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.

中文翻译：

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洗瓶刷结构的葡聚糖前药可作为酸度响应性载体，以提高化疗效率。

与正常组织相比，肿瘤微环境中的独特条件（例如较低的pH值）可以诱导药物准确释放到特定病变中。该策略提供了一种有效的方法来克服药物意外泄漏和循环稳定性差的问题，从而减少副作用并增强癌症治疗的效果。在这项研究中，我们基于葡聚糖（DEX）多糖设计了一类具有瓶刷结构的酸活化超分子纳米前药（DOM @ DOX），该多糖通过原子转移自由基聚合与亲水性聚乙二醇链连接，并进一步与抗癌药阿霉素（DOX）在共聚物的骨架上通过酸响应性肼键。此外，DOM @ DOX前药对DOX的载药量高达48 wt％，并且该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。在肿瘤细胞内部的酸性环境中，前药的肼键断裂，导致母体胶束释放出DOX。由于载体尺寸小，该前药在荷瘤小鼠模型中表现出良好的瘤内通透性，良好的循环稳定性和显着的肿瘤抑制效率，这有利于开发用于增强化学疗法的新一代纳米药物。