Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude

Amphiphilic chitosan-based polymers (Mw < 20 kDa) self-assemble in aqueous media at low micromolar concentrations to give previously unknown micellar clusters of 100-300 nm in size. Micellar clusters comprise smaller 10-30 nm aggregates, and the nanopolarity/drug incorporation efficiency of their hydrophobic domains can be tailored by varying the degree of lipidic derivatization and molecular weight of the carbohydrate. The extent of drug incorporation by these novel micellar clusters is 1 order of magnitude higher than is seen with triblock copolymers, with molar polymer/drug ratios of 1:48 to 1:67. On intravenous injection, the pharmacodynamic activity of a carbohydrate propofol formulation is increased by 1 order of magnitude when compared to a commercial emulsion formulation, and on topical ocular application of a carbohydrate prednisolone formulation, initial drug aqueous humor levels are similar to those found with a 10-fold dose of prednisolone suspension.     

Combined Delivery of Paclitaxel and Tanespimycin via Micellar Nanocarriers: Pharmacokinetics,Efficacy and Metabolomic Analysis

Background

Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo.

Methodology/Principal Findings

Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles.

Conclusions/Significance

We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.     

Linoleic acid-grafted chitosan oligosaccharide micelles for intracellular drug delivery and reverse drug resistance of tumor cells

Intracellular drug delivery is an important rout to reverse drug resistance of tumor cells. In this study, the linoleic acid (LA)-grafted chitosan oligosaccharide (CSO) was synthesized to construct a micellar delivery system for intracellular delivery. The synthesized linoleic acid-grafted chitosan oligosaccharide (CSO-LA) with 10.3% graft ratio of LA could form micelles in aqueous with 86.69 μg/ml critical micellar concentration (CMC). The CSO-LA micelle had 46.2±3.6 nm number average diameter and 36.0±3.3 mV zeta potential. Taking doxorubicin base (DOX) as a model drug, the drug-loaded CSO-LA micelles (CSO-LA/DOX) was then prepared. The drug encapsulation efficiencies of CSO-LA/DOX were as high as 80%, and the drug loading capacity could be improved by increasing the charged DOX. Using MCF-7, Doxorubicin·HCl resistant MCF-7 (MCF-7/ADR), K562 and Doxorubicin·HCl resistant K562 (K562/ADR) cells as model drug sensitive and drug resistant tumor cells, the experiments demonstrated the CSO-LA had excellent cellular uptake ability by either drug sensitive tumor cells or drug resistance tumor cells. The CSO-LA micelles could deliver DOX into tumor cells, and the DOX in cells was increased with incubation time. As a result, the cytotoxicities of DOX encapsulated in CSO-LA micelles against drug resistance tumor cells were improved significantly, comparing to that of Doxorubicin·HCl solution.     

Targeted albumin-based nanoparticles for delivery of amphipathic drugs

We report the preparation and physical and biological characterization of human serum albumin-based micelles of approximately 30 nm diameter for the delivery of amphipathic drugs, represented by doxorubicin. The micelles were surface conjugated with cyclic RGD peptides to guide selective delivery to cells expressing the α(v)β(3) integrin. Multiple poly(ethylene glycol)s (PEGs) with molecular weight of 3400 Da were used to form a hydrophilic outer layer, with the inner core formed by albumin conjugated with doxorubicin via disulfide bonds. Additional doxorubicin was physically adsorbed into this core to attain a high drug loading capacity, where each albumin was associated with about 50 doxorubicin molecules. The formed micelles were stable in serum but continuously released doxorubicin when incubated with free thiols at concentrations mimicking the intracellular environment. When incubated with human melanoma cells (M21+) that express the α(v)β(3) integrin, higher uptake and longer retention of doxorubicin was observed with the RGD-targeted micelles than in the case of untargeted control micelles or free doxorubicin. Consequently, the RGD-targeted micelles manifested cytotoxicity at lower doses of drug than control micelles or free drug.     

