.Aerosol Sci.22(1991)555–Development of poly(dialkyl methylidenemalonate) 584.nanoparticles as drug carriers,Int.J.Pharm.92(1993) [39]T.W.Randolph,A.D.Randolph,M.Mebes,S.Yeung,Sub-71–79.

micron-sized biodegradable particles of poly(L-lactic acid)[54]P.Breton, D.Roy,L.Marchal-Heussler, C.Seguin,P.

via the gas antisolvent spray precipitation process,Biotech-Couvreur, F.Lescure,New poly(methylidene malonate nol.Prog.9(1993)429–435. 2.1.2)nanoparticles:Recent developments,in:G.Gre-[40]L.Benedetti,A.Bertucco,M.Lora,P.Pallado,in:Atti del38goriadis, B.McCormack,G.Poste(Eds.),Targeting of

Congresso I?uidi Supercriticai e le Loro Applicazioni,I.Drugs,Advances in System Constructs,Vol.4,Plenum Press, Kikic and P.Alessi(Eds.),Trieste,1995,p.221.New York,1994,pp.161–172.

[41]K.Mishima,K.Matsuyama, D.Tanabe,S.Yamauchi,[55]F.Lescure,C.Seguin,P.Breton,P.Bourrinet,D.Roy,P.

Microencapsulation of proteins by rapid expansion of super-Couvreur,Preparation and charecterization of novel poly-critical solution with a nonsolvent,AIChE J.46(2000)(methylidene malonoate2.1.2.)-made nanoparticles,Pharm.

857–865.Res.11(1994)1270–1277.

[42]J.W.Tom,P.G.Debenedetti,Formation of bioerodiable[56]P.Breton,X.Guillon,D.Roy,F.Lescure,G.Riess,N.Bru,

polymeric microspheres and microparticles by rapid expan- C.Roques-Carmes,Physico-chemical characterization,prep-sion of supercritical solution,Biotechnol.Prog.7(1991)aration and performance of poly(methylidene malonate2.1.2) 403–411.nanoparticles,Biomaterials19(1998)271–281.

[43]J.W.Tom,P.G.Debenedetti,R.Jerome,Preparation of[57]N.Bru-Magniez,X.Guillon,P.Breton,P.Couvreur, F.

poly(L-lactic acid)and composite poly(L-lactic acid)-pyrene Lescure,C.Roques-Carmes,G.Riess,Method for preparing by rapid expansion of supercritical solution,J.Supercrit.malonate methylidene nanoparticles,nanoparticles optionally Fluids7(1994)9–29.containing one or several biologically active molecules, [44]S.Mawson,K.P.Johnston,https://www.360docs.net/doc/aa5215004.html,bes,J.M.DeSimone,International Patent PCT WO98/18455,1998.

Formation of poly(1,1,2,2-tetrahydroper?uorodecyl acrylate)[58]N.Bru-Magniez,https://www.360docs.net/doc/aa5215004.html,rras,G.Riess,P.Breton,P.Couvreur, submicron?bers and particles from supercritical carbon C.Roques-Carmes,Novel surfactant copolymers based on dioxide solutions,Macromolecules28(1994)3182–3191.methylidene malonate,International Patent PCT WO99/ [45]K.C.Pani,G.Gladieux,G.Brandes,R.K.Kulkarni, F.38898,1999.

Leonarda,The degradation of n-butyl alpha-cyanoacrylate[59]A.N.Mitra,P.K.Ghosh,S.Sahoo,pH and thermoresponsive tissue adhesive,II,Surgery63(1968)481–489.hydrogel nanoparticles,Proc.Intern.Symp.Control.Rel.

[46]F.Leonarda,Hemostatic application of alpha cyanoacrylates:Bioact.Mater.25(1998)234–235.

bonding mechanism and physiological degradation of bonds,[60]A.N.Mitra,P.K.Ghosh,S.Sahoo,Long circulating RES

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–2017 evading hydrophilic nanoparticles,Proc.Intern.Symp.Con-dable comb polyesters,Proc.Intern.Symp.Control.Release.

Bioact.Mater.26(1999)159–160.

trol.Rel.Bioact Mater.25(1998)168–169.

[75]M.A.Breitenbach,W.Kamm,K.-D.Hungere,E.Hund,T.

