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Near-Critical Fluid Micellization for High and Efficient Drug Loading: Encapsulation of Paclitaxel into PEG-b-PCL Micelles Zachary L. Tyrrell,† Youqing Shen,*,‡ and Maciej Radosz*,† †
Soft Materials Laboratory, Department of Chemical & Petroleum Engineering, University of Wyoming, 1000 E University Ave, Laramie, Wyoming 82071, United States ‡ Center for Bionanoengineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China 310027 ABSTRACT: Paclitaxel, an expensive first-line anticancer drug, is known to have better pharmacokinetics and therapeutic efficacy if encapsulated in polymeric micelles. However, the conventional encapsulation methods using incompressible aqueous solutions are limited to low drug loading, less than 3% of micelle weight, and low efficiency, more than two-thirds of the drug in solution remains unencapsulated, and hence wasted, not to mention the burst release problems. This work demonstrates that expansion of near-critical fluid solutions, for example in compressible dimethyl ether and trifluoromethane not too far from their critical region, can lead to a much higher drug loading, for example in micelles formed from poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL). By controlling the drug precipitation within the micellar solution region, the loading of paclitaxel in PEG-b-PCL can reach over 12% with a loading efficiency of 87%, which is unattainable by conventional methods. Moreover, the burst release fraction of the drug can be reduced despite the higher drug loading. This means that the new near-critical fluid micellization (NCFM) method will allow not only for a lower exposure of the body to the copolymer at the same treatment drug rate, due to the high drug loading, but also for less waste of the expensive drug, due to the high efficiency.
’ INTRODUCTION Block copolymers that contain a hydrophilic block, which forms the corona, and a hydrophobic block, which forms the core in aqueous environment, can self-assemble into nanosized micelles, which are precursors of carriers for hydrophobic drugs, including many used for cancer therapy.17 Similar to other drug-delivery diblocks, poly(ethylene glycol)-block-poly(ε-caprolactone)8,9 is not soluble in water in its virgin disordered state, so its micellar dispersion in water requires special preparation. The conventional micelle preparation method is through solvent evaporation or dialysis, in which the polymer and drug are first dissolved in a nonselective water-miscible organic solvent to form a homogeneous molecular solution. As the solution is either added dropwise to or dialyzed against water, the micelles that are formed encapsulate the drug in their cores. The organic solvent is removed by evaporation or continued dialysis and water can be removed by freeze-drying.913 Two properties are commonly used to characterize the encapsulation effectiveness: the drug loading content (DLC), defined as the weight percent of drug in the micelles, and the drug loading efficiency (DLE), defined as the percentage of the initial drug added to the organic solution that is incorporated into the micelles. A more detailed description of all these nanoparticle preparation methods, including DLC and DLE characterization, is available in a recent review paper.14 Typically, the conventional nanoparticle preparation methods result in low drug loading content and r 2011 American Chemical Society
efficiency, particularly for highly hydrophobic drugs due to their low solubility in water-rich solvents.9,12,15 For example, paclitaxel loading content in PEG-b-PCL micelles by solvent evaporation was found to be 1.42.3 wt % and its loading efficiency to be 2040%.15 This is because the conventional nanoparticle preparation methods rely on incompressible liquid solvents that allow for a very limited micellization control, and almost no micellization versus drug precipitation control, which is critical. This problem can be addressed with compressible solvents, such as near-critical fluids, which allow for a much more selective and flexible micellization control with pressure alone, not to mention an option to synchronize it with drug precipitation control and no residual solvent in the final product.16 In our previous work, we demonstrated and characterized pressure-tuned micellization for well-defined and uniform model styrene-block-diene copolymers in near-critical propane.17 More relevant to this work, we characterized PEG-b-PCL micellization in supercritical trifluoromethane and demonstrated that, following rapid removal of trifluoromethane by decompression, the precipitated copolymer, in contrast to the virgin copolymer, can be easily redispersed in water,18 which is important from the delivery standpoint. We also Received: March 11, 2011 Revised: April 27, 2011 Published: May 25, 2011 11951
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The Journal of Physical Chemistry C demonstrated that, by varying the solvent type and composition, it was possible to control the micellization and precipitation pressures for PEG-b-PCL in a predictable way.19 However, we do not understand how drug presence can affect micellization and what it takes to achieve high drug loading without affecting the release kinetics too much. The objective of this work, therefore, is to characterize compressible solutions of model drugs and PEG-b-PCL in near-critical solvents that can allow not only for molecularly homogeneous solutions at high pressures but also for micellar solutions at moderate pressures, and hence for drug-loaded micelle-structured precipitates upon decompression to ambient pressure, without having to add, subtract, or dialyze any components. Examples of specific questions addressed in this work are the following: How will the drug-loading content of PEG-bPCL micelles be affected by processing in supercritical fluids relative to that in conventional liquid solvents? How will it depend on the cloud pressure of drug alone relative to the cloud pressure of the copolymer alone? For example, in order to maximize drug loading, should the drug remain in solution during micellization or should it precipitate before micellization or perhaps simultaneously with micellization? The proposed compressible-solvent method offers a unique way to address these questions.
