Synthesis of linear, β-cyclodextrin-based polymers and their camptothecin conjugates
Synthesis of linear, β-cyclodextrin-based polymers and their camptothecin conjugates
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DOI：
10.1021/bc0340924
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发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Davis, ME
中科院分区：
文献类型：
--
作者：
Cheng, JJ;Khin, KT;Davis, ME
合成6（A），6（D）-双-（2-氨基-2-羧基乙硫基）-6（A）6（D）-双脱氧-β-环糊精1，β-环糊精的二氨基酸衍生物，并与双官能化PEG共聚单体缩合，得到具有侧基官能团（羧酸酯）的线性高分子量（M-w超过50 kDa）β-环糊精基聚合物（2-4）。2-4都高度溶于水溶液（超过200 mg/mL）。合成20-O-三氟甘氨酰喜树碱5a和20-O-三氟甘氨酰甘氨酰喜树碱5 b，并将其与2缀合，得到聚合物-喜树碱（CPT）前药。CPT的溶解度增加了超过三个数量级时，它是共轭2。CPT从缀合物HGGG 6的释放速率（高分子量聚合物（M-w 97 kDa），glyglygly接头和6重量% CPT负载）和HG 6（高MW聚合物（M-w 97 kDa），gly连接体和6重量% CPT负载）在小鼠或人血浆中的水解速率在pH = 7.4时比纯水解速率显著加速，这表明在CPT释放中在该pH下存在酶促裂解作为速率决定步骤。水溶液的pH值对HGGG 6和HG 6水解CPT的速率有很大影响，在4.1 ≤ pH ≤ 13.1的范围内，pH值越低，速率越慢。使用体外MTT测定，发现聚合物2 e、CPT和CPT缀合物HG 6和HGGG 6的IC 50对LS 174 T、HT 29、A2780和PC 3细胞具有细胞系依赖性。母体聚合物2 e对所有测试的培养细胞具有非常低的毒性。
6(A),6(D) -Bis-(2-amino-2-carboxylethylthio)-6(A) 6(D)-dideoxy-beta-cyclodextrin 1, a diamino acid derivative of beta-cyclodextrin, is synthesized and condensed with difunctionalized PEG comonomers to give linear, high molecular weight (M-w over 50 kDa) beta-cyclodextrin-based polymers (2-4) with pendant functionality (carboxylate). 2-4 are all highly soluble in aqueous solutions (over 200 mg/mL). 20-O-trifluoroglycinylcamptothecin, 5a, and 20-O-trifluoroglycinylglycinylglycinylcamptothecin, 5b, are synthesized and conjugated to 2 to give polymer- camptothecin (CPT) prodrugs. The solubility of CPT is increased by more than three orders of magnitude when it is conjugated to 2. The rates of CPT release from the conjugates HGGG6 (high molecular weight polymer (M-w 97 kDa), glyglygly linker and 6 wt % CPT loading) and HG6 (high MW polymer (M-w 97 kDa), gly linker and 6 wt % CPT loading) in either mouse or human plasma are dramatically accelerated over the rates of pure hydrolysis at pH = 7.4, indicating the presence of enzymatic cleavage as a rate-determining step at this pH in the release of the CPT. The pH of aqueous solution has a large effect on hydrolysis rate of CPT from HGGG6 and HG6; the lower the pH, the slower the rate in the range at 4.1 less than or equal to pH less than or equal to 13.1. The IC50's of polymer 2e, CPT, and the CPT conjugates HG6 and HGGG6 are found to be cell-line dependent with LS174T, HT29, A2780, and PC3 cells using in vitro MTT assays. The parent polymer 2e has very low toxicity to all cultured cells tested.