[61]R.Gref,Y.Minamitake,M.T.Peracchia,V.Trubetskoy,V.P.

Kissel,Oral and nasal administration of tetanus toxoid Torchilin,https://www.360docs.net/doc/aa5215004.html,nger,Biodegradable long circulating poly-

loaded nanoparticles consisting of novel charged biodegra-meric nanospheres,Science18(1994)1600–1603.

dable polyesters for mucosal vaccination,Proc.Intern.Symp.

[62]M.Amiji,K.Park,in:S.W.Shalaby,Y.Ikada,https://www.360docs.net/doc/aa5215004.html,nger,J.

Control.Release.Bioact.Mater.26(1999)348–349.

Williams,(Eds.),Polymers of Biological Signi?cance,ACS

[76]M.J.Alenso,C.Losa,P.Calvo,J.L.Vila-Jato,Approaches to

Symp.Ser.540,Washington,DC,1994.

improve the association of amikacin sulphate to poly-[63]P.Calvo,C.Remunan-Lopez,J.L.Vila-Jato,M.J.Alonso,

(cyanoacrylate)nanoparticles,Int.J.Pharm.68(1991)69–Novel hydrophilic chitosan and chitosan/polyethylene oxide

76.

nanoparticles as protein carriers,J.Appl.Polym.Sci.63

[77]M.Ueda,A.Iwara,J.Kreuter,In?uence of the preparation

(1997)125–132.methods on the drying release behavior of loperamide-loaded [64]P.Calvo,C.Remunan-Lopez,J.L.Vila-Jato,M.J.Alonso,nanoparticles,J.Microencapsulation15(1998)361–372.

Chitosan and chitosan/ethylene oxide–propylene oxide[78]P.Couvreur,B.Kante,M.Roland,P.Speiser,Adsorption of block copolymer nanoparticles as novel carriers for proteins antineoplastic drugs to polyalkylcyanoacrylate nanoparticles and vaccines,Pharm.Res.14(1997)1431–1436.and their release in calf serum,J.Pharm.Sci.68(1979) [65]R.Fernandez-urrusuno,P.Calvo,C.Remunan-Lopez,J.L.1521–1523.

Vila-Jato,M.J.Alonso,Enhancement of nasal absorption of[79]M.A.Radwan,In vitro evaluation of poly-insulin using chitosan nanoparticles,Pharm.Res.16(1999)isobutylcyanoacrylate nanoparticles as a controlled drug 1576–1591.carrier for theophylline,Drug Dev.Ind.Pharm.21(1995) [66]P.Calvo A.S.Boughaba,M.Appel,E.Fattal,M.J.Alonso,P.2371–2375.

Couvreur,Oligonucleotide–chitosan nanoparticles as new[80]M.A.Egea, F.Gamisani,J.Valero,M.E.Garcia,M.L.

gene therapy vector,Proc.2nd World Meeting APGI/APV Garcia,Entrapment of cisplatin into biodegradable poly-Paris,1998,pp.1111–1112.alkylcyanoacrylate nanoparticles,Farmaco49(1994)211–[67]H.-Q.Mao,K.Ray,S.M.Walsh,J.T.August,K.W.Leong,217.

DNA–chitosan nanoparticles for the gene delivery,Proc.[81]K.Chukwu,U.Ishroder,P.Sommerfeld,B.A.Sabel,Load-Intern.Symp.Control.Release.Bioact.Mater.23(1996)ing some psychopharmacologic agents onto poly(butyl-401–402.cyanoacrylate)nanoparticles-a means of targeting to the [68]K.Ray,H.-Q.Mao,K.Y.Lin,S.-K.Huang,K.W.Leong,brain and improving therapeutic ef?ciency,Proced.Intern.

Oral immunization with DNA–chitosan nanoparticles,Proc.Symp.Control.Rel.Bioact.Mater.26(1999)1148–1149.

Intern.Symp.Control.Release.Bioact.Mater.26(1999)[82]J.Vora,N.Bapat,M.Boroujerdi,Investigation of the relative 348–349.af?nity of doxorubicin for neutral and negatively charged [69]V.L.Truong-Le,H.Mao,S.Walsh,K.W.Leong,J.T.August,particulate carriers,Drug Dev.Ind.Pharm.19(1993)759–

Delivery of DNA vaccine using gelatin–DNA nanoparticles,771.

