A Novel Monomethoxy Polyethylene Glycol-Polylactic Acid Polymeric Micelles with Higher Loading Capacity for Docetaxel and Well-Reconstitution Characteristics and Its Anti-metastasis Study
A Novel Monomethoxy Polyethylene Glycol-Polylactic Acid Polymeric Micelles with Higher Loading Capacity for Docetaxel and Well-Reconstitution Characteristics and Its Anti-metastasis Study
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DOI：
10.1248/cpb.c12-00323
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发表时间：
2012-09-01
影响因子：
1.7
通讯作者：
Gao, Zhonggao
中科院分区：
文献类型：
--
作者：
Li, Yunfei;Yang, Feifei;Gao, Zhonggao
多西紫杉醇(DTX)是疏水性的，它的现有制剂(Taxotere(R)和Duopafei(R))需要Tween80和乙醇载体来允许父母给药。载药聚(D，L-丙交酯)-b-聚乙二醇甲氧基(mpeg-b-PDLLA)聚合物胶束(PM)是一种不含吐温80的DTX聚合物胶束，已被广泛研究，但很少涉及工业化问题。在这项工作中，开发了新型的DTX-PM，具有更好的负载能力和良好的复合能力。用高效液相色谱法、透射电子显微镜和动态光散射法对冻干DTX-PM进行了分析，分别测定了DTX的载药量、胶束形态和尺寸。用四甲基偶氮唑盐(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium)比色法测定其对4T1细胞的体外杀伤活性，并以荷4T1肿瘤的BALB/c小鼠为模型进行体内实验。DTX在胶束中的载量和效率分别为20.74+/-1.23%和93.7+/-1.03%，远高于文献报道的PMDTX-PM为球形，平均粒径为16.62+/-0.31 nm，表明其能通过增强渗透性和滞留(EPR)效应选择性地在实体瘤中蓄积。DTX-PM的另一个重要特点是长期储存和作为水溶液重复使用。对多种冻融保护剂进行了研究，发现葡萄糖是一种较好的冻融保护剂。与多巴非(R)相比，DTX-PM在体内外对4T1细胞具有更好的细胞毒性和抗转移能力。综上所述，DTX-PM显著提高了DTX的载药量，具有良好的重组能力，有望成为一种具有临床应用前景的药物载体。
Docetaxel (DTX) is hydrophobic, and its available formulations (Taxotere (R) & Duopafei (R)) require Tween80 and ethanol vehicle to allow parental administration. DTX-loaded poly(D,L-lactide)-b-polyethylene glycol methoxy (mPEG-b-PDLLA) polymeric micelle (PM) is a Tween80-free formulation of DTX, which has been extensively studied but rarely involved with industrialization issues. In this work, novel DTX-PM with improved loading capacity and well-reconsitution ability was developed. The freeze-dried DTX-PM was analyzed by HPLC, transmission electron microscopy (TEM) and dynamic light scattering (DLS) to determine the DTX loading, micelle morphology and size respectively. The in vitro cytotoxic activity of DTX-PM in 4T1 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the corresponding in vivo study was assessed in BALB/c mice bearing 4T1 tumor through intravenous administration. The DTX-loading and efficiency into the micelles were 20.74 +/- 1.23% and 93.7 +/- 1.03% respectively, which was much higher than ever reported PM. The DTX-PM was spherical with a mean particle size of 16.62 +/- 0.31 nm, which suggested that they were able to selectively accumulate in solid tumors by enhanced permeability and retention (EPR) effect. Another important characteristic of DTX-PM is the long term storage and reuses as aqueous injection solution. Many kinds of lyoprotectants were also investigated and dextrose was found to an excellent one. Compared with Duopafei (R), DTX-PM showed better cytotoxicity and anti-metastasis ability against 4T1 cells in vitro and in vivo. In conclusion, DTX-PM significantly enhanced drug-loading capacity of DTX and had well-reconsitution ability, which could be a promising drug delivery system for clinic.