Poly(D,L-lactic-co-glycolic acid) microspheres for sustained delivery and stabilization of camptothecin
Poly(D,L-lactic-co-glycolic acid) microspheres for sustained delivery and stabilization of camptothecin
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DOI：
10.1016/s0168-3659(99)00122-4
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发表时间：
1999-09-20
影响因子：
10.8
通讯作者：
Gabor, F
中科院分区：
文献类型：
--
作者：
Ertl, B;Platzer, P;Gabor, F
喜树碱（CPT）及其水不溶性衍生物是拓扑异构酶I抑制剂，对多种人类恶性肿瘤表现出高的抗肿瘤活性。目前，CPT的临床应用受到其活性内酯形式的不溶性和不稳定性的限制，导致其抗肿瘤效力较低，生物利用度较差。由于这些原因，通过溶剂蒸发法使用H系列的聚（D，L-丙交酯-共-乙交酯）（H-PLGA）制备CPT负载微球，其含有比非K系列更多的羧酸末端链并且水合更快。在1.2%CPT-有效载荷下，药物分子分散在整个基质中，而在更高的CPT-有效载荷下，结晶CPT-胰岛的量随着CPT含量而增加。CPT的释放模式是双相的，包括递送20-35%的有效载荷并随着载药量增加的第一突释效应。该阶段之后是CPT的持续递送，在160小时内释放40-75%的有效载荷。与PLGA-微球相比，CPT-从H-PLGA的释放速率高两倍并且加速。活性CPT-内酯在制备、储存和释放过程中由于酸性低聚物的扩散受阻等机制而得以保持。因此，CPT从PLGA-微球中的稳定和持续释放可能减少局部毒性，并延长疗效，为CPT化疗提供新的前景。(C)1999年由Elsevier Science B. V.出版，版权所有。
Camptothecin (CPT) and its water-insoluble derivatives are known as topoisomerase-I inhibitors exhibiting high antitumoral activity against a wide spectrum of human malignancies. Until now clinical application of CPT is restricted by insolubility and instability of the drug in its active lactone form resulting in less antitumor potency and poor bioavailability. For these reasons CPT-loaded-microspheres were prepared by the solvent evaporation method using the H-series of poly(D,L-lactide-co-glycolide) (H-PLGA), which contain more carboxylic acid end chains and hydrate faster than the non-K-series. At 1.2% CPT-payload the drug was molecular dispersed throughout the matrix whereas at higher CPT-payload the amount of crystalline CPT-islets increased with the CPT content. The release pattern of CPT was biphasic comprising a first burst effect delivering 20-35% of the payload and increasing with drug-loading. This phase was followed by sustained delivery of CPT releasing 40-75% of the payload within 160 h. In comparison to PLGA-microspheres, the CPT-release rate from H-PLGA was twofold higher and accelerated. The active CPT-lactone was maintained during preparation, storage and release due to hindered diffusion of acidic oligomers among other mechanisms. Thus stabilization and sustained release of CPT from PLGA-microspheres might reduce local toxicity combined with prolonged efficacy offering new perspectives in CPT chemotherapy. (C) 1999 Published by Elsevier Science B.V. All rights reserved.