Proc.Intern.Symp.Control.Rel.Bioact.Mater.24(1997)[83]J.Martin,P.Macchi,M.Hoffman,P.Maincent,Study of the 39–40.binding mechanisms of drugs onto polyalkylcyanoacrylate [70]X.-X.Tian,M.J.Groves,Formulation and biological activity nanoparticles,J.Pharm.Belg.49(1994)498–508.

` of antineoplastic proteoglycans derived from Mycobacterium[84]E.Benoit,O.Prot,P.Maincent,J.Bessiere,Adsorption of vaccae in chitosan nanoparticles,J.Pharm.Pharmacol.51beta-blocker onto polyisobutylcyanoacrylate nanoparticles (1999)151–157.measured by depletion and dielectric method,Pharm.Res.11 [71]H.Tokumitsu,H.Ichikawa,Y.Fuukumori,Chitosan–(1994)585–588.

gadopenteic acid complex nanoparticles for gadolinium[85]H.S.Yoo,J.E.Oh,K.H.Lee,T.G.Park,Biodegradable neutron-capture therapy of cancer:preparation by novel nanoparticles containing doxorubicin–PLGA conjugate for emulsion–droplet coalescence technique and characteriza-sustained release,Pharm.Res.16(1999)1114–1118.

tion,Pharm.Res.16(1999)1830–1835.[86]C.Washington,Drug release from microdisperse systems.A [72]C.Vautheir,I.Aynie,P.Couvreur,E.Fattal,Pharmacokinetic critical review,Int.J.Pharm.58(1990)1–12.

and tissue disposition of oligonucleotide associated with[87]B.Magenheim,S.Benita,Nanoparticle characterization:a alginate nanoparticles,https://www.360docs.net/doc/aa5215004.html,prehensive physicochemical approach,S.T.P.Pharm.Sci.

Bioact.Mater.25(1998)228–229.1(1991)221–224.

[73]T.Jung,A.Breitenbach,T.Kissel,Sulfobutylated poly(vinyl[88]M.S.El-Samaligly,P.Rohdewald,H.A.Mohmoud,Poly-

alcohol)-graft-poly(lactide-co-glycolide)facilitate the prepa-alkylcyanoacrylate nanocapsules,J.Pharm.Pharmacol.38 ration of small negatively charged biodegradable nanos-(1986)216–218.

pheres for protein delivery,J.Control.Rel.67(2000)157–[89]A.M.LeRay,M.Vert,J.C.Gautier,J.P.Benoit,End-chain 169.radiolabeling and in vitro stability studies of radiolabeled [74]A.Breitenbach,G.Nykamp,T.Kissel,Self-assembling poly(hydroxy)nanoparticles,J.Pharm.Sci.83(1994)845–

colloidal carriers for protein delivery:nanoparticulate poly-851.

mer protein conjugates with novel water soluble biodegra-[90]M.Fresta,G.Puglisi,G.Giammona,G.Cavallaro,N.

18K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

¨Micali,P.M.Furneri,Pe?oxacin mesilate-and o?oxacin-[105]R.Gref,A.Domb,P.Quellec,T.Blunk,R.H.Muller,J.M.

loaded polyethylcyanoacrylate nanoparticles;characterization Verbavatz,https://www.360docs.net/doc/aa5215004.html,nger,The controlled intravenous delivery of the colloidal drug carrier formulation,J.Pharm.Sci.84of drugs using PEG-coated sterically stabilized nanos-(1995)895–901.pheres,Adv.Drug Deliv.Rev.16(1995)215–233. [91]G.Cavallaro,M.Fresta,G.Giammona,G.Puglisi,A.Villari,[106]M.T.Peracchia,S.Harnisch,H.Pinto-Alphandary, A.

