pH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Liu, Xin; Wang, Zhexiang; Ren, Xiaoyan; Chen, Xinyang; Tao, Jiangchuan; Guan, Yuanhui; Yang, Xuefeng; Tang, Rupei; Yan, Guoqing

doi:10.1016/j.ajps.2023.100832

Cited by 1 publication

(1 citation statement)

References 39 publications

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“…Additionally, such a hydrophobic 5FU derivative could easily self-assemble into pH-responsive SMNs (SA-OE-5FU-NPs) through O/W emulsion solvent evaporation method . Notably, the ortho ester linkages can endow hydrophobic NPs with dynamic large-to-small size transition via pH-triggered surface erosion, which facilitates targeted and controlled drug release . In addition, doxorubicin (DOX), a DNA topoisomerase inhibitor, has displayed a synergistic effect when administered in combination with 5FU, , therefore it can be introduced into SA-OE-5FU-NPs for enhanced synergistic therapy.…”

Section: Introductionmentioning

confidence: 99%

pH-Sensitive Nanodrug Self-Assembled from Aliphatic 5-Fluorouracil Derivative and Doxorubicin for Synergistic Cancer Therapy

Li,

Zhang,

Sun

et al. 2024

ACS Appl. Nano Mater.

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5-Fluorouracil (5FU) and its derivatives have been widely used for cancer treatment; however they fail to achieve selective chemotherapy. Herein, this work highlights a successful development of a pH-sensitive aliphatic 5fluorouracil (5FU) derivative prodrug, which is synthesized via chemically linking 5FU and stearyl alcohol (SA) using ortho ester linkage. It can further selfassemble into a synergistic small molecule nanodrug through a noncovalent interaction with doxorubicin (DOX). The nanodrug displays precise structure and high drug loading (more than 15% of drug loading content (DLC) and 87% of drug loading efficiency (DLE)). SA and ortho ester linkages endow the nanodrug with high lipophilicity on tumor cell membrane and tumoral intracellular pH response, respectively. The nanodrug also exhibits a slightly negatively charged surface (−0.513 mV) at physiological pH (7.4) and a large-to-small size change from 176.2 to 128.9 nm at tumoral intracellular pH (5.0). These superior characteristics endow the nanodrugs with blood circulation stability, selective tumor accumulation, improved cellular uptake, efficient drug release, as well as synergistic effect on tumor cells, thereby significantly inhibiting tumor growth (smaller than initial tumor size), reducing side effects, and prolonging survival time. Thus, such a pH-sensitive small molecule nanodrug self-assembled from the aliphatic 5FU derivative and DOX has a great potential for selective synergistic cancer therapy, greatly advancing their clinical use.

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