Preparation and Characterization of Nimodipine-loaded Methoxy Poly (ethylene glycol)-poly (lactic ac

Joumal of Donghua University (Eng. Ed.) Vol.23, No,2 (2006) 107Preparation and Characterization of Nimodipine-loaded Methoxy Poly(ethylene glycol)-poly(lactic acid) Diblock Copolymer Nanoparticles .ZHA Liu-sheng (查刘生)12 , LI Lan (李兰): , ZHAO Hui-peng (赵辉鹏)21 Stale Key Laboratory of Modification of Chemipal Fibers and Polsmer Materials, Donghua University, Shanghai 200051Research Center of Analysis and Measurement , Donghua University, Shanghai 200051Amphiphilili diblck copolymers, methoxy poly (ethyleneblocks, which are often composed of poly(ethylene oxide)glycol)-poly(lactic acid) (MePEG-PLA), were synthesized(PEO)，can form hydrogen bonds with the aqueousfrom monomers of DL-lactide and methoxy poly (ethylenesurroundings and form a hydrophilic shell around theglycol) by a ring opening bulk polymerization in the presencehydrophobic core. The PEO corona prevents recognitionof stannous octoate. Their chemical structure and physicalby the reticuloendothelial system and therefore preliminaryproperties were investigated using FTIR, NMR, GPC, andelimination of the nanoparticles from the blodstream.fluorescence spectroscopy. To estimate the feasibility aThus, these so-called ‘ stealth’properties of the PEOcolloidal drug carrier, nimodipine (ND) was loaded intocorona result in increased blood circulation times and allowMePEG-PLA block copolymer nanoparticles by phasedrugs to be administered over prolonged periods ofseparation/dialysis method. The mean diameter and drugtime[l0]. A final feature that makes amphiphilic blockloading eficiency of ND-loaded MePEG-PLA copolymercopolymers attractive for drug delivery applications is thenanoparticles depended o PLAMePEG block compositionfact that their chemical composition, total molecularof the copolymer and dng/polymer feed ratio inweight, and the ratio of the constituting block can be easilypreparation. NMR study confimed that nlmodipine wEadjusted, which allows control of the size and morphologyentrapped into the hydrophobic inner core of MePEG-PLAof the nanoparticles.copolymer nanoparticles and hydrophillic PEG chains wereBlock copolymers are cassified into several types bylocated on the surface of the drugloaded polymnersequential arrangement of component segment, such as AB-nanoparticles. In vitro release experiments exhilbited thtype diblock copolymer, ABA-type triblock copolymer,sustained release behavior of nimodipine fro MePEG-PLA( AB)。type multiblock copolymer and star blockcopolymer nanoparticles, without any burst effect.copolymer. Block copolymers composed of hydrophobicKeywords: colloidal nanoparticles, biodegradable, drugand hydrophilic segments are known to assemble intodelivery system, diblock copolymer , nimodipine.polymeric nanoparticles in an aqucous medium[ .Compared to other type of amphiphilic block copolymers,AB type amphiphilic diblock copolymers are the mostIntroductionappropriate candidates for forming nanoparticles in sizedesign, aggregation number, and nanoparticle stability dueOver the past few decades, tremendous efforts haveto simple architecture of their molecules[12].been done in developingbiodegradable polymerIt is well known that PEG pssesses a number ofnanoparticles as effective drug delivery devicesl.2]。 Inexcellent physicochemical and biological properties,order to deliver the drug to a target site effectively and thusincluding hydrophilicity, solubility in water and in organicincrease the therapeutic benefit, while minimizing sidesolvents, lack of toxicityta), and absence of antigenicityeffects, various polymers have been employed to prepareand immunogenicityl4n. In recent years, PEG and itsbiodegradable nanopartices3bl. In recent years, thederivatives have been widely applied in biomedical fieldf[5].biodegradable polymer nanoparticles obtained fromPoly(lactic acid) (PLA) has been found to be a veryamphiphilic block opolymers have attracted considerableattractive biomaterial for pharmaceutical and medicalattention as potential drug delivery devices because of theirapplication due to its non-toxicity, biocompatibility