¨¨Entrapment of b-lactams antibiotics in poly-Gulik,J.C.Dedieu,D.Desmaele,J.d’Angelo,R.H.Muller, ethylcyanoacrylate nanoparticles:studies on the possible in P.Couvreur,Visualization of in vitro protein-rejecting

?vivo application of this colloidal delivery system,Int.J.properties of PEGylated stealth polycyanoacrylate Pharm.111(1994)31–41.nanoparticles,Biomaterials20(1999)1269–1275. [92]M.Y.Leavy,S.Benita,Drug release from submicron O/W[107]B.D.Ratner,A.B.Johnston,T.J.Lenk,Biomaterial surface,

emulsion:A new in vitro kinetic evaluation model,Int.J.J.Biomed.Mat.Res.Appl.Biomat.21(1987)59–90.

Pharm.66(1990)29–37.[108]H.Carstensen,B.W.Muller,R.H.Muller,Adsorption of [93]R.Jalil,J.R.Nixon,Biodegradable poly(lactic acid)and ethoxylated surfactants on nanoparticles.I.Characterization

poly(lactide-co-glycolide)microcapsules:problems associ-by hydrophilic interaction chromatography,Int.J.Pharm.

ated with preparative techniques and release properties,J.67(1991)29–37.

Microencapsul.7(1990)297–325.[109]R.Gref,Y.Minamitake,M.T.Peracchia,V.Trubetskoy,R.

[94]B.Magenheim,M.Y.Levy,S.Benita,A new in vitro Langer,Biodegradable long-circulating polymeric

technique for the evaluation of drug release pro?les from nanoparticles,Science263(1994)1600–1603.

colloidal carriers-ultra?ltration technique at low pressure,Int.[110]S.I.Joen,J.H.Lee,J.D.Andrade,P.G.de Gennes,Protein-J.Pharm.94(1993)115–123.surface interactions in the presence of polyethylene oxide.I.

[95]J.M.Rodrigues Jr,H.Fessa,C.Bories,F.Pusieux,J.-Ph.Simpli?ed theory,J.Colloid.Interf.Sci.142(1991)149–

Devissaguet,Premaquine-loaded poly(lactide)nanoparticles:158.

physicochemical study and acute tolerance in mice,Int.J.[111]D.Bazile,C.Prud Homme,M.Bassoullet,M.Marlard,G.

Pharm.126(1995)253–260.Spenlehauer,M.Veillard,Stealth Me-PEG–PLA nanoparti-[96]M.Polakovic,T.Gorner,R.Gref,E.Dellacherie,Lidocaine cles avoid uptake by the mononuclear phagocyte system,J.

loaded biodegradable nanospheres.II.modeling of drug Pharm.Sci.84(1995)493–498.

release,J.Control.Rel.60(1999)169–177.[112]M.Tobio,R.Gref,A.Sanchez,https://www.360docs.net/doc/aa5215004.html,nger,M.T.Alonso, [97]Z.Lu,J.Bei,S.Wang,A method of the preparation of Stealth PLA–PEG nanoparticles as protein carriers for nasal

polymeric nanocapsules without stabilizer,J.Control.Rel.administration,Pharm.Res.15(1998)270–275.

61(1999)107–112.[113]R.Gref,G.Miralles, E.Dellacherie,Polyoxyethylene-[98]H.Muller,K.M.Willis,Surface modi?cation of i.v.inject-coated nanospheres:effect of coating on zeta potential and

able biodegradable nanoparticles with poloxamer polymers phagocytosis,Polymer Int.48(1999)251–256.

and poloxamine908,Int.J.Pharm.89(1993)25–31.[114]https://www.360docs.net/doc/aa5215004.html,ender,T.Riley,S.Stolnik,M.C.Garnett,L.Illum, [99]C.J.Van Oss,Phagocytosis as a surface phenomenon,Annu.S.S.Davis,PLA–PEG nanoparticles for site speci?c deliv-

Rev.Microbiol.32(1978)19–39.ery:drug incorporation studies,J.Control.Rel.64(2000) [100]E.Allemann,G.Patricia,J.C.Leroux,B.Luc,R.Gurnay,269–347.

Kinetics of blood component-adsorption on poly(D,L-lac-[115]S.Y.Kim,I.G.Shin,Y.M.Lee,Preparation and characteriza-tide)nanoparticles:Evidence of compliment C component tion of biodegradable nanospheres composed of methoxy

involvement,J.Biomed.Mater.Res.37(1997)229–234.poly(ethylene glycol)and DL-lactide block copolymer as ¨

[101]T.Blunk,M.Luck,A.Calvoer,D.F.Hochstrasser,J.C.novel drug carriers,J.Control.Rel.56(1998)197–208.

