Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids

Paclitaxel-loaded mixed polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-PE), solid triglycerides (ST), and cationic Lipofectin lipids (LL) have been prepared. Micelles with the optimized composition (PEG-PE/ST/LL/paclitaxel = 12/12/2/1 by weight) had an average micelle size of about 100 nm, and zeta-potential of about -6 mV. Micelles were stable and did not release paclitaxel when stored at 4 degree C in the darkness (just 2.9% of paclitaxel have been lost after 4 months with the particle size remaining unchanged). The release of paclitaxel from such micelles at room temperature was also insignificant. However, at 37 degree C, approx. 16% of paclitaxel was released from PEG-PE/ST/LL/paclitaxel micelles in 72 h, probably, because of phase transition in the ST-containing micelle core. In vitro anticancer effects of PEG-PE/ST/LL/paclitaxel and control micelles were evaluated using human mammary adenocarcinoma (BT-20) and human ovarian carcinoma (A2780) cell lines. Paclitaxel in PEG-PE/ST/LL micelles demonstrated the maximum anti-cancer activity. Cellular uptake of fluorescently-labeled paclitaxel-containing micelles by BT-20 cells was investigated using a fluorescence microscopy. It seems that PEG-PE/ST/LL micelles, unlike micelles without the LL component, could escape from endosomes and enter the cytoplasm of BT-20 cancer cells thus increasing the anticancer efficiency of the micellar paclitaxel.     

Dehydroascorbic Acid and pGPMA Dual Modified pH-Sensitive Polymeric Micelles for Target Treatment of Liver Cancer

In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as lack of potency of tumor penetration. In this work, we developed actively tumor-targeting micelles with pH-sensitive linker as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable poly(ethylene glycol)-poly(aspartate) polymers, in which paclitaxel can be covalently conjugated to pAsp via an acid-labile acetal bond to form pH-responsive structures. In vitro drug release studies showed that these structures were stable in physiological condition, whereas collapsed once internalized into cells due to the mildly acidic environment in endo/lysosomes, resulting in facilitated intracellular paclitaxel release. In addition, dehydroascorbic acid and guanidinopropyl methacrylamide polymers were decorated on the surface of micelles to achieve specific tumor accumulation and tumor penetration. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.     

A novel lanreotide-encoded micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors

Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 ± 0.4 nm, high drug encapsulation (87.1 ± 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b-PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2-positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors.     

RGD-modified polymeric micelles as potential carriers for targeted delivery to integrin-overexpressing tumor vasculature and tumor cells

Integrins αvβ3 and αvβ5 are overexpressed in angiogenic tumor endothelial cells and malignant tumor cells, making them attractive targets for cancer therapy. In this study, an integrin αvβ3 and αvβ5 binding tripeptide, RGD (Arg-Gly-Asp), was conjugated with the surface of poly(ethylene glycol)–block–poly(d,l-lactide) (PEG–PLA) micelles. A lipophilic fluorescent probe, DiI, was loaded into both the nontargeted methoxy PEG–PLA (mPEG–PLA) micelles and the targeted RGD-modified PEG–PLA micelles. The DiI-loaded targeted micelles had a size of 24.2?nm. The targeted micelles were stable in phosphate buffered saline and exhibited a negligible leakage in culture medium. Transmission electron microscopy analysis showed that targeted micelles were spherical in shape. Cell uptake of DiI-labeled targeted micelles by human umbilical vein endothelial cells and melanoma B16 cells was investigated by spectrophotofluorometry and confocal microscopy techniques. Results revealed that RGD-modified micelles significantly facilitated the intracellular delivery of the encapsulated agents via integrin-mediated endocytosis. This study suggests that RGD-modified PEG–PLA micelles are promising drug carriers for targeted delivery to both angiogenic tumor endothelial cells and tumor cells and that the targeted micelles may be attractive carriers for combination cancer therapy against both targets.     

Vapreotide-modified nanomicelle as a targeted nanocarrier for delivering paclitaxel to the tumors with overexpression of somatostatin receptors

