Targeted drug delivery systems exploiting the acidic tumor microenvironment have been thriving, with responsive modifications to the active sites like hydroxyl groups enhancing stability, reducing toxicity, and boosting targeted bioavailability. Yet, the utility of hydroxyl-based acid-sensitive linkages is currently constrained by the intricacy of synthesis, questionable stability, and an inability to discern between physiological pH levels associated with health and disease. Here, we unveiled a novel hydroxyl-based acid-labile linkage, the "acetal ester bond", which not only excelled in its hypersensitive acid responsiveness, but was also facile to synthesize, with exceptionally high yields (>80 %) of final products derived from primary, linear secondary, cyclic secondary, and tertiary alcohols consistently, demonstrating its broad applicability. Further research indicated that the acetal ester bond bearing-paclitaxel conjugate (PTX-COU) with the ability to self-assembly, remained intact in simulated physiological settings, while swiftly hydrolyzed to release PTX in the acidic tumor environment within minutes, contributing to mitigated systemic toxicity and improved bioavailability. In vitro and in vivo experiments demonstrated that PTX-COU outperformed PTX in tumor growth inhibition due to drug accumulation facilitated by acid-responsive target release. This discovery offered a promising solution for pH-triggered drug release, providing new insights and methods for the development of novel targeted drug delivery systems.

中文翻译：

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羟基酸-超敏缩醛酯键的设计、合成及其在纳米药物中的应用潜力


利用酸性肿瘤微环境的靶向药物递送系统一直在蓬勃发展，对羟基等活性位点的响应性修饰增强了稳定性、降低了毒性并提高了靶向生物利用度。然而，羟基酸敏感键的效用目前受到合成的复杂性、可疑的稳定性以及无法区分与健康和疾病相关的生理 pH 值的限制。在这里，我们揭示了一种新型的羟基酸不稳定键，即“缩醛酯键”，它不仅具有出色的超敏酸响应性，而且易于合成，来自伯醇、线性仲醇、环仲醇和叔醇的最终产物的产率极高（>80%），证明了其广泛的适用性。进一步的研究表明，具有自组装能力的醛酯键-紫杉醇偶联物 （PTX-COU） 在模拟生理环境中保持完整，同时在几分钟内在酸性肿瘤环境中迅速水解释放 PTX，有助于减轻全身毒性和提高生物利用度。体外和体内实验表明，PTX-COU 在肿瘤生长抑制方面优于 PTX，这是由于酸反应性靶点释放促进了药物积累。这一发现为 pH 触发的药物释放提供了一种有前途的解决方案，为开发新型靶向药物递送系统提供了新的见解和方法。