Micelle-like structures of poly(ethylene oxide)-block-poly(2-hydroxyetbyl aspartamide)-methotrexate conjugates
Micelle-like structures of poly(ethylene oxide)-block-poly(2-hydroxyetbyl aspartamide)-methotrexate conjugates
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DOI：
10.1016/s0927-7765(99)00072-7
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发表时间：
1999-11-01
影响因子：
5.8
通讯作者：
Kwon, GS
中科院分区：
文献类型：
--
作者：
Li, Y;Kwon, GS
本研究的目的是制备并表征一种由两嵌段共聚物-甲氨蝶呤(MTX)结合物组成的胶束状结构。将甲氨蝶呤固定在聚氧化乙烷嵌段聚(2-羟乙基天冬酰胺)(PEO-b-PHAA)上，得到聚氧化乙烯-b-聚(β-苄基-L-天冬氨酸)(PBLA)与乙醇胺的氨解产物。假设MTX通过酯键连接到PEO-b-PHAA上后，由于非极性核的不利于水解，两亲性偶联物将自组装成胶束状结构，从而逐渐释放MTX。MTX-NAR的活性酯与PEO-b-PHAA反应，提供了20-45%的取代比(药物与天冬氨酰胺单元的摩尔比)。在这些水平上，PEO-b-PHAA-MTX共轭化合物可以在水介质中自组装。透射电子显微镜显示小的球形颗粒，平均直径为14 nm。没有证据表明有二次聚集。在D2O中没有MTX的H-1-核磁共振峰，这表明PEO-b-PHAA-MTX自组装成超分子结构，MTX位于一个迁移率高度受限的位置，很可能是胶束状结构的核心，因此，在中性pH下，PEO-b-PHAA-MTX共轭物中MTX的水解损失很慢，10天后释放不到20%。胶束状结构非极性核中酯键的稳定在可溶聚合物-药物结合物的设计中是一种新颖的方法。PEO-b-PHAA-MTX共轭胶束有助于改善MTX的生物分布，有助于克服耐药性。(C)1999 Elsevier Science B.V.保留所有权利。
The objective of this research was to prepare and characterize a micelle-like structure composed of a diblock copolymer-methotrexate (MTX) conjugate. MTX was attached on poly(ethylene oxide)-block-poly(2-hydroxyethyl aspartamide) (PEO-b-PHAA), obtained by aminolysis of PEO-b-poly(beta-benzyl-L-aspartate) (PBLA) with ethanolamine. It was hypothesized that after attachment of MTX onto PEO-b-PHAA through an ester bond, the amphiphilic conjugate would self-assemble into a micelle-like structure that would gradually release MTX, owing to unfavorable hydrolysis in a nonpolar core. An active ester of MTX nar reacted with PEO-b-PHAA, providing a substitution ratio of 20-45% (molar ratio of drug to aspartamide units). At these levels, PEO-b-PHAA-MTX conjugate may self-assemble in an aqueous medium. Transmission electron microscopy revealed small spherical particles that had a mean diameter of 14 nm. There was no evidence of secondary aggregation. An absence of H-1-NMR peaks of MTX in D2O indicated that PEO-b-PHAA-MTX conjugates self-assembled into supramolecular structure where MTX resides in a site with highly restricted mobility, likely a core of a micelle-like structure, Accordingly the loss of MTX by hydrolysis from PEO-b-PHAA-MTX conjugates was slow at neutral pH, with less than 20% released after 10 days. The stabilization of ester bonds in a nonpolar core of a micelle-like structure is novel in the design of soluble polymer-drug conjugates. PEO-b-PHAA-MTX conjugate micelles may help improve the biodistribution of MTX and help overcome drug resistance. (C) 1999 Elsevier Science B.V. All rights reserved.