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Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA)


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Biomaterials 25 (2004) 2843–2849

Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs
Y

uancai Dongb, Si-Shen Fenga,b,*
b a Division of Bioengineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore Department of Chemical & Environmental Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore

Received 21 August 2003; accepted 15 September 2003

Abstract Methoxy poly(ethylene glycol)-poly(lactide) copolymer (MPEG-PLA) was synthesized and used to make nanoparticles by the nanoprecipitation method for clinical administration of antineoplastic drugs. Paclitaxel was used as a prototype drug due to its excellent ef?cacy and commercially great success. The size and size distribution, surface morphology, surface charge and surface chemistry of the paclitaxel-loaded nanoparticles were then investigated by laser light scattering, atomic force microscopy, zetapotential analyzer and X-ray photoelectron spectroscopy (XPS). The drug encapsulation ef?ciency (EE) and in vitro release pro?le were measured by high-performance liquid chromatography. The effects of various formulation parameters were evaluated. The prepared nanoparticles were found of spherical shape with size less than 100 nm. Zeta potential measurement and XPS analysis demonstrated the presence of PEG layer on the particle surface. Viscosity of the organic phase was found to be one of the main process factors for the size determination. The EE was found to be greatly in?uenced by the drug loading. The drug release pattern was biphasic with a fast release rate followed by a slow one. The particle suspension exhibited good steric stability in vitro. Such a nanoparticle formulation of paclitaxel can be expected to have long-circulating effects in circulation. r 2003 Elsevier Ltd. All rights reserved.
Keywords: AFM (atomic force microscopy); Biodegradable polymers; Chemotherapy; Taxanes; XPS (X-ray photoelectron spectroscopy)

1. Introduction Nanoparticles of biodegradable polymers have attracted great interest in the recent years for clinical administration of anticancer drugs. The advantages of such a formulation include the sustained drug action on the lesion, reduced systemic side effects, facilitated extravasation into the tumor, high capability to cross various physiological barriers as well as controlled and targeted delivery of the drug [1–3]. However, there have been concerns that the advantages may be compromised by the particles’ short residence time in the blood system due to the recognition and capture by the macrophages in the mononuclear phagocyte system. It is generally accepted that the phagocytosis results from the nanoparticles’ interaction with some blood proteins (opsonization) [4–6]. Therefore, the ef?cient prevention of the phagocytosis is to avoid or minimize the adsorption of the particles onto the phagocytes. Particles invisible to
*Corresponding author. Tel.: +65-6874-3835; fax: +65-6779-1936. E-mail address: chefss@nus.edu.sg (S.-S. Feng). 0142-9612/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2003.09.055

the body defense system, which can avoid being cleared from the blood system, are called stealthy or longcirculating particles, which can be realized by achieving extremely small particle size as well as applying appropriate matrix material and surface coating [7–10]. Polyethylene glycol (PEG) is widely used to cloak the particles and obtain stealthy properties. With one end being adsorbed on or attached to the particles surface, PEG chain extrudes outwards to form hydrophilic and ?exible ‘‘conformational clouds’’, which become an effective protective layer to inhibit the opsonization [11–14]. The particles with PEG coating can be obtained by the physical adsorption of PEG or its derivatives, such as poloxamer and poloxamine on the particle surface [15–17]. They can also be directly prepared from the amphiphilic block copolymer PEG-R, where R is a hydrophobic block such as PLA, PLGA, etc.) or from the blend of a biodegradable polyesters (PLA, PLGA, etc.) and other PEG-containing polymers [10,18–20]. Paclitaxel, extracted from the bark of a naturally occurring plant, Taxus brefolia has exhibited potent cytotoxic activity against a wide spectrum of cancers,

