Key Laboratory of Molecular Engineering of Polymers, Ministry of Education, Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai, China.
J Control Release. 2011 Nov 30;156(1):21-7. doi: 10.1016/j.jconrel.2011.07.008. Epub 2011 Jul 14.
Poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) hydrogels were tried as implants to encapsulate antitumor drug topotecan (TPT), a derivative of camptothecin (CPT). Despite of water solubility of TPT, the in vitro release of this low-molecular-weight drug from hydrogels sustained for 5 days with only a mild initial burst. The antitumor efficacy of the released TPT was further validated in S180-bearing mice. Surprisingly, the fraction of the active lactone form of TPT was increased to above 50% in the hydrogel matrix, while the fraction was just about 10% in phosphate buffer saline under physiological pH at 37°C. This significant effect was interpreted not by the local acidic pH within the hydrogel, but by the increase of pK(a) of the carboxylate group of the open-ring form due to the hydrophobic interaction between the amphiphilic polymer and TPT. Theoretical analysis via a pK(a)-related mechanism was also performed, which was consistent with our experimental measurements. Hence, this study has revealed that an appropriate biomaterial could, via drug-material interactions, enhance the drug efficacy by increasing the active fraction of some drugs which exhibit a reversible conversion between the active and inactive structures.
聚（D，L-乳酸-co-乙醇酸）-b-聚（乙二醇）-b-聚（D，L-乳酸-co-乙醇酸）（PLGA-PEG-PLGA）水凝胶被尝试用作包裹抗肿瘤药物拓扑替康（TPT）的植入物，TPT 是喜树碱（CPT）的衍生物。尽管 TPT 具有水溶性，但从水凝胶中释放的这种低分子量药物的体外释放持续了 5 天，仅出现轻微的初始突释。释放的 TPT 的抗肿瘤功效在 S180 荷瘤小鼠中得到了进一步验证。令人惊讶的是，在生理 pH 值为 37°C 的磷酸盐缓冲盐水中，TPT 的活性内酯形式的比例仅约为 10%，而在水凝胶基质中增加到了 50%以上。这种显著的效果不是由水凝胶内的局部酸性 pH 值引起的，而是由于亲脂性聚合物与 TPT 之间的疏水相互作用，开环形式的羧酸盐基团的 pK(a)增加所致。通过与 pK(a)相关的机制进行了理论分析，这与我们的实验测量结果一致。因此，这项研究表明，适当的生物材料可以通过药物-材料相互作用，通过增加某些药物的活性部分来提高药物功效，这些药物在活性和非活性结构之间表现出可逆转换。
