Membrane-disruptive homo-polymethacrylate with both hydrophobicity and pH-sensitive protonation for selective cancer therapy. Issue 15 (8th March 2023)

• Record Type: Journal Article
• Authors: Yu, Rongrong; Geng, Tingting; Wei, Taotian; Wang, Meng; Cao, Yin; Du, Mengting; He, Weidong; Haleem, Abdul; Hu, Rongfeng; Cao, Yu; Chen, Shengqi
• Is Part Of: Journal of materials chemistry. Volume 11:Issue 15(2023)
• Page Start: 3364
• Page End: 3372
• Publication Date: 2023-03-08
• Subjects: Materials -- Periodicals; Chemistry, Analytic -- Periodicals; Biomedical materials -- Research -- Periodicals; 543.0284
• DOI: 10.1039/d2tb02749f
• Languages: English
• ISSNs: 2050-750X

Abstract

Abstract : The membrane-disruptive activity of PEG-PAEMA nanoparticles are silenced at physiological pH, while activated by characteristic tumor acidity via protonation of the PAEMA block, resulting in high selectivity towards tumors. Abstract : The membrane-disruptive strategy, which involves host defense peptides and their mimetics, is a revolutionary cancer treatment based on broad-spectrum anticancer activities. However, clinical application is limited by low selectivity towards tumors. In this context, we have established a highly selective anticancer polymer, i.e. poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA), that can mediate the membrane-disruptive activity via a subtle pH change between physiological pH and tumor acidity for selective cancer treatment. Specifically, the resulting PEG-PAEMA can assemble into neutral nanoparticles and silence the membrane-disruptive activity at physiological pH and disassemble into cationic free-chains or smaller nanoparticles with potent membrane-disruptive activity after the protonation of the PAEMA block due to tumor acidity, resulting in high selectivity towards tumors. Dramatically, PEG-PAEMA exhibited a >200-fold amplification in hemolysis and <5% in IC50 against Hepa1-6, SKOV3 and CT-26 cells at pH 6.7 as compared to those at pH 7.4, thanks to the selective membrane-disruptive mechanism. Moreover, mid- and high-dose PEG-PAEMA demonstrated higher anticancer efficacy than an optimal clinical prescription (bevacizumab plus PD-1) and, significantly, had few side effects on major organs in the tumor-bearing mice model, agreeing with the highly selective membrane-disruptive activity in vivo . Collectively, this work showcases the latent anticancer pharmacological activity of the PAEMA block, and also brings new hope for selective cancer therapy.