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especially breast and ovarian cancer [21–24]. However, it has dif?culties in clinical formulation due to its extremely low aqueous solubility. The only dosage in its current clinical administration is Taxols, which is a mixture of 50% Cremophor EL and 50% dehydrated alcohol (v/v). It has been reported that such a formulation may cause serious side effects, which include hypersensitivity reaction, nephrotoxicity, neurotoxicity and cardiotoxicity [25–27]. Various alternative formulations have been developed to avoid using Cremophor EL [28,29]. Among them, polymeric nanoparticles have attracted great interest. In most cases, poly(lactic-co-glycolic acid) (PLGA) was used as the matrix material [30–33]. The present paper synthesized a new kind of copolymer, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA), for preparation of stealthy nanoparticles by the nanoprecipitation method for controlled release of paclitaxel. Although paclitaxel has been reported to be successfully encapsulated in the MPEG-PLGA nanoparticles by the solvent extraction/evaporation method [34] and in the PLGA nanoparticles by the nanoprecipitation method [32], the formulation proposed in this paper may have advantages over the previous work in resulting in smaller size, better surface properties, desired in vitro drug release kinetics and longer circulating period. In the present work, the copolymer MPEG-PLA was synthesized by the ringopening polymerization and used to prepare paclitaxelloaded nanoparticles by the nanoprecipitation method. The size and size distribution of the prepared nanoparticles were measured by laser light scattering (LLS). The surface morphology was investigated by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Zeta potential measurement and X-ray photoelectron spectroscopy (XPS) were employed to determine surface charge and surface chemistry of the prepared nanoparticles. High-performance liquid chromatography (HPLC) was used to measure the drug encapsulation ef?ciency (EE) in the nanoparticle and the in vitro release pro?le. The effects of the formulation variables such as the amount of the copolymer, the surfactant emulsi?er used in the preparation process, the oil/water phase ratio as well as the drug loading were evaluated.

day and stannous octoate was dissolved in distilled benzene to form 1% w/v fresh solution. Paclitaxel was obtained from Hande Biotechnology Ltd., Yunnan, China. All other chemicals including HPLC grade actonitrile from Aldrich, dichloromethane (DCM) from Fisher Scienti?c and Pluronic F-68 from Sigma were used as received. 2.2. Synthesis of MPEG-PLA copolymer MPEG-PLA copolymer was synthesized by the ringopening polymerization. In brief, appropriate amount of lactide, 10 wt% MPEG and 0.75 wt% stannous octoate (in distilled benzene) were added to a tube for polymerization. The tube was evacuated under vacuum for 1 h and sealed. The polymerization started in the oil bath at 155 C. After the completion of the reaction, the resulted product was dissolved in DCM and then precipitated in excess cold methanol and ?ltered. The ?nal copolymer was vacuumed at 40 C for 48 h. The structure, number average molecular weight and the MPEG content of the copolymer were determined by 1H NMR in CDCl3 at 300 Hz (Bruker ACF300). 2.3. Preparation of paclitaxel-loaded MPEG-PLA nanoparticles Paclitaxel-loaded nanoparticles were prepared by the nanoprecipitation method [35]. Brie?y, 1 mg paclitaxel and 100 mg MPEG-PLA were dissolved in 10 ml acetonitrile. This organic solution was drop-wise added to 20 ml deionized water (or with different amount of Pluronic F-68) under magnetic stirring. The nanoparticles were formed immediately and the solvent was removed through the overnight evaporation at room temperature. The resulting suspension was ?ltered through 0.8 mm membrane ?lter (Whatman) and then centrifuged for 1 h at 11,000 rpm. The supernatant was discarded and the pellet was resuspended in water. The ?nal suspension volume was 10 ml. 2.4. Characterization of the nanoparticles 2.4.1. Size and size distribution The particles size and size distribution were measured by the LLS technique (Brookhaven Instruments Corporation 90 plus Particle Sizer) at 25 C and at a scattering angle of 90 . The obtained particles suspension was diluted appropriately in deionized water before measurement. 2.4.2. Encapsulation ef?ciency Two ml particle suspension was freeze-dried and the drug encapsulated in the lyophilized particles was determined using HPLC (Agilent LC 1100). Brie?y, 3 mg particles were dissolved in 1 ml DCM under

2. Materials and methods 2.1. Materials Lactide (3,6-Dimethyl-1, 4-dioxane-2, 5-dione) was purchased from Aldrich and recrystallized twice in ethyl acetate before use. MPEG (Mw 5000) and stannous octoate were supplied by Sigma. Before polymerization, MPEG was vacuum-dried at room temperature for 1

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Y. Dong, S.-S. Feng / Biomaterials 25 (2004) 2843–2849 2845