’ APPROACH Materials. PEG (5K)PCL (5K) was obtained from Polymer Source, Inc., with an Mw/Mn of 1.10. Paclitaxel and tamoxifen were obtained from Sigma-Aldrich and used without further purification. Doxorubicin HCl was obtained from Sigma-Aldrich and converted to it base form (doxorubicin base) by dissolving in water and adding excess triethylamine. The precipitated doxorubicin base was centrifuged and dried under vacuum for 48 h. The solvents dimethyl ether (DME) and trifluoromethane (R23) were obtained from Airgas at 99.5% purity. Cloud Point and Micellization Experiments. The cloud point refers to the onset of a bulk transition of a binary solution from a homogeneous one-phase region to a heterogeneous twophase region. The cloud point transition for systems studied in this work can be induced either by decreasing temperature at constant pressure, which results in the cloud temperature, or by decreasing pressure at constant temperature, which results in the cloud pressure (CP). Upon increasing pressure or temperature beyond the cloud point boundary, the solution returns to its homogeneous one-phase state. The micellization pressure (MP) refers to the highest pressure at which micelles can be formed in a homogeneous solution upon decompression or, conversely, decomposed upon compression, at constant temperature. The nanosized micelle-containing phase is referred to as the micellar solution, in contrast to the molecular solution observed following micelle decomposition. The CP and MP transitions are measured in a small (about 1 cm3 in volume) high-pressure variable-volume cell coupled with transmitted- and scattered-light intensity probes and with a borescope for visual observation of the phase transitions. This apparatus is equipped with a data acquisition and control systems described elsewhere.20The control system allows not only for constant temperature and pressure measurements but also for decreasing and increasing temperature and pressure measurements at a constant rate. The cloud points reported in this work are detected with a transmitted-light intensity probe.
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The micellization points are detected with a scattered-light intensity probe. A detailed description of the apparatus and of its transmitted- and scattered-light intensity probes is given elsewhere.20,21 The cell has a floating piston, which can change the volume of the cell, to compress or decompress the mixture to a desired pressure, without having to change the mixture composition. A known amount of the copolymer that will typically lead to a 1.0 wt % solution and solvent are loaded into the cell, which is then brought to and maintained at a desired pressure and temperature at which copolymer can be dissolved. After the mixture is well equilibrated in a one-phase region for at least 90 min by stirring at constant temperature and pressure, the pressure is decreased slowly, while holding the temperature constant, until the solution turns turbid, which indicates the onset of phase separation. In this study, a pressure rate as low as 15 bar/min is chosen to obtain a reproducible cloud pressure as suggested by previous studies.17 Cloud pressures are reproducible to within (3 bar. Upon decompression, the bulk phase boundary (e.g., CP) is approached from the one-phase or micellar phase side, and the transmitted light intensity (TLI) starts decreasing. Conversely, upon compression, the phase boundary is approached from the two-phase side, and TLI starts increasing. A new data point is taken after equilibrating the mixture for 15 min in the one-phase region, well above the expected cloud temperature and pressure. In all cases, the TLI data are stored and analyzed as a function of time, temperature, and pressure. The cloud pressure in this work is taken as the inflection point on the TLI curve, which corresponds to a peak on its first derivative. Micelle formation is probed using high-pressure dynamic light scattering. The scattered-light intensity and the hydrodynamic radius sharply increase on approaching the micellization pressure from the high-pressure side. For these measurements, we couple our high-pressure equilibrium cell with an argon