anunique advantages'-)]. First of all, hydrophobic drugs canbiodegradability. Especially, the PLA polymer degradesbe physically entrapped in the core of block copolymerinto lactic acid which enters the tricarboxylic acid cycle andnanoparticles and high drug-loading capacity for the type ofis metabolized and subsequently eliminated from the bodydrug carrier can be achieved. Secondly, the bhydrophilicas carbon dioxide and water[16]. Lately, many efforts have中国煤化工Received Apr.1, 2005MHCNMHGCorrespondence should be adressed to ZHA Liu-sheng, researcher, E-mail; LsZhac@anu.edu.cn108Jourmal of Donghua University (Eng. Ed.) Vol. 23, No.2 (2006)been made to form a new family of block copolymersdialysis method, deionized water and cellulose dialysis bagcomprising PEG and PLA29121. The bright part of this(molecular weight cut off: 14 000) were used.family is that one can modulate the biodegradation rate and2 Synthesis of MPEG-PLA diblock copolymershydrophilicity of polymer by adjusting the ratio of itsMPEG-PLA diblock copolymers were synthesized inhydropilic and hydrophobic constituents. Moreover, boththe bulk state by the ring opening polymerization of DL~PEG and PLA were approved for clinical use by the Foodlactide in the presence of MePEG homopolymer usingand Drug Administration (FDA)is.16].stannous octoate as a catalyst. By variation of the ratio ofThe objective of the present study was to synthesizemonomer to initiator ([ M]/[I])，where [M]= DL-biodegradable amphiphilic diblock copolymer, methoxylactide units and [I] = MePEG homopolymer, the PLApoly (ethylene glycol)-poly (lactic acid) (MePEG-PLA)to PEG segment molecular weight ratio of the copolymer(shown in Fig. 1 (a)), and to evaluate the feasibility ofwas controlled. A weighed amount of MePEG and DL-MePEG-PLA copolymeric nanoparticles as drug carrierlactide were placed in a dried round-bottomed flasksystems. Nimodipine (ND) (shown in Fig. 1 (b)), aconnected with a vacuum joint, and the appropriatesecond-generation dihydropyridine calcium antagonist withamount of stannous octoate was added as a solution inapparent selectivity for cerebral blood vsselsln]， wasdried toluene. The reactants were dried under reducedselected as a hydrophobic model drug to incorporate intopressure at 70C for 2 hours, and then the copolymeri-the nanoparticles. ND-loaded McPEG-PLA copolymerication reaction was alowed to proceed at 160C fornanoparticles were prepared by phase separation/dialysis2 hours. The cooled product was dissolved in dichlorome-method. The characteristics of these ND-loaded polymericthane and precipitated into an excess of the mixed solventnanoparticles were investigated by dynamic light scatteringof ethyl ether and petroleum, and then the precipitant was(DLS), scanning electron microscopy (SEM) and nucleardissolved in acetone and precipitated into an excess ofmagnetic resonance (NMR). Their drug loading eficiencywater. The purified copolymers were dried in a vacuumand in vitro release behavior were examined usingoven at 40C for 24 h, and then stored in a desiccator underultraviolet spectrophotometer(UV).vacuum.3 Preparation of ND-loeded polymeric nanoparticdeshC-x°Mo士人、o巾MePEG-PLA block copolymeric nanoparticles containingND were prepared by phase separation/dialysis method.Briefly，MePEG-PLA block copolymer (0.2g) waa)dissolved in 6 mL N, N-dimethylformamide ( DMF)followed by adding ND with various weight ratios of ND toHC、N.CH,polymer (0.25:1-1:1) and sirred at room temperature.To form ND-loaded nanoparticles, the solution was(CH)HCOOC“C0OCH.CH2OCH,dropwise added into 14 mL of water under agitation. Theproduced emulsion was dialyzed for 48 h against 3 I ofdeionized water using cellulose dialysis bag to removeNO:b)DMF. The nanoparticle' dispersion was centrifuged toFig. 1 The molcular formula of (a) methoary (polyethylene gyoa)-eliminate unloaded ND and agregated particles, and thecopolvm ，poly (lactic acid) diblock copolymer and (b) nimodipinesupernatants obtained in this process were lyophilized byfreeze dryer system using 1% sucrose as cryoprotectant, toExperimentalobtain dried ND-loaded nanoparticle products.4 Characterization of MPEG-PLA diblock1 MaterialscopolymersMethoxy poly(ethylene glycol) (MePEG, Mn= 5 000The structure of the synthesized polymers wasby supplier) was supplied by Aldrich and dried underconfirmed by Fourier transform infrared spetroscopyvacuum in a desiccator with P2O. overnight before using.