Investigation on the interactions between pirarubicin and phospholipids

Differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and quantum calculation based on molecular modeling were applied to investigate the interaction between pirarubicin (THP), an anthracycline antibiotic frequently used in chemotherapy, and zwitterionic distearoylphosphatidylcholine (DSPC) or anionic distearoylphosphatidylglycerol (DSPG). DSC and FTIR studies suggested that DSPG bilayers were less perturbed by THP than those of DSPC, and this might be due to the strong interactions between NH₃⁺ of THP and the phosphate (PO₂⁻) group in the polar head of DSPG, which limit the further access of THP into its bilayers. Quantum calculation results based on molecular modeling could further confirm the DSC and FTIR conclusions. Meanwhile, it could well translate the calorimetric and spectroscopic phenomena into the underlying physical knowledge. Interactions between THP and phospholipids can play a critical role in the liposomal drug delivery system, especially in the safety mechanism elucidation and rational formulation design.     

Characteristics of protein partitioning in an aqueous micellar-gel system

Partitioning of proteins has been studied experimentally in a system combining a gel-bead phase and a nonionic micellar phase. The micellar phase consists of cylindrically shaped micelles, which are completely excluded from the gel-bead phase. Partitioning of single-component protein solutions (myoglobin, ovalbumin, and BSA) is determined by excluded-volume interactions in the micellar phase, and as a result the proteins prefer the gel-bead phase to the micellar phase. The protein concentration inside the gel beads increases with an increase in volume fraction of the micelles and increases with an increase in the size of the proteins. The protein partition coefficients obtained for a binary mixture of myoglobin and bovine serum albumin (BSA) show the same protein concentration dependence as the single-component protein partition coefficients.     

Anticancer effect of atorvastatin nanostructured polymeric micelles based on stearyl-grafted chitosan

The purpose of this study was to develop a new therapeutic approach for atorvastatin (ATV) adopting nanostructured polymeric micelles for its controlled delivery to the cancer cells. Amphiphilic block copolymers of stearyl chitosan (SC) and sulfated stearyl chitosan (S-SC) that could self assemble to form polymeric micelles with different degree of substitution (DS) were synthesized and characterized. The synthesized chitosan derivatives were able to self assemble and form micelles encapsulating ATV with critical micellar concentrations ranging from 6.9 to 21μg/ml, drug-loading ranging from 40% to 84.1% and encapsulation efficiency ranging from 10.4% to 35%. ATV caused a significant decrease in particle size and zeta potential of both SC and S-SC micelles. Micelles encapsulating ATV exhibited a sustained release and more cytotoxic activity against MCF 7 and HCT 116 cell lines than ATV alone. The 50% cellular growth inhibition (IC50%) of the drug decreased from 10.4 to 3.7 in case of MCF 7 and from 9.4 to 3.4 in case of HCT 116 after its loading in micelles. These results indicate that SC ATV polymeric micelles can be considered as a promising system for site specific controlled delivery of ATV to tumor cells.     

Redox-responsive polyphosphate nanosized assemblies: a smart drug delivery platform for cancer therapy

Novel redox-responsive polyphosphate nanosized assemblies based on amphiphilic hyperbranched multiarm copolyphosphates (HPHSEP-star-PEP(x)) with backbone redox-responsive, good biocompatibility, and biodegradability simultaneously have been designed and prepared successfully. The hydrophobic core and hydrophilic multiarm of HPHSEP-star-PEP(x) are composed of hyperbranched and linear polyphosphates, respectively. Benefiting from the amphiphilicity, HPHSEP-star-PEP(x) can self-assemble into spherical micellar nanoparticles in aqueous media with tunable size from about 70 to 100 nm via adjusting the molecular weight of PEP multiarm. Moreover, HPHSEP-star-PEP(x) micellar structure can be destructed under reductive environment and result in a triggered drug release behavior. The glutathione-mediated intracellular drug delivery was investigated against a HeLa human cervical carcinoma cell line, and the results indicate that doxorubicin-loaded (DOX-loaded) HPHSEP-star-PEP(x) micelles show higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated ones. In contrast, the DOX-loaded micelles exhibit lower inhibition against buthionine sulfoximine pretreated HeLa cells. These results suggest that such redox-responsive polyphosphate micelles can rapidly deliver anticancer drugs into the nuclei of tumor cells enhancing the inhibition of cell proliferation and provide a favorable platform to construct excellent drug delivery systems for cancer therapy.     