vigorous vortexing. This solution was transferred to 5 ml of the mixture of 50/50 (v/v) acetonitrile and water. The nitrogen was introduced to evaporate dicholoromethane and a clear solution was obtained for HPLC analysis. The mobile phase of HPLC was composed of acetonitrile and water of 50/50 (v/v). The measurement was performed triplicate. The EE was expressed as the percentage of the drug loaded in the ?nal product. 2.4.3. Morphology The morphology was investigated by observing the freeze-dried particles using AFM (Mutimode Scanning Probe Microscope, Digital Instruments) with Nanoscope IIIa by applying the tapping mode. Before observation, the particles were ?xed on a double-sided sticky tape, which was adhered to a sample stand. 2.4.4. Zeta potential measurement Zeta potential was measured by the laser Doppler anemometry (Zeta Plus, Zeta Potential Analyzer, Brookhaven Instruments Corporation). Before measurement, the particle suspension was diluted in deionized water. The value was recorded as the average of ?ve measurements. 2.4.5. X-ray photoelectron spectroscopy (XPS) The XPS (AXIS His-165 Ultra, Kratos Analytical, Shimadzu) was used to analyze the surface composition of the nanoparticles. Fixed transmission mode was utilized with pass energy of 80 eV for the survey spectrum covering a binding energy from 0 to 1200 eV. Peak curve ?tting was carried out using the software provided by the instrument manufacturer. 2.4.6. In vitro release One ml particle suspension was put in a centrifuge tube containing 10 ml phosphate buffer solution (PBS, pH 7.4). The tube was placed in an orbital shaker water bath at 37 C. At particular time intervals, the tube was taken out and centrifuged. The supernatant was poured out and extracted with 1 ml DCM to determine the content of the drug released. The pellet was resuspended in 10 ml fresh PBS for continuous release measurement. The analysis procedure was same as described in the determination of the EE.
CH

CH3 1.65 ppm

CH2 3.65ppm

5.20ppm

7

6
1

5

4

3

2

1

0

ppm
Fig. 1. H NMR spectrum of MPEG-PLA in CDCl3.

1.65 and 5.20 ppm belong to a methine (–CH) and methyl proton (–CH3) of PLA segment, respectively, while the methene protons (–CH2–) of PEG segment appear at 3.65 ppm. No other peaks were detected. This demonstrates successful synthesis of MPEG-PLA copolymer with high purity. From the ratio of peak area at 5.20 and 3.65 ppm, the number average molecular weight of the synthesized copolymer was determined to be 62,500 and the weight content of MPEG is 8%. 3.2. Effects of formulation variables on the nanoparticle properties Size and size distribution play an important role in determining the drug release behavior of the paclitaxelloaded nanoparticles as well as their fate after administration. It was reported that smaller particles tended to accumulate in the tumor sites due to the facilitated extravasation [2] and a greater internalization was also observed [3]. Less than 200 nm particles can prevent spleen ?ltering [36]. In addition, smaller particles make intravenous injection easier and their sterilization may be simply done by ?ltration [12,37]. Drug EE is another factor to be considered, especially for such a precious drug as paclitaxel. Therefore, in the present work, the effects of the formulation variables on the prepared nanoparticles were evaluated in terms of the size and the drug EE, which are summarized in Table 1. It can be seen that whatever the concentration of the surfactant Pluronic F-68 (0, 0.25% and 0.5%) was in the water phase, the prepared nanoparticles exhibited little difference in the size and EE. The size was between 83.4 and 89.5 nm with low polydispersity and the EE ranged 41.6–47.8%. Pluronic F-68, a polyoxyethylene-polyoxypropylene triblock copolymer is widely used as surfactant in the nanoprecipitation method. However, its function is different from poly(vinyl alcohol) (PVA)

3. Results and discussion 3.1. Synthesis of MPEG-PLA copolymer MPEG-PLA copolymer was synthesized from lactide in the presence of MPEG, whose hydroxyl group initiated the ring-opening of lactide. The structure of the synthesized polymer was determined by 1H NMR in CDCl3 and the spectrum is shown in Fig. 1. The peaks at

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2846 Y. Dong, S.-S. Feng / Biomaterials 25 (2004) 2843–2849 Table 1 Effects of fabrication variables on the size and drug encapsulation ef?ciency of MPEG-PLA nanoparticles Fabrication variables Surfactant concentration (w/v) 0 0.25% 0.50% 1 2 3 40 100 130 5 10 25 Size Polydispersity EE (nm) (%) 83.4 0.174 89.0 0.094 89.5 0.123 83.4 0.174 87.8 0.108 83.1 0.090 77.0 0.235 83.4 0.174 111.2 0.116 89.8 0.112 83.4 0.174 79.7 0.062 47.5 41.6 42.8 47.5 29.7 22.6 21.8 47.5 77.2 46.7 47.5 39.9

Drug amount (mg)

Polymer amount (mg)