Somatostatin receptors (SSTRs) were widely expressed in many tumor cells. As a somatostatin analogue, vapreotide (VAP) can be exploited as a modifier for targeting tumor therapy based on its high affinity to SSTR. In this study, we conjugated α-NH₂ of exocyclic D-phenylalanine (D-Phe) of vapreotide to N-hydroxysuccinimidyl-PEG₂₀₀₀-DSPE (NHS-PEG-DSPE), and the resulted DSPE-PEG-VAP was used as a targeting component to construct the targeted micelles for delivering paclitaxel (VAP-M-PTX) through a thin-film hydration method. Similar particle size, zeta potential, drug encapsulation efficiencies, drug release behaviors and hemolysis effects were observed between the targeted micelles (VAP-M-PTX) and the non-targeted micelles (M-PTX). In MCF-7 cells, significantly higher intracellular fluorescence intensity (1.5-fold) was determined by flow cytometry after incubation of coumarin-6 loaded targeted micelles (VAP-M-Cou) for 3 h compared with non-targeted micelles (M-Cou), and similar finding was observed confocal microscopy. Furthermore, in comparison with non-targeted formulations, higher antitumorefficacy and higher drug accumulation were found in MCF-7 tumors in nude mice after intravenous injection of the targeted micelles. In conclusion, we believed that the vapreotide-modified nanomicelles could be a promising targeted nanocarrier for delivering anticancer drugs to the tumors with overexpression of somatostatin receptors.     

Selectivity of folate conjugated polymer micelles against different tumor cells

Folate or folic acid has been employed as a targeting moiety of various anticancer agents to increase their cellular uptake within target cells since folate receptors are vastly overexpressed in several human tumors. In this study, a biodegradable polymer poly(d,l-lactide-co-glycolide)-poly(ethylene glycol)-folate (PLGA-PEG-FOL) was used to form micelles for encapsulating anticancer drug doxorubicin (DOX). The drug loading content, encapsulation efficiency and in vitro release were characterized. To evaluate the targeting ability of the folate conjugated micelles, the cytotoxicity and cellular uptake of DOX-loaded micelles on three cancer cell lines with different amount of folate receptors (KB, MATB III, C6) and normal fibroblast cells (CCL-110) were compared. The cytotoxicity of PLGA-PEG-FOL micelles to cancer cells was found to be much higher than that of normal fibroblast cells, demonstrating that the folate conjugated micelles has the ability to selectively target to cancer cells. For normal cells, the cellular uptake of PLGA-PEG-FOL micelles was similar to PLGA-PEG micelles without folate conjugation, and was substantially lower than that of cancer cells. In addition, the cell cycle analysis showed that the apoptotic percentage of normal fibroblasts was substantially lower compared with the cancer cells after exposing to DOX-loaded PLGA-PEG-FOL micelles. An optimal folate amount of approximately 40-65% on the micelles was found to be able to kill cancer cells but, at the same time, to have very low effect to normal cells.     

Cholesterol-conjugated poly(D,L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy

Polymeric micelles have been widely explored preclinically as suitable delivery systems for poorly soluble chemotherapeutic drugs in cancer therapy. The present study reported the development of cholesterol (Ch)-conjugated poly(D,L-Lactide) (PLA)-based polymeric micelles (mPEG–PLA-Ch) for effective encapsulation and delivery of curcumin (CUR) at the tumor site. Cholesterol conjugation dramatically affected the particle size and improved drug loading (DL) and encapsulation efficiency (EE). mPEG–PLA-Ch-CUR showed bigger hydrodynamic diameter (104.6?±?2.1?nm, and 169.3?±?1.52?nm for mPEG–PLA and mPEG–PLA-Ch, respectively) due to increased size of the hydrophobic core. The newly developed polymer exhibited low critical micelles concentration (CMC) (25?μg/mL) which is close to lipid-based polymer, PEG-phosphatidyl ethanolamine (12.5?μg/mL) compared to mPEG–PLA (50?μg/mL). mPEG–PLA-Ch micelles exhibited relatively higher EE (93.74?±?1.6%) and DL (11.86?±?0.8%) compared to mPEG–PLA micelles (EE 91.89?±?1.2% and DL 11.06?±?0.8%). mPEG–PLA-Ch micelles were internalized by the cancer cells effectively and exhibited higher cytotoxicity compared to free CUR in both, murine melanoma (B16F10) and human breast cancer (MDA-MB-231) cells. mPEG–PLA-Ch exhibited satisfactory hemocompatibility indicating their potential for systemic application. Further, mPEG–PLA-Ch-CUR demonstrated higher rate of reduction of tumor volume in B16F10-xenografted tumor-bearing mice compared to free CUR. At the end of 22 days, the tumor reduced to 1.87-fold (627.72?±?0.9?mm³ versus 1174.68?±?1.64?mm³) compared to the treatment with free CUR. In conclusion, the experimental data in vitro and in vivo indicated that the newly developed CUR-mPEG–PLA-Ch micelles may have promising applications in solid tumors.     