(FTIR) (Magna 550, Nicolet), 500 MHz 'H- and "CDL-lactide (purity; 99. 5%) was purchased from PURACnuclear magnetic resonance spectroscopy (NMR) (DMX-and purified by twice rersallization from dried ethyl500, Bruker) and gel permeation chromatography (GPC)acetate. Stannous octoate (stannous content: 26. 5%-27.5%)(HP1 100, Hewlett Packard). In FTIR measurements, thewas supplied by Shanghai Chemical Reagent Company.synth中国煤仆"Cle were coated onNimodipine was obtained from Xinyi PharmaceuticalKBr化工in NMR analysis.Factory (Shanghai, China). All other chemicals were ofTetraliYC N M H Gnobile phase with areagent grade and used without further purification. In theflow-rate of 1 mL/ min in GPC measurements.Joumal of Donghua University (Eng. Ed.) Vol. 23, No.2 (2006) 109The molecular weight and mlecular weight dstribution of6 In vitro drugrelease studiesMePEG- PLA block copolymers were characterized by elutionThe appropriate amount of ND-loaded polymertime relative to polystyrene mondisperse standerds fromnanoparticles were precisely weighed and dispersed in 2 mLGPC, in which differential refractomneteric detector were usedof phosphate buffer solution(PBS) (0.1 M, pH= 7.4).and the mobile phase was THF with a flow-rate of 1 mL/min. .The dispersion was introduced into a dialysis bag with aIn addition, the composition and the number-averagecutoff molecular weight of 14 000 g/mol. The tied bag wasmolecular weight of each copolymer in CDCk solution wereplaced in 80 mL of 20% ethanol-PBS (pH= 7.4) releasedetermined by 500 MHz 'H NMR.medium at 37C, and the medium was sirred at 70 rpm.3In order to determine the critical associationmL of the solution was sampled periodically to measure theconcentration (CAC) of MePEG-PLA block copolymers,drug concentration using UV spectrophotometer at 356 nm.fluorescence measurements were carried out using pyrene asEach sample was replaced with an equal volume of freshprobe. The fluorescence excitation spectra of pyrene weremedium and the correction for the cumulative dilution wasmeasured at various concentration of MePEG-PLA blockcalculated. The ND solution with equal amount of drug wascopolymer using a spectrofluorometer (RF-540, Shimadzu) .used as a control.Characterization of ND-loaded polymericnanoparticlesResults and DiscussionTo determine the mean particle size and sizedistribution of ND-loaded MePEG-PLA block copolymeric1 Structural identification of MePEG-PLAnanoparticles, dynamic light scattering (DLS) (Autosizerdiblock copolymer4 700，Malvern) measurements were carried out at aIn this study, a series of amphiphilic diblockwavelength of 532 nm at 25C. The intensity of thecopolymers, MePEG-PLA, were firstly synthesized by ascattered light was detected at 90C to the incident beam.ring opening polymerization of DL-lactide initiated withThe morphological examination of nanoparticles wasthe hydroxyl group of methoxy poly(ethylene glycol) usingperformed using a scanning electron microscopy (SEM)stannous octoate as a catalyst. In order to confirm the(XL 30, Philips), where the diluted aqucous dispersion ofsynthesized polymers were MePEG-PLA diblockthe nanoparticles was put onto a glass slide using acopolymers, they were characterized by FTIR, NMR andmicrosyringe. After this slide was fixed on the cirlcularGPC. For comparison, the FTIR spectra of MePEGholder, the particles were coated with gold in a vacuum andhomopolymer, DL-lactide and the synthesized polymer arethen the microphotographs were obtained.shown in Fig. 2. The ester carbonyl stretching band of DLThe structure of ND loaded polymeric nanoparticleslactide appears at 1 756 cm~1 due to the effet of ring-was analysed by 'H NMR. The 'H NMR spectra of ND-inside tension, while a new absoption band at 1 735 cm-1loaded polymeric nanoparticles dispersed in D2O orattributed to the ester carbonyl of straight chain appears indissolved in