Sanchez, B.W.Muller,R.H.Muller,Kinetics of plasma[116]M.T.Peracchia,E.Fattal,D.Desmaele,M.Bensard,J.P.

protein adsorption on model particles for controlled drug Noel,J.M.Gomis,M.Appel,J.d’Angelo,P.Couvreur,

delivery and drug targeting,Eur.J.Pharm.Biopharm.42Stealth PEGylated polycyanoacrylate nanoparticles for (1996)262–268.intravenous administration and spleenic targeting,J.Con-¨¨

[102]K.Thode,M.Luck,W.Semmler,R.H.Muller,M.Kresse,trol.Rel.60(1999)121–128.

Determination of plasma protein adsorption on magnetic[117]A.Gessnerl, B.R.Paulke,R.H.Muller,Plasma protein iron oxide:sample preparation,Pharm.Res.14(1997)adsorption on poly(ethylene-glycol)(PEG)modi?ed poly-905–910.styrene nanoparticles:in?uence of PEG surface density,¨¨

[103]K.Thode,M.Luck,W.Semmler,R.H.Muller,M.Kresse,Proc.Intern.Symp.Control.Rel.Bioact.Mater.26(1999) In?uence of sample preparation on plasma protein ad-597–598.

sorption patterns on polysaccharide-stabilized iron oxide[118]M.T.Peracchia,R.Gref,Y.Minamitake, A.Domb,R.

particles and end-terminal microsequencing of unknown Langer,PEG-coated injectable nanospheres prepared from proteins,J.Drug Target.5(1997)35–43.amphiphilic diblock and multiblock copolymers:investiga-¨¨

[104]M.Luck,K.F.Pistel,Y.Li,T.Blunk,R.H.Muller,T.tion of drug encapsulation and release characteristics,J.

Kissel,Plasma protein adsorption on biodegradable micro-Control.Rel.46(1997)223–231.

spheres consisting of poly(D,L-lactide-co-glycolide),poly(L-[119]M.T.Peracchia, C.Vauthier, F.Puisieux,P.Couvreur, lactide)or ABA triblock copolymers containing poly(oxy-PEG–PIBCA nanoparticles with different PEG-coating ethylene),J.Control.Rel.55(1998)107–120.con?gurations formed by chemical coupling of PEG,

K.S.Soppimath et al./Journal of Controlled Release70(2001)1–2019 Proced.Intern.Symp.Control.Rel.Bioact.Mater.23[132]M.Demoy,J.P.Andreux,C.Weingarten,B.Gouritin,V.

(1996)395–396.Guilloux,P.Couvreur,Spleen capture of nanoparticles: [120]M.T.Peracchia, C.Vauthier, F.Puisieux,P.Couvreur,In?uence of animal species and surface characteristics, Development of sterically stabilized poly(isobutyl-2-Pharm.Res.16(1999)37–41.

cyanoacrylate)nanoparticles by chemical coupling of poly-[133]T.Shinoda,A.Maeda,S.Kojima,S.Kagatani,Y.Konno, (ethylene glycol),J.Biomed.Mater.Res.34(1997)317–T.Sonobe,T.Akaike,Nanosphere coated with lactosyl-326.polystyrene polymer as a targeting carrier to hepatocytes, [121]M.T.Peracchia,C.Vauthier,D.Desmaele,A.Gulik,J.C.Drug Deliv.6(1999)147–151.

Dedieu,M.Demoy,J.d’Angelo,P.Couvreur,PEGylated[134]C.S.Cho,Y.I.Jeong,T.Ishihara,R.Takei,J.U.Park,K.H.

nanoparticles from a novel methoxypolyethylene glycol Park, A.Maruyama,T.Akaike,Simple preparation of cyanoacrylate–hexadecyl cyanoacrylate amphiphilic co-nanoparticles coated with carbohydrate-carrying polymers, polymer,Pharm.Res.15(1998)550–556.Biomaterials18(1997)323–326.

