当前，由于其精确结构、高药物负载量以及通过克服胃肠道、血液循环和肿瘤组织中的各种生理屏障而提高口服生物利用度，动态侵蚀性小分子纳米前药在口服化疗方面具有巨大需求。在此，本研究突出了基于体内显著pH变化而成功开发的pH触发型动态侵蚀性小分子纳米前药，其通过氯环磷酰胺和星状正酯之间的酰胺反应合成。精确的纳米前药表现出异常高的药物负载量（68.16%）、电中性、强疏水性以及从胃肠道pH到肿瘤pH的动态大到小的尺寸转变。这些有利的理化特性可以有效促进胃肠道吸收、血液循环稳定、肿瘤积累、细胞摄取和细胞毒性，从而实现高口服相对生物利用度（358.72%）以及显著的抑制肿瘤生长同时降低副作用。因此，本研究可能为有吸引力的临床转化固体口服化疗开辟了新途径。©2023年沈阳药科大学。由Elsevier B.V.出版。

Currently, the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy, owing to its precise structure, high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract, blood circulation and tumor tissues compared to other oral nanomedicines. Herein, this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes, which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters. The precise nano-prodrugs exhibit extraordinarily high drug loading (68.16%), electric neutrality, strong hydrophobicity, and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH. These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.© 2023 Shenyang Pharmaceutical University. Published by Elsevier B.V.