d-dimnethylsulfoxide ( d-DMSO) werethe spectrum of the synthesized polymer，ilustrating thatobtained using a 500 MHz 'H NMR. For cormparison, thethe ring ester bond of DL-lactide was opened to form theH NMR spectra of ND or MePEG-PLA block copolymerstraight chain ester bond. In addition, the overlapping ofsolubilized in d-DMSO were also measured.the aliphatic CH stretching band of DL-lactide at 2 943The drug loading efficiency (DLE) of ND loadedcm~' and the absorption band of CH stretching vibration inMePEG-PLA copolymeric nanoparticles was examinedMePEG at 2 881 cm~' is also observed in the spectra. Fig. 3using UV spectrophotometer (Lambda 35, PE). After theshows typical 'H and "C NMR spectra of the synthesizednanoparticle was disrupted by an addition of ethanol andpolymer. In Fig.3 (a), the peaks at 5.2 and 1.6 ppm areTHF (1 : 1, v/v)，the amount of ND entrapped wasassigned to methine (CH) proton and methyl (CH )determined by measuring the UV absorbance at 350 nm.protons of PLA component, respectively, and the peak atThe DLE was calculated from the amount of initial loaded3.7ppm is due to the methylene protons of MePEGnanoparticles and the amount of ND entrapped from thecomponent. In Fig.3 (b), the peaks at 170.4, 69. 8 andfollowing equation:17.4 ppm are atributed to the carbons of carbonyI, CHand CHs group of PLA units, respectively, and the peak atweight of ND in nanoparticlesDLE(%) = weight of ND-loaded nanoparticles x10071.4ppmis due to the carbon of CH2 group of MePEG(1)units. From the above FTIR and NMR results, it can be煤化干er is MePEG-PLAPrior to this analysis, we calibrated with ND standardcopoly中国烧-vn in Fig.4)， wesolutions in ethanol-THF (1 : 1, v/v) at 350 nm UVconfirTHCNM H GEG peak and theabsorbance.appearance ot a new elution peak, which further indicates110Joumal of Donghua University (Eng. Ed.) Vol.23, No. 2 (2006)that the synthesized polymer is MePEG-PLA copolymer,2 The composition and molecular weight ofnot the mixture of MePEG and PLA homopolymers.MePEG-PLA block copolymersThe number average molecular weight and molecular(aweight distribution of MePEG-PLA copolymers were(bmeasured by GPC. In addition, their number average(emolecular weight was determined from the peak areaat 1.6ppm and 3.7 ppm in the 'HNMR spectra of MePEG-PLAcopolymers assuming that the number average molecularweight of MePEG block is 5 000，as calculated from thefollowing eqation;4 0003 00020001 0000mi'M.(NMR)=Cx5000x72x4+5000.44X3Fig.2 FTIR spectra of(a) the synthesized copolymer,San : the peak area at 3.7 ppm(b) DL-lactide and (c) MePEGSay: the peak area at 1.6 ppm72: the molecular weight of lactic acid unit44: the molecular weight of ethylene oxide unitThe composition of MePEG-PLA diblock copolymers wasestimated from their number-average molecular weightdetermined by 'HNMR and the molecular weight ofMePEG block. As ilustrated in Table 1，the numberaverage molecular weight of the copolymers measured byGPC was low than the ones by 'HNMR, and the ltterapproximated to the theoretical value calculated from thefeed recipe in the synthesis of MePEG-PLA copolymers.pm6sa)As the amount of DL -lactide in the feed recipe increased,the molecular weight of MePEG-PLA copolymersincreased, but the difference from the theoretical valuebecame larger and the molecular weight distributionbecame broader. The phenomena may stem from the factthe high viscosity of the reaction system due to highmolecular weight of the copolymers during the late periodof polymerization led to the dfficult diffusion of DL-lactide, and the bulk polymerization terminated before themonomer was used up.3 Critical association concentration of MePEG-ppm160140 120100806040200PLA block copolymersThe critical association concentration (CAC) ofFig.3 (a) IHNMR and (b) 1CNMR typical spectraof the synthesized polymeramphiphilic block copolymer is employed to characterizethe stability of the formed polymeric nanpariclel4. The0most common way to determine the CAC of amphiphilicblock copolymer is by the use of a hydrophobic fluorescence爹-50001probe that is sensitive to changes in the vicinal polarityl9l. W.10 000estimated the CAC of MePEG-PLA block copolymers