Solvent volume (ml)

employed in the emulsion/solvent evaporation method. In the latter case, the nanoparticles are formed with the aid of PVA to stabilize the nanoemulsion droplets produced by the sonication or homogenization. Otherwise, the emulsion droplets will coalesce and no nanoparticles can be formed. In the former case, the nanoparticles are spontaneously formed by the interfacial turbulence resulted from the rapid diffusion of water miscible solvent to the water. The energy released in this diffusion process provides the formation of the particles [38–40]. The surfactant is actually not involved in the formation of the nanoparticles. Its addition is to keep good steric stability of the formed particles. Though the size and the EE were not signi?cantly affected by the surfactant in the present study, a trend could still be concluded: the nanoparticles prepared without surfactant exhibited a slight smaller size and higher EE than those prepared with surfactant. The larger size of the nanoparticles with surfactant may be due to the adsorbed surfactant on the particle surface, while the lower EE can also be ascribed to the residue surfactant molecules on the particles surface, which were not washed away. This residue, existing in the ?nal particles, is neglected in the calculation of EE, which leads to a slightly smaller result. No signi?cant effect of the drug loading was observed on the particles size. However, the EE was found greatly affected by the drug loading. With an increase of the drug loading from 1% to 3%, the EE declined drastically from 47.5% to 22.6%. It seems that the higher the drug loading is, the lower the EE could be. A possible explanation is that the higher drug loading resulted in the increased drug concentration gradient between the polymer matrix and the outer aqueous phase, which in turn led to more drug loss in the

fabrication process. The polymer itself may have a limited capacity to encapsulate the speci?c drug. Beyond its maximum capacity, more drug might be wasted during the fabrication process and the EE thus decreased correspondingly. This phenomenon was also observed by other researchers [41,42]. The particle size increased from 77.0 to 111.2 nm when the polymer amount in the organic solvent was increased from 40 to 130 mg while the drug was kept 1 mg. Also, the EE showed a drastic enhancement from 21.8% to 77.2%. This demonstrates that the particle size and the EE could be signi?cantly affected by the polymer amount when other formulation variables are kept constant. It is well accepted that the nanoparticle size is directly dependant on the rate of the diffusion of the organic solvent to the outer aqueous environment. The faster the diffusion rate is, the smaller the particles would result. The reduction of the organic phase viscosity or the interfacial tension can facilitate the solvent diffusion and thus tends to produce the nanoparticles with smaller size [38–40,43]. In the present work, the increased polymer amount in the solvent resulted in the higher viscosity, which thus led to larger nanoparticle size. In our experiment, the drug weight was kept 1 mg. Therefore, when the polymer amount was increased from 40 to 130 mg, the actual drug loading decreased from 2.5% to 0.77%, which thus resulted in a higher drug encapsulation. In addition, the drug loss might be further reduced due to the enhancement of the interaction between the polymer and the drug. The prepared nanoparticles of larger size have relatively smaller surface area, which thus caused less drug leakage in the fabrication process. The solvent volume increase (from 5 to 25 ml) makes the reduction of particles size from 89.8 to 79.7 nm. This size decrease may still be ascribed to the reduced viscosity of the organic phase, which facilitates the solvent diffusion to the water. In the case of EE, the nanoparticles showed insigni?cant difference in the EE with 5 and 10 ml solvent (47.5% and 46.7%, respectively). However, a decrease of the EE to 39.9% was observed with 25 ml solvent. The possible reason was that, the increase of the solvent volume decreased the polymer concentration in the organic phase. Hence, the interaction between the polymer and the drug was reduced, which ultimately led to higher drug loss [32]. The present work demonstrated that sub 100 nm MPEG-PLA nanoparticles loaded with paclitaxel can be readily prepared by the nanoprecipitation method with good reproducibility. The particles size depends mainly on the organic phase viscosity: the less viscous organic phase tends to produce the smaller particles. Therefore, increasing the solvent volume or decreasing the polymer amount tends to produce smaller particles. The drug loading is the main determinant of the drug EE: the lower the drug loading is, the higher the EE could be. By

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adjusting formulation variables, the particles size and the drug EE can be optimally controlled. 3.3. Morphology The particles under AFM investigation as shown in Fig. 2 are spherical and the size is less than 100 nm, which is similar to the results obtained by the LLS technique. 3.4. Surface properties Zeta potential, i.e., surface charge can greatly in?uence the particles stability in suspension through the electrostatic repulsion between the particles. It is also an important factor to determine their interaction in vivo with the cell membrane, which is usually negatively charged. In addition, from the zeta potential measurement, we can roughly know the dominated component on the particles surface. The samples in the present work exhibited a zeta potential between ?9.0 and ?12.3 mV (data were not detailed). No evidence for de?nite dependence of the formulation variables on the zeta potential was found. Compared with the PLA or PLGA nanoparticles, whose zeta potential is around ?50 mV [42], a great increase in the absolute value of the MPEG-PLA nanoparticle surface charge could be observed. Since PEG is non-ionic, this surface charge increase demonstrated the presence of PEG layer on the surface, which shifted the shear plane of the diffusive layer to a larger distance [11]. To investigate the chemical composition of the nanoparticle surface, XPS was carried on the MPEGPLA copolymer and freeze-dried paclitaxel-loaded nanoparticles. XPS allows to determine the elemental and average chemical composition of the material at its surface in 5–10 nm depth by measuring the binding energy of electrons associated with atoms. The C1s XPS