pH敏感的肿瘤靶向聚合物胶束的体外性质

目的 制备肿瘤微环境敏感、具有肿瘤细胞靶向能力和穿膜能力的融合肽FQSIYPpIKRRRRRRRRHHHHC (FRH)修饰的聚合物胶束,并对其体外性质进行初步考察.方法 采用FRH修饰N-(2-羟丙基)-甲基丙烯酰胺(HPMA)聚合物-β-谷甾醇(β-SITO),形成HPMA聚合物胶束(FRH-M),考察其理化性质、肿瘤细胞的摄取和抑制肿瘤细胞生长的效果.结果 透射电镜显示:胶束为均匀的类球形.FRH-M胶束粒径约为55 nm,阿霉素载药量8.3％.该胶束在pH7.4条件下,Zeta电位为-3.01±0.05 mV,在pH6.4条件下,电荷翻转为5.27-0.32 mV.FRH-M的药物释放速度随释放介质的pH降低而加快.FRH-M的细胞摄取较未经修饰胶束的P-M提升了1.9倍;且在pH6.4条件下的细胞摄取明显高于pH7.4的,FRH-M的IC50值为1.40 ±0.41 μg·mL-1,明显低于未经配体修饰的胶束(5.08±0.33 μg· mL-1).结论 经FRH多肽修饰的聚合物胶束具有良好的肿瘤微环境响应能力,且有更好的细胞摄取能力和体外抗肿瘤活性,极具发展前景.     

A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs

Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 h at 25 °C. The half-life for in vitro drug release (t(1/2)) for 3-in-1 PEG-b-PLA micelles was 1-15 h under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t(1/2) values correlated with log P(o/w) values, implicating a diffusion-controlled mechanism for drug release. The IC(50) value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (iv) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and efficacious 3-in-1 nanomedicine for cancer therapy.     

Multi-drug delivery to tumor cells via micellar nanocarriers

The aim of this study was to develop micellar nanocarriers for concomitant delivery of paclitaxel and 17-allylamino-17-demethoxygeldanamycin (17-AAG) for cancer therapy. Paclitaxel and 17-AAG were simultaneously loaded into polymeric micelles by a solvent evaporation method. Two candidate nanocarrier constructs, polyethylene glycol-poly(D, L-lactic acid) (PEG-PLA) micelles and PEG-distearoylphosphatidylethanolamine/tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles, were assessed for the release kinetics of the loaded drugs. Compared to PEG-PLA micelles, entrapment of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles resulted in significantly prolonged release half-lives. The simultaneous incorporation of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles was confirmed by (1)H NMR analysis. Paclitaxel/17-AAG-loaded PEG-DSPE/TPGS mixed micelles were as effective in blocking the proliferation of human ovarian cancer SKOV-3 cells as the combined free drugs. PEG-DSPE/TPGS mixed micelles may provide a novel and advantageous delivery approach for paclitaxel/17-AAG combination therapy.     

Ultrasound-enhanced chemotherapy of drug-resistant breast cancer tumors by micellar-encapsulated Paclitaxel

Background and aim

Currently, delivery of the poorly water-soluble chemotherapeutic agent paclitaxel is associated with a substantial array of systemic toxicities and results in low-efficiency tumor treatment. A novel on-demand delivery system based on paclitaxel encapsulated in polymeric micelles in conjunction with triggered release of the drug by local ultrasonic irradiation of the tumor was evaluated in vitro and in vivo using a drug-resistant MCF7/ADmt breast cancer human cell line.

Method

The effects of local ultrasonic tumor irradiation on cellular proliferation and intracellular drug uptake were compared for a developmental micellar paclitaxel formulation (SYP-PM) and a currently available clinical intravenous formulation of paclitaxel.

Results

Without ultrasound, the uptake of paclitaxel from the micellar formulation was significantly lower than that from the clinical formulation, which is advantageous for preventing unwanted drug interactions with healthy tissues in vivo. When micellar encapsulation was combined with ultrasonically triggered release, drug uptake from micellar paclitaxel was increased more than 20-fold and cellular proliferation was inhibited by nearly 90%. Without ultrasound, the clinical formulation of paclitaxel and SYP-PM manifested low efficacy in vivo, whereas injections of SYP-PM combined with ultrasound resulted in complete tumor resolution.

Conclusion

The ability of micellar-encapsulated paclitaxel to exert a significant cytotoxic effect only when subjected to ultrasound proves promising for the development of a tumor-targeted ultrasound-enhanced paclitaxel delivery system for clinical application. This treatment modality could be successfully used for the therapy of both drug-sensitive and drug-resistant tumors. The major advantages of a micellar formulation of paclitaxel combined with local tumor sonication are the aqueous base of the drug formulation, reduced systemic toxicity, potential for tumor targeting, and on-demand delivery of drug to tumor cells.     

Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents

A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analogues have substantially improved aqueous solubility (48.9 μg/mL for 5ga vs 0.909 μg/mL for SMART-1, 0.137 μg/mL for paclitaxel, and 1.04 μg/mL for combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogues is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors.     

Self-assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid

A drug carrier based on glycyrrhetinic acid-modified sulfated chitosan (GA-SCTS) was synthesized. The glycyrrhetinic acid (GA) acted as both a hydrophobic group and a liver-targeting ligand. The GA-SCTS micelles displayed rapid and significant ability to target the liver in vivo. The IC(50) for doxorubicin (DOX)-loaded GA-SCTS micelles (DOX/SA-SCTS micelles) against HepG2 cells was 54.7 ng/mL, which was extremely lower than the amount of no-GA-modified DOX-loaded micelles. In addition, DOX/SA-SCTS micelles could target specifically the liver cancer cells. They had higher affinity for the liver cancer cells (HepG2 cells) than for the normal liver cells (Chang liver cells). There was nearly 2.18-fold improvement in uptake of the DOX/SA-SCTS micelles by HepG2 cells than that by Chang liver cells. These results indicate that GA-SCTS is not only an excellent carrier for drugs, but also a potential vehicle for liver-cancer targeting.     

Synthesis of Novel Biodegradable Methoxy Poly(ethylene glycol)-Zein Micelles for Effective Delivery of Curcumin

Novel biodegradable micelles were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG) to zein, a biodegradable hydrophobic plant protein. The mPEG-zein micelles were in the size range of 95-125 nm with a low CMC (5.5 × 10(-2) g/L). The micelles were nonimmunogenic and were stable upon dilution with buffer as well as 10% serum. Curcumin, an anticancer agent with multiple delivery challenges, was encapsulated in mPEG-zein micelles. The micelles significantly enhanced the aqueous solubility (by 1000-2000-fold) and stability (by 6-fold) of curcumin. PEG-zein micelles sustained the release of curcumin up to 24 h in vitro. Curcumin-loaded mPEG-zein micelles showed significantly higher cell uptake than free curcumin in drug-resistant NCI/ADR-RES cancer cells in vitro. Micellar curcumin formulation was more potent than free curcumin in NCI/ADR-RES cancer cells, as evidenced from the 3-fold reduction in IC(50) value of curcumin. Overall, this study for the first time reports a natural protein core based polymeric micelle and demonstrates its application for the delivery of hydrophobic anticancer drugs such as curcumin.     

pH Triggered Doxorubicin Delivery of PEGylated Glycolipid Conjugate Micelles for Tumor Targeting Therapy

The main objective of this study was aimed at tumor microenvironment-responsive vesicle for targeting delivery of the anticancer drug, doxorubicin (DOX). A glucolipid-like conjugate (CS) was synthesized by the chemical reaction between chitosan and stearic acid, and polyethylene glycol (PEG) was then conjugated with CS via a pH-responsive cis-aconityl linkage to produce acid-sensitive PEGylated CS conjugates (PCCS). The conjugates with a critical micelle concentration (CMC) of 181.8 μg/mL could form micelles in aqueous phase, and presented excellent DOX loading capacity with a drug encapsulation efficiency up to 87.6%. Moreover, the PCCS micelles showed a weakly acid-triggered PEG cleavage manner. In vitro drug release from DOX-loaded PCCS micelles indicated a relatively faster DOX release in weakly acidic environments (pH 5.0 and 6.5). The CS micelles had excellent cellular uptake ability, which could be significantly reduced by the PEGylation. However, the cellular uptake ability of PCCS was enhanced comparing with insensitive PEGylated CS (PCS) micelles in weakly acidic condition imitating tumor tissue. Taking PCS micelles as a comparative group, the PCCS drug delivery system was demonstrated to show much more accumulation in tumor tissue, followed by a relatively better performance in antitumor activity together with a security benefit on xenograft tumor model.     

Preparation and anti-MDR tumors study of folate and TPGS dual-modified DSPE-PEG micelles loaded with docetaxel

Multidrug resistance (MDR) operated by P-glycoprotein (P-gp) is one of the major causes in the treatment failure of cancers. In this work,docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene-glycol)₂₀₀₀ (DSPE-PEG₂₀₀₀),D-α-Tocopherylpolyethylene glycol 1000 succinate (TPGS₁₀₀₀) and DSPE-PEG₂₀₀₀-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG₂₀₀₀ and TPGS₁₀₀₀ ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS₁₀₀₀ amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells.The study provides a method for overcoming MDR in cancer therapy.     