by-150000measuring the fluorescence excitation spectra of pyrene at号-200000various concentrations of the copolymer. Emission wavelength- 25 000会was 390 nm and pyrene concentration was kept constant at015”20”25”3036.0x 10~°M. Fig. 5 plos the itensity ratio of lao.s/ Is fromElution volume (mL)pyrene中国煤化工PLE21 among theFig.4 Typical GPC chromatogram of theMePEC;asured CAC valuessynthesized polymerfrom tYHc N M H Gonts, drawn troaghJournal of Donghua University (Eng. Ed.) Vol.23, No.2 (2006) 111Table 1 Molecular weight and composition of MePEG- PLA diblock copolymersMn(x 10-3)Feed weight ratioMe(Pu)/M(ro)SamplePolydispersity index*Lactide/MePEGCalc"GPCNMRin the copolymerPLE11/10’8.69.84 800/5 0001.38PLE212/11513.715.110 100/5 0001.51PLE414/12521.824.719 700/5 000PLE8139.643.438 400/5 0001.64* Number average molecular weight calculated from feed recipe.'●obtained by GPC.the points at the lowest polymer concentrations, which lie4 Structure of ND-loaded MePEG-PLA blockon a nearly horizontal line, with that going through thecopolymer nanoparticlespoints on the rapidly rising part of the plot[xo. The CACIn the present work, NMR was employed to study thevalues of MePEG-PLA block copolymers are much lowerstructure of ND loaded polymeric nanoparticles. This isthan that of common low molecular weight surfactant,possible since the nanoparticle system is in the sameexhibiting that the. block copolymeric system can fornconformational state whether the PLA- PEG copolymericnanoparticle even in a very diluted condition. Fig. 6 showsnanoparticles are dispersed in water or in D2O. 1 HNMRthe correlation between the CAC of MePEG-PLA blockspectra of ND-loaded polymeric nanoparticles dissolved incopolymers and the weight percentage of PLA block in thed-DMSO (a), ND dissolved in d-DMSO (b), MePEG-copolymers. As PLA block lengths in MePEG-PLA blockPLA diblock copolymer dissolved in d-DMSO (c)，ND-copolymers increases, their CAC values gradually decrease,loaded polymeric nanoparticles dispersed in D20 (d) areindicating that the stability. of. the formed polymershown in Fig. 7. Fig. 7 (a) shows tbat in d.-DMSO, ananoparitcles show a inverse correlation with the PLAnonselective solvent for the MePEG-PLA polymer and ND,block length in the block copolymers.complete structural resolution of both MPEG-PLA copolymerand ND was observed. The spectra of ND-loaded polymernanoparticles in d:-DMSO are overlapping of these of ND.8-(b) and MePEG-PLA polymer (c), respectively in df :DMSO. However, as shown in Fig. 7 (d), only the signal.6-of PEG segment is seen in the spectrum of ND-loaded14-polymeric nanoparticles in D2O, indicating that the PEG.2+.segment is in an extended solvated state to form thehydrophilic outer shell of ND-loaded nanoparticles and.0-stabilize the colloidal nanoparticles dispersed in water. Theprotons in PLA segment and ND have disappeared from the-10logCie/L)spectrum, implying that PLA segment and ND are in adifferent environment to them in d-DMSO, that is, ND isFig.5 Plots of the intensity ratio from pyreneexcitation spectra vs. log c for PLE21. .entrapped in the central solidlike hydrophobic core formedby PLA segments to minimize their interaction with water14due to their hydrophobic character.12E6820.5T s 0.60.70.9The weight percentage of PLA segmentin PLA-PEG copolymer中国煤化工尘Fig.6 Critial asciation concentrations as a function2”Tof the weight percent of PLA segmentYHCNMHG112Jouma/ of Donghua University (Eng. Ed.) Vol. 23, No. 2 (2006)absence of any residual DMF, the produced nanoparticledispersions were assayed by gas chromatography massspectrum (GC/MS) (Saturn 2 200, Varian), and no traceof the organic solvent was detected.Using MePEG-PLA copolymer with various molecularweight and changing the weight ratio of ND to polymer, aseries of ND-loaded polymer nanoparticles were prepared,as shown in Table 2. From the DLS measurements, theaverage size of ND-loaded MePEG-PLA copolymericnanoparticles is smaller than 150 nm, and increases withthe molecular weight of the copolymer or with the feedppmg8765432iratio of ND to polymer. It is observed from SEMmicrographs (see Fig. 8) that the drug loaded nanoparticlesexhibit