spectrum is shown in Fig. 3. The peak at the binding energy 286.6 eV is regarded as the indicator of MPEG as described by Peracchia [18]. From Fig. 3, the presence of PEG on the particle surface can be con?rmed by an increased –C–O– peak ratio (18%) compared with the pure MPEG-PLA copolymer (14%). 3.5. In vitro release Fig. 4 shows the accumulative release curve of paclitaxel from the particles in vitro. It is a biphasic

282 (A)

284

286 288 Binding Energy (ev)

290

292

282 (B)

284

286 288 Binding Energy (ev)

290

292

Fig. 3. XPS spectrum of: (A) MPEG-PLA copolymer; and (B) paclitaxel-loaded MPEG-PLA nanoparticles.

1.0 Accumulative Release 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 Time (days) 12 14 16

Fig. 2. AFM images of paclitaxel-loaded MPEG-PLA nanoparticles.

Fig. 4. The in vitro release pro?le of paclitaxel-loaded MPEG-PLA nanoparticles.

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release pattern. At the ?rst 7 days, 85% paclitaxel was released at a constant faster rate. After that, a slower release rate could be observed and nearly 90% paclitaxel was released in 14 days. Compared with the release pro?le of paclitaxel from PLGA nanoparticles prepared by the emulsion/solvent evaporation method in our former work [30,31,33] in which only 30% paclitaxel was released in 1 month, MPEG-PLA nanoparticles exhibited a much faster release rate. This facilitated release can be ascribed to the high surface to volume ratio of MPEG-PLA nanoparticles prepared by the nanoprecipitation method. It may also be caused by the presence of PEG in the polymer matrix, which reduced the hydrophobic interaction between the polymer and the drug. Moreover, PEG could induce easier penetration of the water and promote the erosion of the polymer matrix. All these factors can accelerate the release of the drug from the particles. 3.6. Physical stability of the nanoparticle suspension In the clinical administration of the nanoparticle suspension, vessel occlusion due to the particle aggregation may occur. The steric stability of nanoparticles in the biological milieu is thus important aspect to be considered. An improved safety pro?le of MPEG-PLA nanoparticles was observed in comparison with the PLA nanoparticles, which was attributed to the presence of PEG on the particles surface to prevent the coagulation cascade [44]. In the nanoprecipitation method, the surfactant does not really attend the formation of nanoparticles. It acts as a stabilizer for keeping the particles’ stability. It was reported that a four-fold increase of the size was observed for the particles without surfactant. Instead, only small variations in size were observed in 2 month for those prepared with the surfactant [38]. MPEG-PLA nanoparticles are of a coreshell structure: the hydrophobic PLA compromised the pact core while the hydrophilic PEG extended to the

outer aqueous environment to form a shell. This structure is believed to possess self-stabilization function. In our work, the particles were suspended in PBS and the size was recorded (Fig. 5). Only a small size variation from 83.4 to 125 nm is observed in 14 days. This demonstrates that MPEG-PLA nanoparticles possess good steric stability in vitro.

4. Conclusions Stealthy nanoparticles were prepared in the present study from synthesized MPEG-PLA copolymer by the nanoprecipitation method for controlled release of an antineoplastic drug paclitaxel. The prepared particles looked spherical in nanometer scale under AFM. They were of size less than 100 nm. Zeta potential measurements and XPS analysis demonstrated the dominance of the PEG shell on the particle surface. The particles size was found mainly affected by the organic phase viscosity while the drug EE was greatly in?uenced by the drug loading. By adjusting the protocol parameters, the size and the drug EE as well as the drug release kinetics can be optimally controlled. The particles suspension exhibited good steric stability in vitro. This research may have potential to provide an alternative dosage form for paclitaxel, one of the best anticancer drugs found from the nature in the past decades and the commercially most successful anticancer agents.

Acknowledgements This research is supported by Grant I3-14, Singapore Cancer Syndicate (SCS). DYC is indebted of NUS scholarship for his Ph.D.

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Fig. 5. Steric stability of paclitaxel-loaded MPEG-PLA nanoparticles in PBS.

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