Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Biomater Sci. 2022 Jun 14;10(12):3122-3136. doi: 10.1039/d1bm01947c.
Poorly water-soluble small hydrophobic compounds can be conjugated to a hydrophilic polymer such as methoxypolyethylene glycol (mPEG) to form amphiphilic prodrugs that can self-assemble into nanoparticles (NPs) with increased aqueous solubility, prolonged circulation, and improved delivery. There have been numerous reports utilizing this strategy to improve delivery of small molecule drugs, but few reports take systematic, structure-activity relationship (SAR)-based approaches to develop optimal prodrug conjugates. Additionally, it is important to study interplay of different components within the conjugate, such as polymer molecular weight (M.W.) and linker to obtain optimal efficacy and safety. In this study, we developed a click chemistry platform to conjugate mPEG of three different M.W. (low: 550 Da; medium: 2000 Da; high: 5000 Da) to a small molecular anti-tumor drug, gambogic acid (GA) two different linkers (ester: fast release; amide: slow release) to generate six distinct conjugates. NPs formed from conjugates of mPEG displayed significantly higher hemolytic toxicity compared to those with higher M.W. (<10%), regardless of the linker type. Drug release studies showed that NPs with an amide linker displayed insignificant drug release (<0.5% per day) compared to those with an ester linker (1-2% per day). NPs formed with mPEG using an ester linker (5000-E-NP) possessed the optimal balance between prolonged circulation (223-fold higher AUC than free GA) and sufficient drug release (1.68 ± 0.13% per day), leading to superior anti-tumor efficacy compared to other formulations, while the corresponding amides (5000-A-NP) displayed the most prolonged circulation but only moderate efficacy likely due to insufficient drug release. Our work highlights the importance of diligently studying SAR on drug conjugates to improve drug delivery and confirms the robustness of using the click platform to generate a conjugate library with chemical diversity.
疏水性差的水溶性小化合物可与亲水性聚合物（如甲氧基聚乙二醇（mPEG））缀合形成两亲前药，前药可自组装成纳米颗粒（NPs），从而增加水溶解度、延长循环时间并改善递送。已经有许多利用该策略来改善小分子药物递送的报道，但很少有报道采用系统的、基于结构-活性关系（SAR）的方法来开发最佳前药缀合物。此外，研究缀合物中不同成分之间的相互作用（如聚合物分子量（M.W.）和连接子）对于获得最佳疗效和安全性非常重要。在本研究中，我们开发了一种点击化学平台，将三种不同分子量（低：550 Da；中：2000 Da；高：5000 Da）的 mPEG 与小分子抗肿瘤药物藤黄酸（GA）偶联两种不同的连接子（酯：快速释放；酰胺：缓慢释放），生成六种不同的缀合物。与具有较高分子量（<10%）的缀合物相比，mPEG 缀合物形成的 NPs 表现出明显更高的溶血毒性，无论连接子类型如何。药物释放研究表明，酰胺连接子的 NPs 药物释放量（<0.5%/天）明显低于酯连接子（1-2%/天）的 NPs。使用酯连接子（5000-E-NP）形成的 NPs 具有延长循环时间（与游离 GA 相比 AUC 高 223 倍）和足够药物释放（每天 1.68 ± 0.13%）之间的最佳平衡，与其他制剂相比具有更好的抗肿瘤疗效，而相应的酰胺（5000-A-NP）显示出最长的循环时间，但只有中等疗效，可能是由于药物释放不足。我们的工作强调了在药物缀合物上认真研究 SAR 以改善药物递送的重要性，并证实了使用点击平台生成具有化学多样性的缀合物文库的稳健性。