[122]M.T.Peracchia,C.Vauthier,C.Passirani,P.Couvreur,D.[135]A.Maruyama,T.Ishihara,S.W.Kim,T.Akaike,Nanoparti-Labarre,Compliment consumption by poly(ethylene glycol)cle DNA carrier with poly(L-lysine)grafted polysaccharide in different conformations chemically coupled to copolymer and poly(D,L-lactic acid),Bioconjug.Chem.8 poly(isobutyl-2-cyanoacrylate)nanoparticles,Life Sci.61(1997)735–742.

(1997)741–761.[136]D.Duchene,D.Wouessidjewe,G.Ponchel,Cyclodextrins [123]F.D.Jaeghere, E.Allemann,J.C.Leroux,W.Stevels,J.and carrier systems,J.Control.Rel.62(1999)263–268.

Feijen,E.Doelker,R.Gurny,Formulation and lyoprotec-[137]S.Raeissi,K.Audus,In vitro characterization of blood–tion of poly(lactic acid-co-ethylene oxide)nanoparticles:brain barrier permeability to delta sleep-inducing peptide,J.

In?uence on the physical stability and in vitro cell uptake,Pharm.Pharmacol.41(1989)848–852.

Pharm.Res.16(1999)859–866.[138]B.Zlokovich,The in vivo approaches for studying peptide [124]M.Vittaz, D.Razile,G.Spenlehauer,T.Verrecchia,M.interaction at the blood–brain barrier,Peptides10(1989) Veillard,F.Puisieux,https://www.360docs.net/doc/aa5215004.html,barre,Effect of PEO surface249–254.

density on long-circulating PLA–PEO nanoparticles which[139]U.Schroeder, B.A.Sabel,Nanoparticles,a drug carrier are very low complement activators,Biomaterials17system to pass the blood–brain barrier,permit central (1996)1575–1581.analgesic effects of i.v.dalargin injections,Brain Res.710 [125]J.C.Ha,S.Y.Kim,Y.M.Lee,Poly(ethylene oxide)–poly-(1996)121–124.

(propylene oxide)–poly(ethylene oxide)(Plunoric)/poly(e-[140]U.Schroeder,P.Sommerfeld,B.A.Sabel,A ef?cacy of oral caprolactone)(PCL)amphiphilic block copolymeric nanos-dalargin-loaded nanoparticle delivery across the blood–pheres I.Preparation and characterization,J.Control.Rel.brain barrier,Peptide19(1998)777–780.

62(1999)381–392.[141]R.Alyautdin, D.Gothier,V.Petrov, D.Kharkevich,J. [126]S.Storm,S.O.Belliot,T.Daemen, https://www.360docs.net/doc/aa5215004.html,sic,Surface Kreuter,Analgesic activity of the hexapeptide dalargin modi?cation of nanoparticles to oppose uptake by the adsorbed on the surface of polysorbate80-coated poly(butyl mononuclear system,Adv.Drug Deliv.Rev.17(1995)cyanoacrylate)nanoparticles,Eur.J.Pharm.Biopharm.41 31–48.(1995)44–48.

[127]L.Illum,S.S.Davis,Effect of the nonionic surfactant[142]G.Borchardt,L.A.Kenneth,S.Fenlin,J.Kreuter,Uptake poloxamer338on the fate and deposition of polystyrene of surfactant-coated poly(methyl methacrylate)-nanoparti-microspheres following intravenous administration,J.cles by bovine brain microvessel endothelial cell mono-Pharm.Sci.72(1983)1086–https://www.360docs.net/doc/aa5215004.html,yers,Int.J.Pharmacol.110(1994)29–35.

[128]L.Illum,S.S.Davis,The organ uptake of intravenously[143]S.D.Troster,U.Muller,J.Kreuter,Modi?cation of the administered colloidal particles can be altered using a body distribution of poly(methyl methacrylate)nanoparti-non-ionic surfactant(poloxamer338),FEBS Letts.167cles in rats by coating with surfactants,Int.J.Pharm.61 (1984)79–82.(1990)85–100.

[129]S.Rudt,R.H.Muller,In vitro phagocytosis assay of nano-[144]S.Steiniger,D.Zenker,H.V.Briesen,D.Begley,J.Kreuter, and microparticles by chemiluminescence.III.Uptake of The in?uence of polysorbate80-coated nanoparticles on differently sized surface-modi?ed particles,and its correla-bovine brain capillary endothelial cells in vitro,Proced.

tion to particle properties and in vivo distribution,Eur.J.Intern.Symp.Control.Rel.Bioact.Mater.26(1999)790–Pharm.Sci.1(1993)31–39.791.

