Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, and Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei 230026, Anhui, China.
School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, Anhui, China.
J Am Chem Soc. 2023 Aug 16;145(32):17755-17766. doi: 10.1021/jacs.3c04454. Epub 2023 Aug 1.
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 HO, 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.
精确激活病变部位的聚合物纳米颗粒对于实现良好的治疗效果至关重要。然而，传统的内源性刺激响应聚合物纳米颗粒可能受到很少的触发因素的限制，无法刺激聚合物的降解和随后的功能。在这里，我们描述了含有苯硼酸酯和二茂铁作为重复骨架单元的氧化响应性聚（二茂铁）两亲物。在肿瘤细胞内的过氧化氢触发下，苯硼酸酯键断裂，聚（二茂铁）单元降解为游离二茂铁和明显的氢氧根离子。释放的氢氧根离子可以立即提高聚（二茂铁）聚集体内的 pH 值，并且 pH 值的升高进一步促进了苯硼酸酯骨架的降解速率；因此，加速的降解可以释放更多的额外氢氧根离子来提高 pH 值，从而实现聚（二茂铁）聚集体的正自放大级联降解，同时增强氧化应激和有效释放货物。具体而言，当被 HO 触发时，聚（二茂铁）聚集体在 12 小时内可降解约 90%，而无二茂铁的对照纳米颗粒在 12 天内仅降解 30%。此外，亲水冠上的马来酰亚胺部分可以捕获血液白蛋白形成富含白蛋白的蛋白质冠，并显著改善有利的肿瘤积累。当前的氧化响应性聚（二茂铁）两亲物可以在体外和体内有效地抑制肿瘤。这项工作为自放大聚合物降解和并发氧化应激提供了一个概念验证范例，有望在主动调节的精准医学中得到应用。