Synthesis and characterization of a novel polydepsipeptide contained tri-block copolymer (mPEG-PLLA-PMMD) as self-assembly micelle delivery system for paclitaxel

A series of biodegradable polydepsipeptides based new triblock copolymers, poly (ethylene glycol)-poly(L-lactide)-poly(3(S)-methyl-morpholine-2,5-dione) (mPEG-PLLA-PMMD) have been synthesized and characterized as self-assembly micelle delivery system for paclitaxel (PTX). Compared to the mPEG(2000)-PLLA(2000) diblock copolymers, the triblock copolymers present more benefits such as lower CMC value, positive-shifted zeta potential, better drug loading efficiency and stability. Among the triblock polymers, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles present low cytotoxicity and promote the anti-cancer activity of PTX on A-549 and HCT-116cells. In addition, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles prolongs the circulation time of PTX in rat after i.v. injection (5 mg/kg) than that of mPEG(2000)-PLLA(2000) micelles and Taxol. The half life (t(1/2β)), mean residence time (MRT), AUC(0-∞) and clearance (CL) for PTX-loaded mPEG(2000)-PLLA(2000)-PMMD(1400) micelles are determined to be 1.941 h, 2.683 h, 5.220 μg/m Lh (1.8-fold to mPEG(2000)-PLLA(2000) group), 0.967 L/h kg(-1), respectively. In conclusion, mPEG(2000)-PLLA(2000)-PMMD(1400) copolymer could be developed as one of the promising vectors to anti-cancer agents for chemotherapeutics.     

Synthesis and evaluation of biotin-conjugated pH-responsive polymeric micelles as drug carriers

pH-Responsive polymeric micelles have been investigated as drug carriers for chemotherapy. Ligand-mediated polymeric micelles, which can penetrate the target tumors due to their high binding affinity to a specific receptor on the surface of tumors, were developed to achieve targeted drug delivery. In this study, biotin-conjugated methoxypoly(ethylene glycol)-grafted-poly(β-amino ester) was prepared for active and pH-sensitive tumor targeting. These polymers were modified by cholesteryl chloroformate to improve the hydrophobicity of the micelle core. The structure of the biotin-conjugated polymer was confirmed by (1)H NMR spectroscopy, and the existence of biotin at the surface of the polymeric micelles was evaluated by an 4'-hydroxyazobenzene-2-carboxylic acid/avidin (HABA/avidin) binding assay at different pHs. The micelle properties were determined by dynamic light scattering and the result showed that the mean size of the polymeric micelles was approximately 20 nm. For cancer therapy, doxorubicin (DOX) was loaded into the polymeric micelles with a high loading efficiency. From the in vitro cellular uptake results, the biotin-conjugated polymeric micelles can effectively release doxorubicin at acidic tumor cells compared to the micelles without biotin. Overall, biotin-conjugated pH-responsive polymeric micelles have great potential to be used as drug carriers.     

紫杉醇自组装核壳型纳米胶束的制备与性能

本文合成了聚乙二醇-聚谷氨酸苄酯(polyethylene glycol-polybenzyl-L-glutamate， PEG-PBLG)两亲嵌段共聚物， 并采用超微透析法制备了紫杉醇/PEG-PBLG核壳型纳米胶束。通过高效液相色谱测定了胶束的载药量及药物包封率； 采用动态光散射法测定了胶束的粒径及分布； 通过体外试验研究了紫杉醇/PEG-PBLG胶束的释药特性； 采用四噻唑蓝法考察了紫杉醇/PEG-PBLG胶束的体外细胞毒性； 通过裸鼠的抑瘤试验评价了紫杉醇胶束对人肝癌细胞的疗效。结果表明， PEG-PBLG胶束能包埋疏水性药物紫杉醇； 紫杉醇/PEG-PBLG胶束的粒径为80～265 nm， 且随着载体共聚物PBLG嵌段相对分子质量的升高而增大； 紫杉醇/PEG-PBLG胶束的体外释放具有缓释特性； 当紫杉醇浓度大于20 μg·mL^-1时， 紫杉醇/PEG-PBLG胶束的细胞毒性低于相应浓度的紫杉醇/聚氧乙烯蓖麻油注射剂(P<0.05)， 紫杉醇/PEG-PBLG胶束具有与紫杉醇/聚氧乙烯蓖麻油注射剂相似的抑制肿瘤作用。综上所述， 紫杉醇/PEG-PBLG纳米胶束具有较均匀的粒径及粒径分布、 缓释特性、 低毒和较好的抗肿瘤作用。