Polymeric Micelles: Nanocarriers for Cancer-Targeted Drug Delivery

Polymeric micelles represent an effective delivery system for poorly water-soluble anticancer drugs. With small size (10–100 nm) and hydrophilic shell of PEG, polymeric micelles exhibit prolonged circulation time in the blood and enhanced tumor accumulation. In this review, the importance of rational design was highlighted by summarizing the recent progress on the development of micellar formulations. Emphasis is placed on the new strategies to enhance the drug/carrier interaction for improved drug-loading capacity. In addition, the micelle-forming drug-polymer conjugates are also discussed which have both drug-loading function and antitumor activity.     

Thermally controlled release of anticancer drug from self-assembled γ-substituted amphiphilic poly(ε-caprolactone) micellar nanoparticles

A thermo-responsive poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone}-b-poly(γ-octyloxy-ε-caprolactone) (PMEEECL-b-POCTCL) diblock copolymer was synthesized by ring-opening polymerization using tin octanoate (Sn(Oct)(2)) catalyst and a fluorescent dansyl initiator. The PMEEECL-b-POCTCL had a lower critical solution temperature (LCST) of 38 °C, and it was employed to prepare thermally responsive micelles. Nile Red and Doxorubicin (DOX) were loaded into the micelles, and the micellar stability and drug carrying ability were investigated. The size and the morphology of the cargo-loaded micelles were determined by DLS, AFM, and TEM. The Nile-Red-loaded polymeric micelles were found to be stable in the presence of both fetal bovine serum and bovine serum albumin over a 72 h period and displayed thermo-responsive in vitro drug release. The blank micelles showed a low cytotoxicity. As comparison, the micelles loaded with DOX showed a much higher in vitro cytotoxicity against MCF-7 human breast cancer cell line when the incubation temperature was elevated above the LCST. Confocal laser scanning microscopy was used to study the cellular uptake and showed that the DOX-loaded micelles were internalized into the cells via an endocytosis pathway.     

Influence of preparation path on the formation of discs and threadlike micelles in DSPE-PEG(2000)/lipid systems

In a recent study we showed that the surfactant 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG(2000)) induce mixed micelles of either threadlike or discoidal shape when mixed with different types of lipids. In certain lipid systems the discoidal micelles adapt sizes large enough to be characterized as bilayer discs. The discs hold great potential for use in various biotechnical applications and may e.g. be used as model membranes in drug/membrane partition studies. Depending on the application, discs with certain characteristics, such as a particular size or size homogeneity, may be required. These factors can in our experience be influenced by the preparation method. In this study we systematically investigated three different PEG-lipid/lipid mixtures prepared by four commonly used preparation techniques. The techniques used were simple hydration, freeze-thawing, sonication and detergent depletion, and the aggregate size and structure was analyzed by cryo transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS). Our results show that the type and size of the micellar structure found, as well as the structure homogeneity of the preparation, can be modified by the choice of preparation path.     

Unimolecular micelles based on hydrophobically derivatized hyperbranched polyglycerols: ligand binding properties

This paper discusses the binding and release properties of hydrophobically modified hyperbranched polyglycerol-polyethylene glycol copolymers that were originally developed as human serum albumin (HSA) substitutes. Their unimolecular micellar nature in aqueous solution has been proven by size measurements and other spectroscopic methods. These polymers aggregate weakly in solution, but the aggregates are broken down by low shear forces or by encapsulating a hydrophobic ligand within the polymer. The small molecule binding properties of these polymers are compared with those of HSA. The preliminary in vitro paclitaxel release studies showed very promising sustained drug release characteristics achieved by these unimolecular micelles.     