spherical shape and hold narrow size ditribution.Table 2 shows that with the same feed ratio of drug topolymer, the drug loading efficiency (DLE) of ND innanoparticles increases with PLA block length in thecopolymer, which is due to the fact the longer the PLAblock in the amphiphilic block copolymers, the stronger thehydrophobicity of the inner core of the formednanoparticles, causing the enhancement of compatibilitybetween hydrophobic ND and the nanoparticles. Inaddition, the DLE increases with the feed ratio of ND tothe polymer. Comparison of NNP- 11 - 100 and NP -41 -50 having similar DLE, the size of NP - 41 - 50 was largerppm65432”T”6than that of NP - 11 - 100, implying that the size ofnanoparticles was largely influenced by the molecularweight of the copolymer used.Table2 Particle size and drug loading efficiency of ND.loaded MePEG-PLA copolymer nanoparticlesMePEG-PLAFeed weightParticleSarmplescopolymerratio nimodipine;size (nm)●DLE(%)NNP-11-100 PLE111.12.24NNP-21-100 PLE21111NNP-41-100 PLEA1 .4.02NNP-81-100 PLE811: 11235.11NNP-41-75 PLE410.7513.24NNP-41-50 PLE410.50:1ppm876532”ToNNP-41-25 PLE410.25111,,75Fig.7 1 HNMR spectra of (a) NNP-41-100 dissolved in ds-DMSO;* determined by dynamic light scattering(b) ND dssolved in ds-DMSO; (c) MePEG-PLA diblockcopolymer dissolved in ds-DMSO; (d) ND- loadedpolymeric nanoparticles dispersed in D2O.5 Size, shape and drug loading eficiencyn of NDloaded MePEG-PLA block copolymer nanoparticlesIn this study, the phase-separation/ dialysis methoddescribed in experimental section was employed to prepareMePEG-PLA copolymeric nanoparticles containing ND.中国煤化工Compared with the dialysis method reported by Lee et al.,the organic solvent of high boiling point (DMF), used inYHCNMHGpreparation, was reduced 70% in volume. To confirm theJoumal of Donghua University (Eng. Ed.) Vol.23. No.2 (2006) 113initiated with the hydroxyl group of methoxy poly(ethyleneglycol) at one end of the chain using stannous octoate as acatalyst. Their chemical structure and composition wereconfirmed using FTIR, NMR, GPC and TGA. The CACvalues of MePEG-PLA block copolymers determined byfluorescence spectroscopy were not over 1.5X 10-* mol/Lwhich was much lower than that of common low molecularweight surfactants, therefore, we can expect that theseMePEG PLA amphiphilic diblock copolymers form morestable nanoparticles of micelle like structure. MePEG-PLAb)amphiphilic diblock copolymeric nanoparticles entrappedFig.8 SEM images of nimodipine loaod MePEC-PLAwith ND in their inner core were prepared by phase-copolymer nanoparticlesNNP-21- 100separation/dialysis method. The size of ND-loadedand (b) NNP-41-100MePEG-PLA polymer nanoparticles is less than 150 nm and6 In vitro drug releasing behavior of ND-they hold spherical shape and narrow size distribution.loaded MePEG-PLA block copolymer nanoparticlesNMR study confirmed that ND was entrapped into theThe drug release properties for ND-loaded MePEG-hydrophobic inner core of MePEG-PLA copolymnerPLA copolymer nanoparticles were investigated using ananoparticles and hydrophilic PEG chains were located ondialysis bag in phosphate buffer solution (pH 7.4, 37C)the surface of the drug loaded polymer nanoparticles. Irunder in vitro condition. As shown in Fig.9, the free NDvitro release experiments showed that the release of NDexhibited complete release within 6 h, indicating that thefrom the ND loaded MePEG-PLA nanoparticles to PBSdialysis bag had ltte rate-limiting effect on ND releasing.medium exhibited the sustained release behavior, withoutThe ND which was loaded into the nanoparticles showedany burst efect.significant controlled release characteristics, approximately13. 3%，37. 6% and 82% of ND released from theAcknowledgementnanoparticles after 2, 12, 96 h, respetively, without anyburst efect. This implied that ND was entrapped into theThe authors are grateful to the National Naturalinner core of MePEG-PLA nanoparticles, without anscience Foundation of China (no. 50573009) for itsresidual drug on their surfaces. This result is in agreemnentfinancial support.with the above one obtained by NMR. 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