Development of copolymers of poly(D,L-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel
Development of copolymers of poly(D,L-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel
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DOI：
10.1016/s0927-7765(99)00067-3
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发表时间：
1999-11-01
影响因子：
5.8
通讯作者：
Hunter, WL
中科院分区：
文献类型：
--
作者：
Burt, HM;Zhang, XC;Hunter, WL
在辛酸亚锡存在下，通过开环本体聚合合成了含有一个甲氧基聚乙二醇（MePEG）嵌段和一个聚（D，L-丙交酯）（PDLLA）嵌段、聚（D，L-丙交酯-己内酯）（PDLLACL）或聚（乙交酯-己内酯）（PGACL）的共聚物。通过改变单体重量比来控制共聚物的分子量和组成。该共聚物溶解在水性介质中形成具有疏水性聚酯核和水溶性MePEG壳的聚合物胶束。 PGACL-MePEG 共聚物中紫杉醇的胶束溶液表现出较差的物理稳定性并且最不能将紫杉醇维持在溶液中。使用PDLLA-MePEG共聚物获得了具有最高物理稳定性的胶束紫杉醇溶液，这可能是由于与PDLLACL-MePEG共聚物胶束相比，PDLLA-MePEG的胶束核心环境的流动性降低。 PDLLA-MePEG；二嵌段共聚物被认为是紫杉醇增溶的最佳共聚物。一系列动物体外和体内生物相容性/毒理学测试的结果表明，PDLLA-MePEG 胶束具有生物相容性和无毒性。使用放射性标记紫杉醇负载 PDLLA-MePEG 胶束在大鼠体内进行的生物分布研究表明，紫杉醇迅速从血液中的胶束成分中解离，并且超过 95% 的给药胶束二嵌段共聚物剂量在 15 小时内被消除。还有证据表明二嵌段共聚物在血液中裂解成两种聚合物成分。 (C) 1999 Elsevier Science B.V. 保留所有权利。
Diblock copolymers containing one block of methoxypolyethylene glycol (MePEG) and one block of either poly(D,L-lactide) (PDLLA), copolymers of poly(D,L-lactide-co-caprolactone) (PDLLACL) or poly(glycolide-co-caprolactone) (PGACL) were synthesized by a ring opening bulk polymerization in the presence of stannous octoate. The copolymer molecular weight and composition were controlled by changing the monomer weight ratios. The copolymers dissolved in aqueous media to form polymeric micelles with a hydrophobic polyester core and a water soluble MePEG shell. Micellar solutions of paclitaxel in the PGACL-MePEG copolymers showed poor physical stability and were the least able to maintain paclitaxel in solution. Micellar paclitaxel solutions with the greatest physical stability were obtained using PDLLA-MePEG copolymers, probably due to the decreased fluidity of the micellar core environment of PDLLA-MePEG compared to PDLLACL-MePEG copolymer micelles. The PDLLA-MePEG; diblock copolymer was considered to be the optimal copolymer for the solubilization of paclitaxel. The results of a range of in vitro and in vivo biocompatibility / toxicology tests in animals showed the PDLLA-MePEG micelles to be biocompatible and non-toxic. Biodistribution studies using radiolabelled paclitaxel loaded PDLLA-MePEG micelles in rats showed that paclitaxel rapidly dissociated from the micellar components in the blood and that greater than 95% of the administered micellar diblock copolymer dose was eliminated within 15 h. There was also evidence to suggest that the diblock copolymer was cleaved into its two polymer components in the blood. (C) 1999 Elsevier Science B.V. All rights reserved.