Design, Synthesis, and Acid-Responsive Disassembly of Shell-Sheddable Block Copolymer Labeled with Benzaldehyde Acetal Junction

Brandon Andrade-Gagnon, Sofia Nieves Casillas-Popova,Arman Moini Jazani,Jung Kwon Oh

MACROMOLECULAR RAPID COMMUNICATIONS(2024)

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摘要
Smart nanoassemblies degradable through the cleavage of acid-labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid-degradable shell-sheddable nanoassemblies. Herein, the authors report the synthesis and acid-responsive degradation through acid-catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid-labile linkage. The authors explore the synthesis and aqueous micellization of well-defined poly(ethylene glycol)-based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally-stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid-catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid-degradable shell-sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid-degradable shell-sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor-targeting drug delivery. Benzaldehyde acetal is a suitable candidate for junction acid-labile linkage, allowing for the synthesis of well-defined poly(ethylene glycol)-based block copolymer nanoassemblies bearing benzaldehyde acetal linkage at core/corona interfaces that meet the criteria: Slow degradation at tumoral pH, and rapid disassembly at endo/lysosomal pH, while colloidal stability at physiological pH, thus offering the promise to address PEG dilemma and improved endocytosis in tumor-targeting drug delivery. image
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关键词
acetal/ketal chemistry,acid-responsive degradation,amphiphilic block copolymer,controlled release,nanoassemblies
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