ion laser (National Laser) model 800BL operating at λ of 488 nm and a Brookhaven BI-9000AT correlator, as described previously.17 Preparation of Drug-Loaded Micelle Solutions. Aqueous drug-loaded micelle solutions are prepared by the following procedure. The polymer, drug, and selected solvent (trifluoromethane, dimethyl ether, or a mixture of the two) are loaded into the high-pressure cell. The solvent composition is chosen based on the relative phase behavior of the drug and the polymer. The polymer and drug are dissolved by setting the temperature and pressure well into the one-phase region, again determined by the phase diagram of the polymer and drug. Upon dissolution, the temperature is lowered to 35 °C at constant pressure, and the mixture is equilibrated for 15 min. The pressure is then lowered slowly (10 bar/min) to within 50 bar of the cloud point for the mixture to allow adequate time for the equilibration of the micellization process. From this point, the mixture is rapidly depressurized by releasing the pressurizing fluid (propane). The micelles are precipitated as the solvent rapidly evaporates. The solvent is then released slowly from the cell to prevent the loss of solids. The cell is washed with a known volume of distilled water into a flask and stirred. The volume of water is chosen to give a final concentration of 0.1 wt % polymer. As a control, drugloaded micelle solutions are prepared by a conventional solvent evaporation method in which the polymer and drug are dissolved in acetone and added dropwise to distilled water under stirring. Acetone is removed by evaporation over a 24 h period. 11952
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Figure 1. Cloud pressures in trifluoromethane of Tamoxifen, PEG-bPCL [MW = 5000-b-5000], and combination and micellization pressures of PEG-b-PCL. The concentrations of PEG-b-PCL and Tamoxifen are 1 and 0.1 wt %, respectively.
Particle Size Measurements. Particle size measurements of the aqueous solutions are performed using dynamic light scattering after filtering the solution with a 0.2 μm PTFE filter. Drug Loading Measurements. Drug loading is characterized by the drug loading content (DLC) and the drug loading efficiency (DLE) defined as follows:
DLC ¼
weight of drug in micelles 100% total weight of micelles
DLE ¼
weight of drug in micelles 100% initial weight of drug
Prior to determination of drug loading content, all drug-loaded micelle solutions are filtered through a 0.2 μm PTFE filter to remove any crystallized, unencapsulated drug. The amount of drug in the micelles is measured with HPLC using a 50/50 (v/v) mixture of acetonitrile and water or UVvis spectroscopy using DMSO. UV absorbance is monitored at a wavelength of 275 nm for tamoxifen, 225 nm for paclitaxel, and 485 nm for doxorubicin base. Drug concentration is determined by calibration with a series of standards of known concentration. The total weight of the micelles is determined by removing water from the aqueous solution and weighing the sample. Experiments are repeated 35 times to confirm accuracy. Drug Release Kinetics. For paclitaxel-loaded PEG-b-PCL micelles, a known volume of drug-loaded micelle solution is placed in a dialysis bag (MWCO 3500, cellulose acetate). The bag is immersed in a beaker of 100 mL of distilled water, adjusted to pH 7.4 with Na2CO3, and held at a constant temperature of 37 °C in a water bath with horizontal shaking. The water is completely replaced at defined time intervals. For paclitaxel, concentration is measured by HPLC after concentrating the samples by evaporating water under vacuum and replacing with a small volume of 50/50 (v/v) acetonitrile/water.
’ RESULTS AND DISCUSSION One of the advantages of compressible solvents is the fact that pressure alone can be used as a powerful control parameter for
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Figure 2. Micellization and cloud pressures of PEG-b-PCL [MW = 5000-b-5000] þ Paclitaxel in 70% dimethyl ether þ30% trifluoromethane. The concentrations of PEG-b-PCL and Paclitaxel are 1.5 and 0.15 wt %, respectively. The arrows indicate the pressure/time profile of micellization/depressurization process used to recover drugloaded micelles.