Conjugation of arginine-glycine-aspartic acid peptides to poly(ethylene oxide)-b-poly(epsilon-caprolactone) micelles for enhanced intracellular drug delivery to metastatic tumor cells

An arginine-glycine-aspartic acid (RGD) containing model peptide was conjugated to the surface of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles as a ligand that can recognize adhesion molecules overexpressed on the surface of metastatic cancer cells, that is, integrins, and that can enhance the micellar delivery of encapsulated hydrophobic drug into a tumor cell. Toward this goal, PEO-b-PCL copolymers bearing acetal groups on the PEO end were synthesized, characterized, and assembled to polymeric micelles. The acetal group on the surface of the PEO-b-PCL micelles was converted to reactive aldehyde under acidic condition at room temperature. An RGD-containing linear peptide, GRGDS, was conjugated on the surface of the aldehyde-decorated PEO-b-PCL micelles by incubation at room temperature. A hydrophobic fluorescent probe, that is, DiI, was physically loaded in prepared polymeric micelles to imitate hydrophobic drugs loaded in micellar carrier. The cellular uptake of DiI loaded GRGDS-modified micelles by melanoma B16-F10 cells was investigated at 4 and 37 degrees C by fluorescent spectroscopy and confocal microscopy techniques and was compared to the uptake of DiI loaded valine-PEO-b-PCL micelles (as the irrelevant ligand decorated micelles) and free DiI. GRGDS conjugation to polymeric micelles significantly facilitated the cellular uptake of encapsulated hydrophobic DiI most probably by intergrin-mediated cell attachment and endocytosis. The results indicate that acetal-terminated PEO-b-PCL micelles are amenable for introducing targeting moieties on the surface of polymeric micelles and that RGD-peptide conjugated PEO-b-PCL micelles are promising ligand-targeted carriers for enhanced drug delivery to metastatic tumor cells.     

Characterization of lipase in reversed micelles formulated with cibacron blue F-3GA modified span 85

Sorbitan trioleate (Span 85) modified by Cibacron Blue F-3GA (CB) was prepared and used as an affinity surfactant to formulate a reversed micellar system for Candida rugosa lipase (CRL) solubilization. The system was characterized and evaluated by employing CRL-catalyzed hydrolysis of olive oil as a model reaction. The micellar hydrodynamic radius results reflected, to some extent, the redistribution of surfactant and water after enzyme addition, and the correlation between surfactant formulation, water content (W0), micellar size, and enzyme activity. An adequate modification density of CB was found to be important for the reversed micelles to retain enough hydration capacity and achieve high enzyme activity. Compared with the results in AOT-based reversed micelles, CRL in this micellar system exhibited a different activity behavior versus W0. The optimal pH and temperature of the encapsulated lipase remained unchanged, but the apparent activity was significantly higher than that of the native enzyme in bulk solution. Kinetic studies indicated that the encapsulated lipase in the reversed micelles of CB-formulated Span 85 followed the Michaelis-Menten equation. The Michaelis constant was found to decrease with increasing surfactant concentration, suggesting an increase of the enzyme affinity for the substrate. Stability of the lipase in the reversed micelles was negatively correlated to W0.     

Galactose-decorated cross-linked biodegradable poly(ethylene glycol)-b-poly(ε-caprolactone) block copolymer micelles for enhanced hepatoma-targeting delivery of paclitaxel

The inferior in vivo stability of micellar drugs has been a prime challenge for their application in targeted drug delivery. Here we report on novel galactose-decorated covalently cross-linked biodegradable micelles based on photo-cross-linkable poly(ethylene glycol)-b-poly(acryloyl carbonate)-b-poly(ε-caprolactone) (PEG-PAC-PCL) and galactose-conjugated PEG-PCL (Gal-PEG-PCL) copolymers for enhanced hepatoma-targeting delivery of paclitaxel (PTX). The molecular weight of PEG in Gal-PEG-PCL was higher than that in PEG-PAC-PCL, thereby fully exposing Gal ligands at the micellar surface. These micelles, either with or without loading of PTX, were readily cross-linked by UV irradiation to afford micelles with small sizes (ca. 79-94 nm) and enhanced stability. The in vitro release studies confirmed that drug release from cross-linked micelles was significantly inhibited. Interestingly, MTT assays showed that Gal-decorated PTX-loaded cross-linked micelles retained a high antitumor activity in HepG2 cells, which was much more effective than PTX-loaded cross-linked micelles without Gal ligands and comparable to Gal-decorated PTX-loaded non-cross-linked micelles. Remarkably, the preliminary in vivo antitumor efficacy studies in SMMC-7721 tumor (human hepatoma)-bearing nude mice revealed that Gal-decorated PTX-loaded cross-linked micelles inhibited the growth of the human hepatoma more effectively than PTX-loaded cross-linked micelles as well as Gal-decorated PTX-loaded non-cross-linked micelles. These results indicate that Gal-decorated cross-linked PEG-PCL micelles have great potential in liver tumor-targeted chemotherapy.     

