使用 RNAi 特征分析指导具有经过验证的机制、体内功效和低毒性的三药偶联纳米颗粒的设计,Journal of the American Chemical Society

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使用 RNAi 特征分析指导具有经过验证的机制、体内功效和低毒性的三药偶联纳米颗粒的设计
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2016-09-14 , DOI: 10.1021/jacs.6b06321
Jonathan C Barnes ₁ , Peter M Bruno ₁ , Hung V-T Nguyen ₁ , Longyan Liao ₁ , Jenny Liu ₁ , Michael T Hemann ₁ , Jeremiah A Johnson ₁

Affiliation

单纳米颗粒（NP）联合化疗药物迅速成为传统化疗的有吸引力的替代品，因为它们能够增加药物溶解度、减少脱靶毒性、延长血液循环寿命并增加递送至肿瘤的药物量。对于 NP 结合药物，即 NP 前药，当前的实践标准是假设从 NP 释放的每种药物的亚细胞作用机制反映了未结合的游离药物的亚细胞作用机制。在这里，我们首次使用 RNAi 特征分析来检查多药缀合的 NP 前药相对于其小分子前药和天然药物作用机制的作用机制。此外，还描述了单一 NP 平台中三种不同药物的有效附加贡献。结果表明，一些铂（IV）顺铂前药虽然具有细胞毒性，但可能不具有顺铂预期的作用机制。利用这一见解开发了一种新型铂 (IV) 奥沙利铂前药，并将其纳入三药缀合的 NP 中，其中保留了每种药物的作用机制，以用其他致命水平的化疗治疗荷瘤小鼠。

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Using an RNAi Signature Assay To Guide the Design of Three-Drug-Conjugated Nanoparticles with Validated Mechanisms, In Vivo Efficacy, and Low Toxicity

Single-nanoparticle (NP) combination chemotherapeutics are quickly emerging as attractive alternatives to traditional chemotherapy due to their ability to increase drug solubility, reduce off-target toxicity, enhance blood circulation lifetime, and increase the amount of drug delivered to tumors. In the case of NP-bound drugs, that is, NP-prodrugs, the current standard of practice is to assume that the subcellular mechanism of action for each drug released from the NP mirrors that of the unbound, free-drug. Here, we use an RNAi signature assay for the first time to examine the mechanism of action of multidrug-conjugated NP prodrugs relative to their small molecule prodrugs and native drug mechanisms of action. Additionally, the effective additive contribution of three different drugs in a single-NP platform is characterized. The results indicate that some platinum(IV) cisplatin prodrugs, although cytotoxic, may not have the expected mechanism of action for cisplatin. This insight was utilized to develop a novel platinum(IV) oxaliplatin prodrug and incorporate it into a three-drug-conjugated NP, where each drug's mechanism of action is preserved, to treat tumor-bearing mice with otherwise lethal levels of chemotherapy.

更新日期：2016-09-14

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