Ci Tianyuan, Chen Liang, Li Ting, Chang Guangtao, Yu Lin, Ding Jiandong
State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Advanced Materials Laboratory, Fudan University, Shanghai 200433, China.
Biomater Sci. 2013 Dec 29;1(12):1235-1243. doi: 10.1039/c3bm60152h. Epub 2013 Aug 8.
Camptothecin (CPT) and its analogues constitute one of the most important families of anticancer drugs. However, the CPT-family members have to confront the severe problem of hydrolysis from lactone form, the only form capable of antitumor efficacy, to the carboxylate form, leading to a significant decrease in therapy efficiency as well as severe side effects. Herein, two CPT analogues with different water solubilities, 10-hydrocamptothecin (HCPT) and topotecan (TPT), and four poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) (PEG-PPG-PEG, Pluronic) copolymers of varied hydrophilic-lipophilic balance (HLB) values, were examined with emphasis on the change of the equilibrium lactone fraction (f) of the drugs after addition of the copolymers. In all cases, f was enhanced. For weak water-soluble HCPT, the enhancement extent was significantly increased with decrease of the copolymer HLB, which is influenced by the block chain length for a given series of amphiphilic block copolymers. The effect was less significant for TPT, a more hydrophilic drug. The fluorescence experiments confirmed the assembly of the drugs into polymeric micelles. A series of pH titrations were also carried out, which quantified the shift of pH (pH when f = 0.5) after addition of the copolymers. The optimal or most sensitive pH, pH, which gave the maximum enhancement of f by the polymers, was found to depend upon the type of drug, the HLB value of copolymer, and also the polymer concentration. Hence, this work has indicated the universality of the enhancement effect of polymeric micelles on the equilibrium lactone fractions of CPT analogues, and meanwhile revealed the dependence of the enhancement extent upon the HLB values of the copolymer and hydrophilicity of the drug. The concept of optimal pH has also been put forward for the first time.
喜树碱（CPT）及其类似物是最重要的抗癌药物家族之一。然而，CPT家族成员必须面对一个严峻的问题，即从具有抗肿瘤功效的唯一形式内酯形式水解为羧酸盐形式，这导致治疗效率显著降低以及严重的副作用。在此，研究了两种具有不同水溶性的CPT类似物，10-羟基喜树碱（HCPT）和拓扑替康（TPT），以及四种具有不同亲水亲脂平衡（HLB）值的聚（乙二醇）-聚（丙二醇）-聚（乙二醇）（PEG-PPG-PEG，普朗尼克）共聚物，重点考察了加入共聚物后药物平衡内酯分数（f）的变化。在所有情况下，f均有所提高。对于水溶性较弱的HCPT，随着共聚物HLB的降低，提高程度显著增加，对于给定系列的两亲性嵌段共聚物，这受嵌段链长度的影响。对于亲水性更强的药物TPT，这种影响不太显著。荧光实验证实了药物组装成聚合物胶束。还进行了一系列pH滴定，量化了加入共聚物后pH值（f = 0.5时的pH）的变化。发现聚合物使f达到最大提高时的最佳或最敏感pH值，pHopt，取决于药物类型、共聚物的HLB值以及聚合物浓度。因此，这项工作表明了聚合物胶束对CPT类似物平衡内酯分数增强作用的普遍性，同时揭示了增强程度对共聚物HLB值和药物亲水性的依赖性。还首次提出了最佳pH的概念。
