Self-Assembling Prodrugs by Precise Programming of Molecular Structures that Contribute Distinct Stability, Pharmacokinetics, and Antitumor Efficacy
Self-Assembling Prodrugs by Precise Programming of Molecular Structures that Contribute Distinct Stability, Pharmacokinetics, and Antitumor Efficacy
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通过分子结构的精确编程来自组装前药，从而提供独特的稳定性、药代动力学和抗肿瘤功效
DOI：
10.1002/adfm.201501953
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发表时间：
2015-08-19
影响因子：
19
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
--
作者：
Wang, Hangxiang;Xie, Haiyang;Zheng, Shusen
精确调控的化学修饰的可行性极大地影响着原始药物的物理化学性质，且应有助于前药通过两亲性自组装形成超分子纳米前药（SNPs）。然而，合理设计此类前药以实现良好的临床效果仍颇具挑战。在此，通过将多种亲脂性基团位点特异性连接到抗肿瘤药物SN - 38（7 - 乙基 - 10 - 羟基喜树碱）上，构建了一个前药库。利用羟基作为亲溶剂基团的作用，这些前药在水性环境中表现出自我组装特性，从而得以鉴定出五种能够在高药物浓度下自组装形成SNPs的前药。重要的是，体内研究表明，SNPs的抗肿瘤活性与其稳定性和长期循环密切相关。此外，这种SNP设计策略的模块化特点为在颗粒表面轻松整合其他有价值的功能（如肿瘤特异性靶向配体）提供了机会，这一点在小鼠异种移植模型中进一步用于提高抗肿瘤疗效。因此，这种基于结构的SN - 38分子重构显著提升了SNPs用于临床的效力。这些结果也为前药的合理设计提供了新的机制性见解。
The availability of precisely modulated chemical modifications dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self-assembly of prodrugs into supramolecular nano-prodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site-specific attachment of a variety of lipophilic moieties to the antitumor agent SN-38 (7-ethyl-10-hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self-assembly in aqueous environments, allowing for the identification of five prodrugs capable of self-assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long-term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor-specific targeting ligands) to the particle surface, which is further exploited to improve antitumor efficacy in mouse xenograft models. Thus, this structure-based reconstruction of SN-38 molecules significantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs.