Synthesis of well-defined amphiphilic block copolymers having phospholipid polymer sequences as a novel blocompatible polymer micelle reagent
Synthesis of well-defined amphiphilic block copolymers having phospholipid polymer sequences as a novel blocompatible polymer micelle reagent
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DOI：
10.1021/bm0495553
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发表时间：
2005-03-01
影响因子：
6.2
通讯作者：
Morishima, Y
中科院分区：
文献类型：
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作者：
Yusa, SI;Fukuda, K;Morishima, Y
为了实现更安全、有效的给药，我们合成了含有磷脂聚合物序列的新型结构明确且生物相容的两亲性嵌段共聚物。首先，通过可逆加成断裂链转移（RAFT）控制的自由基聚合在水中合成2-甲基丙烯酰氧基乙基磷酰胆碱（MPC）的均聚物。 “活性”聚合通过以下事实得到证实：数均分子量随单体转化率线性增加，而分子量分布与转化率无关地保持窄。由此制备的聚(MPC)用二硫酯部分封端。以二硫酯封端的聚(MPC)作为大链转移剂，合成了MPC与甲基丙烯酸正丁酯(BMA)的AB二嵌段共聚物。使用核磁共振、荧光探针、静态光散射 (SLS) 和准弹性光散射 (QELS) 技术研究了具有不同聚 (BMA) 嵌段长度的两亲性嵌段共聚物 (pMPC(m)-BMA(n)) 的缔合特性。 D2O 中的质子 NMR 数据表明，由于聚 (BMA) 嵌段的疏水缔合，正丁基部分的运动受到高度限制。 N-苯基-1-萘胺的荧光光谱表明探针溶解在水中的聚合物胶束中。 SLS和QELS数据表明，聚合物胶束的形成包括具有聚(BMA)嵌段的核和具有亲水性聚(MPC)嵌段的壳。胶束的尺寸和质量随着聚（BMA）嵌段长度的增加而增加。为了期待 pMPC(m)-BMA(n) 的药物应用，研究了水溶性差的抗癌剂紫杉醇 (PTX) 的增溶作用。与纯水相比，PTX 在 pMPC(m)-BMA(n) 水溶液中溶解良好，这意味着 PTX 被纳入聚合物胶束的疏水核心中。由于优异的生物相容性聚（MPC）序列形成胶束的外壳，pMPC（m）-BMA（n）可能会作为一种有前途的试剂来应用，以与疏水性药物一起制备良好的制剂。
To realize safer and effective drug administration, novel well-defined and biocompatible amphiphilic block copolymers containing phospholipid polymer sequences were synthesized. At first, the homopolymer of 2-methacryloyloxyethylphosphorylcholine (MPC) was synthesized in water by reversible addition-fragmentation chain transfer (RAFT) controlled radical polymerization. The "living" polymerization was confirmed by the fact that the number-average molecular weight increased linearly with monomer conversion while the molecular weight distribution remained narrow independent of the conversion. The poly(MPC) thus prepared is end-capped with a dithioester moiety. Using the dithioester-capped poly(MPC) as a macro chain transfer agent, AB diblock copolymers of MPC and n-butyl methacrylate (BMA) were synthesized. Associative properties of the amphiphilic block copolymer (pMPC(m)-BMA(n)) with varying poly(BMA) block lengths were investigated using NMR, fluorescence probe, static light scattering (SLS), and quasi-elastic light scattering (QELS) techniques. Proton NMR data in D2O indicated highly restricted motions of the n-butyl moieties, arising from hydrophobic associations of poly(BMA) blocks. Fluorescence spectra of N-phenyl-1-naphthylamine indicated that the probes were solubilized in the polymer micelles in water. The formation of polymer micelles comprising a core with poly(BMA) blocks and shell with hydrophilic poly(MPC) blocks was suggested by SLS and QELS data. The size and mass of the micelle increased with increasing poly(BMA) block length. With an expectation of a pharmaceutical application of pMPC(m)-BMA(n), solubilization of a poorly water-soluble anticancer agent, paclitaxel (PTX), was investigated. PTX dissolved well in aqueous solutions of pMPC(m)-BMA(n) as compared with pure water, implying that PTX is incorporated into the hydrophobic core of the polymer micelle. Since excellent biocompatible poly(MPC) sequences form an outer shell of the micelle, pMPC(m)-BMA(n) may find application as a promising reagent to make a good formulation with a hydrophobic drug.