J Control Release 2011 Nov;156 (1): 21-7. [IF:7.164]
Enhancement of the fraction of the active form of an antitumor drug topotecan via an injectable hydrogel.
Chang G , Ci T , Yu L , Ding J .
Key Laboratory of Molecular Engineering of Polymers of Ministry of Education, Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
复旦大学聚合物分子工程教育部重点实验室，复旦大学先进材料实验室
Abstract
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 5days 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.
摘要：
聚D,L-乳酸-乙醇酸-聚乙二醇-D,L-乳酸-乙醇酸共聚物（PLGA-PEG-PLGA）水凝胶尝试被包埋作喜树碱（CPT）衍生物类抗肿瘤药物拓扑替康（TPT）埋植剂。尽管TPT的水溶性（良好），在体外这种低分子量药物从水凝胶中释放可维持5日，且只有一次轻微的突释。这种（缓）释的TPT抗癌效果在S180荷瘤小鼠上进一步得到验证。令人吃惊的是，TPT的活性内酯在这种水凝胶基质中的比率竟增至50%以上，而在生理酸碱值，37°C下，磷酸盐缓冲溶液中的比率仅在10%上下。这一意义非凡的作用可以解释为，两性聚合物与TPT间的疏水作用增加了开环上羧基的pK(a)（解离常数），而不是水凝胶自身的酸性作用。对pK(a)相关机制的理论分析也证实了这一点，与本实验测量一致。因此，本研究揭示合适的生物材料可通过药物-基质作用，增加这些药物活性成分浓度，提高疗效，而这些药物正可进行活性和失活两者形式的转换的。