Figure 3. Drug loading content of tamoxifen and paclitaxel PEG-b-PCL [MW 5000-b-5000]. Error bars represent the standard deviation of n = 3 for tamoxifen and n = 5 for paclitaxel. Literature values for paclitaxel15 were obtained by solvent evaporation method using THF. Literature reference unavailable for tamoxifen in PEG-b-PCL.
adjusting the solvent capacity and selectively, and hence for micelle formation and bulk precipitation, in addition to solvent composition and temperature. This is because discrete changes of solvent composition are inefficient and temperature changes are severely limited due to thermal stability, while pressure can be continuously changed by orders of magnitude. In particular, when continuous pressure control is combined with a judicious choice of the solvent type and composition, one can in general, for the first time, nearly exactly coordinate drug precipitation relative to micellization and optimize it for the best drug loading outcomes. 11953
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Figure 4. Particle size of PEG-b-PCL [MW 5000-b-5000] in water loaded with increasing weight percent of Paclitaxel. Average diameters: no drug, 60.2 nm; 2.6 wt %, 63.1 nm; 12.4 wt %, 68 nm.
We shall explore this hypothesis for three distinct cases of the drug cloud pressure relative to the polymer micellization pressure: (1) the drug cloud pressure is much lower, (2) the drug cloud pressure is much higher, and (3) the drug cloud pressure is below the polymer micellization pressure but above the polymer cloud pressure. The cloud pressure refers to the onset of a bulk separation of a molecularly homogeneous solution into two macroscopically distinct phases. The micellization pressure (MP) refers to the highest pressure at which micelles can be formed at constant temperature upon decompression, upon transition from molecular to micellar solution, or, conversely, decomposed upon compression, upon transition from micellar to molecular solution. An example of the first case is illustrated in Figure 1 for PEG-bPCL [MW 5000-b-5000] and tamoxifen in trifluoromethane. The much lower cloud pressure of tamoxifen (stars) indicates that the drug is significantly more soluble in trifluoromethane than PEG-b-PCL. In other words, it not only remains in solution before micellization, and after micellization (it partitions then between the solvent and the micelle core), but also after polymer precipitation. It is also worth noting that tamoxifen does not affect the cloud pressure or the micellization pressure of the
copolymer itself too much; the open square and filled square curves are close. An example of the other extreme (2) case, for doxorubicin base in a mixture of 70% dimethyl ether and 30% trifluoromethane, is not illustrated with a figure because the doxorubicin solubility is too low to achieve a complete miscibility with the solvent. In other words, the drug solubility is so low that at least a fraction of it remains as a dispersed solid at all conditions, similar to conventional methods where the drug often precipitates prior to micellization, which is undesirable from the drug loading stand point. An example of the intermediate (3) case is illustrated in Figure 2 for PEG-b-PCL [5K-b-5K] and paclitaxel in a mixture of 70% dimethyl ether and 30% trifluoromethane. The solvent composition was chosen on the basis of cloud point data for PEG-b-PCL gathered in a previous work,19 so that the relationship of the cloud pressure of the polymer and drug could be finely tuned for this experiment. As shown in Figure 2, the cloud pressure of paclitaxel lies within the micellar region, in this case just above (but close to) the polymer cloud pressure, which should result in precipitation of the drug from solution just before but close to the onset of the bulk polymer precipitation upon decreasing pressure. 11954
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The Journal of Physical Chemistry C Figure 2 also illustrates the isothermal path taken to prepare drug-loaded micelles from a high-pressure molecular solution (similar for all three cases discussed above). The solution is initially pressurized into the one-phase region of the phase diagram, near 550 bar at 30 °C in this case. The pressure is reduced slowly at a rate of ∼10 bar/min into the micellar region to allow ample time for micelle formation. When the solution reaches a pressure just above the polymer cloud point, in this case around 300 bar, it is depressurized rapidly to atmospheric pressure and then cooled to room