Synthesis, characterization, antitumor activity of pluronic mimicking copolymer micelles conjugated with doxorubicin via acid-cleavable linkage

Pluronic mimicking poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer having multiple hydroxyl groups in the PPO middle segment (core-functionalized Pluronic: CF-PLU) was synthesized for conjugation of doxorubicin (DOX). DOX was conjugated on the multiple hydroxyl groups of CF-PLU via an acid-labile hydrazone linkage (CF-PLU-DOX). In aqueous solution, CF-PLU-DOX copolymers self-assembled to form a core/shell-type micelle structure consisting of a hydrophobic DOX-conjugated PPO core and a hydrophilic PEO shell layer. The conjugated DOX from CF-PLU-DOX micelles was released out more rapidly at pH 5 than pH 7.4, indicating that the hydrazone linkage was cleaved under acidic condition. CF-PLU-DOX micelles exhibited greatly enhanced cytotoxicity for MCF-7 human breast cancer cells compared to naked DOX, while CF-PLU copolymer itself showed extremely low cytotoxicity. Flow cytometry analysis revealed that the extent of cellular uptake for CF-PLU-DOX micelles was greater than free DOX. Confocal image analysis also showed that CF-PLU-DOX micelles had a quite different intracellular distribution profile from free DOX. CF-PLU-DOX micelles were mainly distributed in the cytoplasm, endosomal/lysosomal vesicles, and nucleus, while free DOX was localized mainly within the nucleus, suggesting that CF-PLU-DOX micellar formulation might be advantageously used for overcoming the multidrug resistance (MDR) effect, which gradually develops in many tumor cells during repeated drug administration.     

Stability of a Pseudomonas Sp. Lipase:Comparison Between Solubilized Enzyme in Reverse Micelles and Suspended Lipase in Dry Solvents

The stability of a relatively hydrophobic lipase from Pseudomonas sp., solubilized in reverse micellar media or suspended in dry solvents, was studied and compared. Factors such as the enzyme-solvent interaction, enzyme environment, hydration degree of the system, interphase quality, droplet size, and water activity were studied. A mixed micellar system which stabilized the lipase is reported. In the case of simple AOT micelles, lipase destabilization with respect to water in small droplet sizes and stabilization in the biggest micelles was observed. These effects resulted from lipase penetration into the interphase of the smaller nanodroplets, and the restriction of its conformational mobility in the region of structured water of the largest micelles, respectively. Mixed micelles increased lipase stability, which was mainly related to increased droplet size. Modification with polyethylene glycol decreased lipase stability in reverse micelles, due to the greater interaction with the micellar interphase. The preparation of nanodroplets, in which native and modified lipases were 5.4 and 9.4 times, respectively, more stable than in water, is reported. In contrast to the micellar media, low water contents (low A_w values) stabilized the solid lipase suspended in organic solvent systems. Under the hydration conditions studied here, lipase stability increased when more polar solvents were used. Two alternatives were necessary to obtain similar stabilities in n-heptane as compared with polar solvents: reduction of the water content or use of a low aquaphilic support.     

Preparation and Characterization of Individual and Multi-drug Loaded Physically Entrapped Polymeric Micelles

Amphiphilic block copolymers like polyethyleneglycol-block-polylactic acid (PEG-b-PLA) can self-assemble into micelles above their critical micellar concentration forming hydrophobic cores surrounded by hydrophilic shells in aqueous environments. The core of these micelles can be utilized to load hydrophobic, poorly water soluble drugs like docetaxel (DTX) and everolimus (EVR). Systematic characterization of the micelle structure and drug loading capabilities are important before in vitro and in vivo studies can be conducted. The goal of the protocol described herein is to provide the necessary characterization steps to achieve standardized micellar products. DTX and EVR have intrinsic solubilities of 1.9 and 9.6 µg/ml respectively Preparation of these micelles can be achieved through solvent casting which increases the aqueous solubility of DTX and EVR to 1.86 and 1.85 mg/ml, respectively. Drug stability in micelles evaluated at room temperature over 48 hr indicates that 97% or more of the drugs are retained in solution. Micelle size was assessed using dynamic light scattering and indicated that the size of these micelles was below 50 nm and depended on the molecular weight of the polymer. Drug release from the micelles was assessed using dialysis under sink conditions at pH 7.4 at 37 ^oC over 48 hr. Curve fitting results indicate that drug release is driven by a first order process indicating that it is diffusion driven.     