[130]L.Illum,S.S.Davis,R.H.Muller,E.Mak,P.West,The[145]J.C.Olivier,L.Fenart,R.Chauvet,C.Pariat,R.Cecchelli, organ distribution and circulation time of intravenously W.Couet,Indirect evidence that drug brain targeting using injected colloidal carriers sterically stabilized with a block polysorbate80-coated polybutylcyanoacrylate nanoparticles copolymer poloxamine908,Int.J.Pharm.89(1993)25–is related to toxicity,Pharm.Res.16(1999)1836–1841.

31.[146]A.E.Gulyaev,S.E.Gelperina,I.N.Skidan,A.S.Antropov, [131]S.M.Moghimi,T.A.Gray,Single dose of iv injected G.Y.Kivman,J.Kreuter,Signi?cant transport of doxorubi-poloxamine coated long-circulating particle triggers macro-cin into the brain with polysorbate80-coated nanoparticles, phage clearance of subsequent doses in rats,Clin.Sci.93Pharm.Res.16(1999)1564–1569.

(1997)371–379.[147]R.N.Alyautdin,V.E.Petrov,https://www.360docs.net/doc/aa5215004.html,nger,A.Berthold,D.A.

20K.S.Soppimath et al./Journal of Controlled Release70(2001)1–20

Kharkevich,J.Kreuter,Delivery of lopermide across the[153]N.Wang,X.S.Wu,J.K.Li,A heterogeneously structured blood–brain barrier with polysorbate80-coated poly-composite based on poly(lactic-co-glycolic acid)micro-butylcyanoacrylate nanoparticles,Pharm.Res.14(1997)spheres and poly(vinyl alcohol)hydrogel nanoparticles for 25–328.long-term protein drug delivery,Pharm.Res.16(1999) [148]R.N.Alyautdin,E.B.Tezikov,P.Ramga,D.A.Kharkevich,1430–1435.

D.J.Begley,J.Kreuter,Signi?cant entry of tubocurarin into[154]R.M.M.Gasper, D.Blanco,M.

E.Cruz,M.J.Alonso,

the brain of rats by adsorption to polysorbate80-coated Formulation of L-aspargainase-loaded poly(lactide-co-gly-polybutylcyanoacrylate nanoparticles:in situ brain perfu-colide)nanoparticles:in?uence of polymer properties on sion study,J.Microencapsulation15(1998)67–74.enzyme loading,activity and in vitro release,J.Control. [149]U.Schroeder,P.Sommerfeld,S.Ulrich, B.A.Sabel,Rel.52(1998)53–62.

Nanoparticle technology for delivery of drugs across the[155]I.Fishbein,M.Chorny,L.Rabinovich,S.Banai,I.Gati,G.

blood–brain-barrier,J.Pharm.Sci.87(1998)1305–1307.Golomb,Nanoparticulate delivery system of a tyrphostin [150]P.Couvreur,F.Puiseux,Nano-and microparticles for the for the treatment of restenosis,J.Control.Rel.65(2000) delivery of peptides and proteins,Adv.Drug Deliv.Rev.5221–229.

(1993)141–162.[156]Y.Kawashima,H.Yamamoto,H.Takeuchi,S.Fujioka,T. [151]T.Uchida,A.Yagi,Y.Oda,Y.Dakada,S.Goto,Instability Hino,Pulmonary delivery of insulin with nebulized DL-of bovine insulin in poly(lactide-co-glycolide)(PLGA)lactide/glycolide copolymer(PLGA)nanospheres to microspheres,Chem.Pharm.Bull.44(1996)235–236.prolong hypoglycemic effect,J.Control.Rel.62(1999) [152]J.K.Lin,N.Wang,X.S.Wu,A novel biodegradable system279–287.

based on gelatin NPs and poly(lactic-co-glycolic acid)[157]G.P.Carino,J.S.Jacob,E.Mathiowitz,Nanosphere based microspheres for protein and peptide drug delivery,J.oral insulin delivery,J.Control.Rel.65(2000)261–269.

Pharm.Sci.86(1997)891–895.