temperature, upon which water is added to form an aqueous micellar solution, which is analyzed for drug loading capacity. For the case of paclitaxel-loaded micelles prepared in a mixture of 70% dimethyl ether and 30% trifluoromethane (Figure 2), the paclitaxel loading content is found to be 12.4 ( 1.8 wt %, with an efficiency of 87 ( 8%. By contrast, the drug loading content for the corresponding control solution prepared using a conventional solvent evaporation method with acetone was 2.6 ( 0.8 wt %, with an efficiency of 28 ( 5%, which is close to the value of 2.3 wt % reported by Shuai et al.15 for paclitaxel loaded into PEGb-PCL [MW 5000-b-18000] micelles using the same acetone evaporation method. In addition to a much higher drug-loading efficiency, by a factor of 3, the drug-loading content is also dramatically improved, as shown in Figure 3 (right side). This means that the precipitation of the drug from solution within the micellar region can provide an effective driving force for the drug to become incorporated in the micelle core. It remains to be optimized how close the drug cloud pressure should be to the polymer cloud pressure. By contrast, for tamoxifen-loaded micelles prepared in trifluoromethane (Figure 1), tamoxifen loading content is found to be 3.3 ( 0.5 wt %, while its loading efficiency is found to be 33 ( 4%. For the corresponding control solution prepared using solvent evaporation, the drug loading content is 2.5 wt %, while the drug loading efficiency is 26%. These results, shown in Figure 3 (left side), suggest that tamoxifen-loaded micelles prepared in trifluoromethane offer a slight improvement in terms of drug loading over the conventional solvent evaporation method. This means that if the drug cloud pressure is way below that of the polymer, its partitioning coefficient (between the micelle core and the solvent) is low, and hence the chemicalpotential driving force for the drug to become incorporated in the core is not as strong as that in case (3). Not surprisingly, for doxorubicin base in a mixture of 70% dimethyl ether and 30% trifluoromethane (case 2), where the solid drug is not completely dissolved in the solvent, the drug loading content is found to be essentially zero. This illustrates how important it is for the drug molecules be in solution during micellization to have a chance to find their way into the micelle core. Having demonstrated the drug loading content and efficiency advantage, one needs to verify that the particle size and drug release profile are within the normal ranges. Particle size distributions of micelles prepared by near-critical fluid expansion with no drug present, of the drug-loaded micelles prepared by conventional solvent evaporation, and of the drug-loaded micelles prepared by near-critical fluid expansion were measured by dynamic light scattering. The results are summarized in Figure 4. The average diameter increases on going from left to right, from 60.2 nm for the micelles with no drug, to 63.1 nm for the control micelles with 2.6 wt % drug, to 68.0 nm for the micelles with 12.4 wt % drug. This increase in the average micelle size with
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Figure 5. Drug release profile of paclitaxel from PEG-b-PCL micelles prepared by solvent evaporation (open circles) and supercritical micellization (squares) into distilled water at pH = 7.4 and T = 37 °C. Error bars represent standard deviation of n = 4 experiments.
increasing drug loading content is consistent with the previous observations that the incorporation of additional material within the micelle structure can result in detectable increase in the micelle size.15,2224 These small size differences have negligible consequences for drug delivery where the particle size is normally controlled with the polymer molecular weight.14 Figure 5 shows the paclitaxel release profile of paclitaxelloaded PEG-b-PCL micelles prepared by conventional solvent evaporation with acetone and, separately, by supercritical micellization in 70% dimethyl ether and 30% trifluoromethane. When the cumulative drug released is plotted as a percent of the total amount of drug in the micelles over time, materials obtained from both methods exhibit a relatively rapid release within the first several hours followed by a slower, sustained release, which is common to polymeric micelles.12,25 The rapid-release stage ends at about 5055% for the conventional nanoparticles and at about 35% for the new nanoparticles, which suggests a shift in a desirable direction.