胶束化色胺酮的制备及表征

目的通过制备胶束化色胺酮,增加色胺酮的溶解度,并进一步提高其生物利用度。方法:以酸敏感的腙键连接聚乙二醇和色胺酮,并通过透析法,将聚乙二醇化色胺酮进一步制备成胶束。用动态光散射法测定胶束的粒径分布用透射电镜观察胶束的形貌。通过芘荧光探针法测定胶束的临界胶束浓度。测定胶束在不同pH下的药物释放情况(pH5.5和7.4)。采用薄层色谱法和高效液相色谱法研究腙键的断裂行为。通过CCK-8法比较生理pH和酸性pH下,色胺酮和聚乙二醇化色胺酮胶束(PTMs)对MCF-7细胞的体外细胞毒性。结果:与色氨酸相比,PTMs的溶解度提高了1493倍。制备的胶束粒径为228.8 nm,PDI为0.1,形貌为球形。PTMs的临界胶束浓度为3.5×10^-7mol/L,较低的CMC值表明制备的胶束稳定性高,便于进一步使用。腙键可在酸性条件下发生断裂,且在pH 5.5下,12 h内95%的色胺酮从胶束中释放,而在生理pH下(pH 7.4),药物释放缓慢。在生理条件下胶束的细胞毒性低于色胺酮,说明胶束化色胺酮可降低药物毒性及胶束在生理条件下有一定的稳定性。而在pH 5.5时,色胺酮胶束与色胺酮的细胞毒性相近表明胶束可响应肿瘤细胞内的低pH值成功实现药物释放。结论:胶束化色胺酮不仅能有效改善色胺酮的溶解度,有利于进一步提高其生物利用度,而且是一种很有应用前景的肿瘤靶向前药。     

Hydrotropic polymeric micelles for enhanced paclitaxel solubility: in vitro and in vivo characterization

The purpose of this investigation was to characterize the in vitro stability and in vivo disposition of paclitaxel in rats after solubilization of paclitaxel into hydrotropic polymeric micelles. The amphiphilic block copolymers consisted of a micellar shell-forming poly(ethylene glycol) (PEG) block and a core-forming poly(2-(4-vinylbenzyloxy)-N,N-diethylnicotinamide) (P(VBODENA)) block. N,N-Diethylnicotinamide (DENA) in the micellar inner core resulted in effective paclitaxel solubilization and stabilization. Solubilization of paclitaxel using polymeric micelles of poly(ethylene glycol)-b-P(D,L-lactide) (PEG-b-PLA) served as a control for the stability study. Up to 37.4 wt % paclitaxel could be loaded in PEG-b-P(VBODENA) micelles, whereas the maximum loading amount for PEG-b-PLA micelles was 27.6 wt %. Thermal analysis showed that paclitaxel in the polymeric micelles existed in the molecularly dispersed amorphous state even at loadings over 30 wt %. Paclitaxel-loaded hydrotropic polymeric micelles retained their stability in water for weeks, whereas paclitaxel-loaded PEG-b-PLA micelles precipitated in a few days. Hydrotropic polymer micelles were more effective than PEG-PLA micelle formulations in inhibiting the proliferation of human cancer cells. Paclitaxel in hydrotropic polymer micelles was administered orally (3.8 mg/kg), intravenously (2.5 mg/kg), or via the portal vein (2.5 mg/kg) to rats. The oral bioavailability was 12.4% of the intravenous administration. Our data suggest that polymeric micelles with a hydrotropic structure are superior as a carrier of paclitaxel due to a high solubilizing capacity combined with long-term stability, which has not been accomplished by other existing polymeric micelle systems.