Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada.
Biomaterials. 2022 Oct;289:121735. doi: 10.1016/j.biomaterials.2022.121735. Epub 2022 Aug 13.
A small molecule drug with poor aqueous solubility can be conjugated to a hydrophilic polymer like poly(ethylene glycol) (PEG) to form an amphiphilic polymer-drug conjugate that self-assembles to form nanoparticles (NPs) with improved solubility and enhanced efficacy. This strategy has been extensively applied to improve the delivery of several small molecule drugs. However, very few reports have succeeded to tune the rate of drug release from these NPs. To the best of our knowledge, there have been no reports of utilizing click and steric hindrance chemistry to modulate the drug release of self-assembling polymer-drug conjugates. In this study, we utilized click chemistry to conjugate methoxy-PEG (mPEG) to an anti-tumor drug, paclitaxel (PTX). A focused library of PTX-Rx-mPEG (x = 0, 1, 2) conjugates were synthesized with different chemical modalities next to the cleavable ester bond to study the effect of increasing steric hindrance on the self-assembly process and the physicochemical properties of the resulting PTX-NPs. PTX-R0-mPEG had no added steric hindrance (x = 0; minimal), PTX-R1-mPEG consisted of two methyl groups (x = 1: moderate), and PTX-R2-mPEG consisted of a phenyl group (x = 2: significant). Drug release studies showed that PTX-NPs released PTX at a decreased rate with increasing steric hindrance. Pharmacokinetic studies showed that the AUC of released PTX from the moderate-release PTX-R1-NP was approximately 20-, 6-, and 3-fold higher than that from free PTX, PTX-R0-NP and PTX-R2-NP, respectively. As a result, among these different PTX formulations, PTX-R1-NP showed superior efficacy in inducing tumor regression and prolonging the animal survival. The tumors treated with PTX-R1-NP displayed the lowest tumor progression markers (Ki68 and CD31) and the highest apoptotic marker (TUNEL) compared to the others. This work emphasizes the importance of taking a systematic approach in designing self-assembling polymer drug conjugates and highlights the potential of utilizing steric hindrance as a tool to tune the drug release rate from such systems.
具有较差水溶性的小分子药物可以与亲水性聚合物如聚乙二醇（PEG）连接，形成两亲聚合物-药物缀合物，自组装成具有改善的水溶性和增强的功效的纳米颗粒（NPs）。该策略已被广泛应用于改善几种小分子药物的递送。然而，很少有报道成功地调节这些 NPs 的药物释放速率。据我们所知，还没有利用点击和空间位阻化学来调节自组装聚合物-药物缀合物的药物释放的报道。在这项研究中，我们利用点击化学将甲氧基-聚乙二醇（mPEG）连接到抗肿瘤药物紫杉醇（PTX）上。通过在可裂解酯键附近合成具有不同化学模式的聚焦文库 PTX-Rx-mPEG（x=0,1,2）缀合物，研究了增加空间位阻对自组装过程和所得 PTX-NPs 的物理化学性质的影响。PTX-R0-mPEG 没有增加空间位阻（x=0；最小），PTX-R1-mPEG 由两个甲基组成（x=1：中等），PTX-R2-mPEG 由一个苯基组成（x=2：显著）。药物释放研究表明，随着空间位阻的增加，PTX-NPs 以降低的速率释放 PTX。药代动力学研究表明，从中等释放的 PTX-R1-NP 中释放的 PTX 的 AUC 分别比游离 PTX、PTX-R0-NP 和 PTX-R2-NP 高约 20、6 和 3 倍。因此，在这些不同的 PTX 制剂中，PTX-R1-NP 在诱导肿瘤消退和延长动物存活方面表现出更好的疗效。与其他制剂相比，用 PTX-R1-NP 治疗的肿瘤显示出最低的肿瘤进展标志物（Ki68 和 CD31）和最高的凋亡标志物（TUNEL）。这项工作强调了在设计自组装聚合物药物缀合物时采取系统方法的重要性，并强调了利用空间位阻作为调节此类系统药物释放速率的工具的潜力。