’ CONCLUSION In conclusion, expansion of a near-critical fluid solution of poly(ethylene glycol)-block-poly(ε-caprolactone) can lead to robust micellization and high drug loading if the drug precipitation occurs within the micellar solution region. For example, the loading of a hydrophobic cancer drug Paclitaxel in PEG-b-PCL can be improved from less than 3 wt % for nanoparticles obtained from incompressible liquid solvents to over 12 wt % for nanoparticles obtained by expansion of a dimethyl ether and trifluoromethane solvent, while the loading efficiency is improved from 28 to 87%, and even the rapid-release fraction of the drug is reduced from about one-half to about one-third of the drug initially present. ’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected] (Y.S.);
[email protected] (M.R.). 11955
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’ ACKNOWLEDGMENT The authors acknowledge the National Science Foundation for providing funding for this work through Awards CBET0828472 and CBET-1034530. ’ REFERENCES (1) Alakhov, V.; Moskaleva, E.; Batrakova, E.; Kabanov, A. Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer. Bioconjugate Chem. 1996, 7, 209–216. (2) Gref, R.; Minamitake, Y.; Peracchia, M.; Trubetskoy, V.; Torchilin, V.; Langer, R. Biodegradable long-circulating polymeric nanospheres. Science 1994, 263, 1600–1603. (3) Kabanov, A.; Alakhov, V. Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery; Elsevier: Dordrecht, 1997. (4) Kabanov, A.; Nazarova, I.; Astafieva, I.; Batrakova, E.; Alakhov, V.; Yarostavov, A.; Kabanov, V. Micelle formation and solubilization of fluorescent probes in poly(oxyethylene-b-oxypropylene-b-oxyethylene). Macromolecules 1995, 28, 2303–2314. (5) Kataoka, K.; Kwon, G.; Yokoyama, M.; Okano, T. Block copolymer micelles as vehicles for drug delivery. J. Controlled Release 1992, 24, 119–132. (6) Kwon, G.; Naito, M.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Kataoka, K. Block copolymer micelles for drug delivery: loading and release of doxorubicin. J. Controlled Release 1997, 48, 195–201. (7) La, S.; Okano, T.; Kataoka, K. Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(-benzyl L-aspartate) block copolymer micelles. J. Pharm. Sci. 1996, 85, 85–90. (8) Aliabadi, H.; Mahmud, A.; Sharifabadi, A.; Lavasanifar, A. Micelles of methoxy poly(ethylene oxide)-b-poly(-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A. J. Controlled Release 2005, 104 (2), 301–311. (9) Allen, C.; Yu, Y.; Maysinger, D.; Eisenberg, A. Polycaprolactoneb-poly(ethylene oxide) block copolymer micelles as a novel drug delivery vehicle for neurotrophic agents FK506 and L-685,818. Bioconjugate Chem. 1998, 9 (5), 564–572. (10) Gaucher, G.; Dufresne, M.; Sant, V.; Kang, N.; Maysinger, D.; Leroux, J. C. Block copolymer micelles: preparation, characterization and application in drug delivery. J. Controlled Release 2005, 109, 169–188. (11) Jette, K.; Law, D.; Schmitt, E.; Kwon, G. S. Preparation and drug loading of poly(ethylene glycol)-block-poly(ε-caprolactone) micelles through the evaporation of a cosolvent azeotrope. Pharm. Res. 2004, 21 (7), 1184–1191. (12) Shuai, X.; Ai, H.; Nasongkla, N.; Kim, S.; Gao, J. Micellar carriers based on block copolymers of poly(-caprolactone) and poly(ethylene glycol) for doxorubicin delivery. J. Controlled Release 2004, 98 (3), 415–426. (13) Vangeyte, P.; Gautier, S.; Jerome, R. About the methods of preparation of poly(ethylene oxide)-b-poly(ε-caprolactone) nanoparticles in water: Analysis by dynamic light scattering. Colloids Surf., A 2004, 242, 203–211. (14) Tyrrell, Z.; Shen, Y.; Radosz, M. Fabrication of micellar nanoparticles for drug delivery through the self-assembly of block copolymers. Prog. Polym. Sci. 2010, 35, 1128–1143. (15) Shuai, X.; Merdan, T.; Schaper, A.; Xi, F.; Kissel, T. Core-crosslinked polymeric micelles as paclitaxel carriers. Bioconjugate Chem. 2004, 15 (3), 441–448. (16) Radosz, M.; Shen, Y. International Patent WO 2008/030473 A2, 2008. (17) Winoto, W.; Adidharma, H.; Radosz, M. Micellization temperature and pressure for polystyrene-block-polyisoprene in subcritical and supercritical propane. Macromolecules 2006, 39, 8140–8144. (18) Tyrrell, Z.; Winoto, W.; Shen, Y.; Radosz, M. Block copolymer micelles formed in supercritical fluid can become water-dispensable nanoparticles: Poly(ethylene glycol)-block-poly(ε-caprolactone) in trifluoromethane. Ind. Eng. Chem. Res. 2009, 48, 1928–1932.
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