Key Laboratory of Luminescent and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, School of Materials and Energy, Southwest University, Chongqing, 400715, P. R. China.
Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, No. 355 Luding Road, Shanghai, 200062, P.R. China.
Biomater Sci. 2020 Jan 1;8(1):473-484. doi: 10.1039/c9bm01692a. Epub 2019 Nov 22.
Compared to normal tissues, unique conditions in the tumor microenvironment, such as a lower pH, can induce accurate release of a drug into specific lesions. This strategy provides an efficient approach to overcome the issues of unexpected drug leakage and poor circulation stability, thereby reducing the side effects and enhancing the effect of cancer treatment. In this study, we designed a class of acid activatable supramolecular nano-prodrugs (DOM@DOX) with a bottlebrush architecture based on the dextran (DEX) polysaccharide, which connects with a hydrophilic polyethylene glycol chain by atom transfer radical polymerization and further conjugates with an anticancer drug doxorubicin (DOX) at the backbone of the copolymer via an acidity-responsive hydrazine bond. Furthermore, the DOM@DOX prodrug has a high drug loading up to 48 wt% for DOX, and the prodrug can maintain a stable nano-sized spherical shape in aqueous solution by a self-assembly strategy. In an acidic environment inside tumor cells, the hydrazine bond of the prodrug breaks, leading to the release of DOX from parental micelles. Owing to the small size of the carrier, the prodrug exhibits good intratumoral permeability, good circulation stability and significant tumor suppression efficiency in tumor-bearing mouse models, which is beneficial for the development of new generation nanomedicine for enhanced chemotherapy.
与正常组织相比，肿瘤微环境中的独特条件，如较低的 pH 值，可以诱导药物精确释放到特定的病变部位。这种策略为克服药物意外泄漏和循环稳定性差的问题提供了一种有效的方法，从而降低了副作用并增强了癌症治疗的效果。在这项研究中，我们设计了一类基于葡聚糖（DEX）多糖的酸激活超分子纳米前药（DOM@DOX），具有瓶刷结构，通过原子转移自由基聚合连接亲水性聚乙二醇链，并通过酸响应腙键进一步将抗癌药物阿霉素（DOX）连接到共聚物的主链上。此外，DOM@DOX 前药的 DOX 载药高达 48wt%，并且前药可以通过自组装策略在水溶液中保持稳定的纳米级球形形状。在肿瘤细胞内的酸性环境中，前药的腙键断裂，导致 DOX 从母体胶束中释放。由于载体的尺寸较小，前药在荷瘤小鼠模型中表现出良好的肿瘤内渗透性、良好的循环稳定性和显著的肿瘤抑制效率，这有利于开发新一代增强化疗的纳米医学。
