Self-Amplified Cascade Degradation and Oxidative Stress Via Rational pH Regulation of Oxidation-Responsive Poly(ferrocene) Aggregates

• Published in: Journal of the American Chemical Society 2023-08, Vol.145 (32), p.17755-17766
• Main Authors: Song, Chengzhou, Chen, Minglong, Tan, Jiajia, Xu, Jie, Zhang, Yuben, Zhang, Guoying, Hu, Xianglong, Liu, Shiyong
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.3c04454

Precise activation of polymer nanoparticles at lesion sites is crucial to achieve favorable therapeutic efficacy. However, conventional endogenous stimuli-responsive polymer nanoparticles probably suffer from few triggers to stimulate the polymer degradation and subsequent functions. Here, we describe oxidation-responsive poly­(ferrocene) amphiphiles containing phenylboronic acid ester and ferrocene as the repeating backbone units. Upon triggering by hydrogen peroxide inside the tumor cells, the phenylboronic acid ester bonds are broken and poly­(ferrocene) units are degraded to afford free ferrocene and noticeable hydroxide ions. The released hydroxide ions can immediately improve the pH value within the poly­(ferrocene) aggregates, and the degradation rate of the phenylboronic acid ester backbone is further promoted by the upregulated pH; thereupon, the accelerated degradation can release much more additional hydroxide ions to improve the pH, thus achieving a positive self-amplified cascade degradation of poly­(ferrocene) aggregates accompanied by oxidative stress boosting and efficient cargo release. Specifically, the poly­(ferrocene) aggregates can be degraded up to ∼90% within 12 h when triggered by H2O2, while ferrocene-free control nanoparticles are degraded by only 30% within 12 days. In addition, the maleimide moieties tethered in the hydrophilic corona can capture blood albumin to form an albumin-rich protein corona and significantly improve favorable tumor accumulation. The current oxidation-responsive poly­(ferrocene) amphiphiles can efficiently inhibit tumors in vitro and in vivo. This work provides a proof-of-concept paradigm for self-amplified polymer degradation and concurrent oxidative stress, which is promising in actively regulated precision medicine.