Biomedical Polymers Laboratory, and Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, PR China.
Macromol Biosci. 2009 Dec 8;9(12):1254-61. doi: 10.1002/mabi.200900233.
Reduction-responsive reversibly crosslinked biodegradable micelles were developed and applied for triggered release of doxorubicin (DOX). An amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(epsilon-caprolactone) (PCL) that contains two lipoyl functional groups at their interface (PEG-L(2)-PCL) has been synthesized. (1)H NMR spectroscopy and gel permeation chromatography (GPC) measurements show that the PEG-L(2)-PCL block copolymer had a controlled composition (PEG 5 kDa and PCL 5.4 kDa) and a polydispersity index (PDI) of 1.36. PEG-L(2)-PCL formed micelles with sizes that ranged from 20 to 150 nm in aqueous solutions, wherein a critical micelle concentration (CMC) of 16 mg.L(-1) was determined. The micelles were readily crosslinked by adding 7.6 mol % of dithiothreitol (DTT) relative to the lipoyl groups. Notably, micelles after crosslinking demonstrated a markedly enhanced stability against dilution, physiological salt concentration, and organic solvent. In the presence of 10 x 10(-3) M DTT, however, micelles were subject to rapid de-crosslinking. In vitro release studies showed minimal release of DOX from crosslinked micelles at a concentration of 10 mg L(-1) (C < CMC, analogous to intravenous injection), wherein less than 15% of the DOX was released in 10 h. In contrast, rapid release of DOX was observed for DOX-loaded non-crosslinked micelles under otherwise the same conditions ( approximately 80% release in 0.5 h). In the presence of 10 x 10(-3) M DTT mimicking an intracellular reductive environment, sustained release of DOX from crosslinked micelles was achieved, in which 75% of the DOX was released in 9 h. These novel reduction-sensitive reversibly crosslinked biodegradable micelles are highly promising for targeted intracellular delivery of anticancer drugs.
制备了一种响应还原的可还原交联的生物可降解胶束，并将其应用于阿霉素（DOX）的触发释放。合成了一种两亲性嵌段共聚物聚乙二醇（PEG）和聚己内酯（PCL），其界面处含有两个脂酰基官能团（PEG-L（2）-PCL）。（1）H NMR 光谱和凝胶渗透色谱（GPC）测量表明，PEG-L（2）-PCL 嵌段共聚物具有受控的组成（PEG 5 kDa 和 PCL 5.4 kDa）和多分散指数（PDI）为 1.36。PEG-L（2）-PCL 在水溶液中形成尺寸范围为 20 至 150nm 的胶束，其中确定临界胶束浓度（CMC）为 16mg.L（-1）。通过添加相对于脂酰基基团为 7.6mol%的二硫苏糖醇（DTT），胶束很容易交联。值得注意的是，交联后的胶束在稀释、生理盐浓度和有机溶剂存在下表现出明显增强的稳定性。然而，在存在 10 x 10（-3）M DTT 的情况下，胶束会迅速去交联。体外释放研究表明，在 10mgL（-1）（C < CMC，类似于静脉注射）的浓度下，交联胶束中 DOX 的释放最小，在 10h 内释放少于 15%的 DOX。相比之下，在相同条件下（0.5h 内约 80%的释放），载 DOX 的非交联胶束迅速释放 DOX。在模拟细胞内还原环境的 10 x 10（-3）M DTT 存在下，交联胶束实现了 DOX 的持续释放，其中 75%的 DOX 在 9h 内释放。这些新型的还原敏感可还原交联的生物可降解胶束非常有前途，可用于靶向细胞内递抗癌药物。
