The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin.
The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin.
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DOI：
10.1016/j.biomaterials.2015.05.046
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发表时间：
2015-09
期刊：
影响因子：
14
通讯作者：
Li, Song
中科院分区：
文献类型：
--
作者：
Lu, Jianqin;Liu, Chuang;Wang, Pengcheng;Ghazwani, Mohammed;Xu, Jieni;Huang, Yixian;Ma, Xiaochao;Zhang, Peijun;Li, Song
喜树碱（CPT）是一种有效的抗肿瘤药物，通过抑制DNA复制过程中拓扑异构酶I的活性而发挥作用。然而，CPT的溶解性极差，其活性内酯环在血流中的不稳定性，以及对正常组织的非特异性毒性极大地阻碍了其临床应用。此外，迄今为止开发的大多数制剂不适用于配制CPT。本研究通过碳酸酯键（CPT-VE）或二硫键（CPT-S-S-VE）将CPT与α-生育酚偶联，制备了两种新型CPT前药。两种CPT前药都能够在基于PEG 5 K-Fmoc-VE 2的纳米胶束载体的促进下自组装成纳米纤维。两种前药纳米组装体均表现出优异的稳定性。荧光猝灭、紫外吸收和FT-IR研究表明，载体和前药之间存在强烈的相互作用，包括疏水相互作用、π-π堆积以及氢键。核磁共振研究表明，前药成功地纳入PEG 5 K-Fmoc-VE 2的自组装过程中。在体外实验中，PEG 5 K-Fmoc-VE 2/CPT-S-S-VE对肿瘤细胞的杀伤作用明显高于PEG 5 K-Fmoc-VE 2/CPT-VE。生物分布研究表明，在PEG 5 K-Fmoc-VE 2胶束中配制的CPT-S-S-VE在递送至肿瘤组织后有效地转化为母体CPT。最后，PEG 5 K-Fmoc-VE 2/CPT-S-S-VE纳米纤维在侵袭性鼠乳腺癌模型中显示出上级肿瘤生长抑制（4T1.2）。
Camptothecin (CPT) is a potent antitumor agent and functions via inhibiting the activity of topoisomerase I during DNA replication. However, the clinical application of CPT has been greatly hindered by its extremely poor solubility, the instability of its active lactone ring in blood stream, as well as the non-specific toxicity to normal tissues. In addition, most of the formulations developed so far are not applicable for formulating CPT. In this study, two novel CPT prodrugs were developed by conjugating CPT to α-tocopherol via a carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE). Both CPT prodrugs were able to self-assemble into nanofibers with the facilitation of a PEG5K-Fmoc-VE2-based nanomicellar carrier. Both prodrug nanoassemblies exhibited excellent stability. Fluorescence quenching, UV absorbance, and FT-IR studies demonstrated strong interactions between carrier and prodrugs, including hydrophobic interaction, π-π stacking, as well as hydrogen bonding. NMR studies suggested that prodrugs were successfully incorporated into PEG5K-Fmoc-VE2 during self-assembly process. In vitro, PEG5K-Fmoc-VE2/CPT-S-S-VE presented significantly higher level of cytotoxicity on tumor cells compared to PEG5K-Fmoc-VE2/CPT-VE. Biodistribution study showed that CPT-S-S-VE formulated in PEG5K-Fmoc-VE2 micelles was effectively converted to parent CPT following delivery to tumor tissues. Finally, PEG5K-Fmoc-VE2/CPT-S-S-VE nanofibers showed superior tumor growth inhibition in an aggressive murine breast cancer model (4T1.2).
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DOI：
10.1016/j.jconrel.2014.10.016
发表时间：
2014-12-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Lu J;Zhao W;Liu H;Marquez R;Huang Y;Zhang Y;Li J;Xie W;Venkataramanan R;Xu L;Li S
通讯作者：
Li S
影响因子：
4.2
作者：
Wu, GY;Fang, YZ;Turner, ND
通讯作者：
Turner, ND
影响因子：
10.8
作者：
Caiolfa, VR;Zamai, M;Suarato, A
通讯作者：
Suarato, A
影响因子：
4.7
作者：
Duhem, Nicolas;Danhier, Fabienne;Preat, Veronique
通讯作者：
Preat, Veronique
影响因子：
14
作者：
Lu, Jianqin;Huang, Yixian;Zhao, Wenchen;Marquez, Rebecca T.;Meng, Xiaojie;Li, Jiang;Gao, Xiang;Venkataramanan, Raman;Wang, Zhou;Li, Song
通讯作者：
Li, Song