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Degradation of acetalated dextran can be broadly tuned based on cyclic acetal coverage and molecular weight

作者： Naihan Chen^a, Michael A. Collier^a, Matthew D. Gallovic^{a, b}, Graham C. Collins^a, Carla C. Sanchez^a, Elizabeth Q. Fernandes^a, Eric M. Bachelder^a, Kristy M. Ainslie^a

^a Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, NC, USA

^b Department of Chemical and Biomolecular Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA

摘要：Microparticles (MPs) derived from acid-sensitive biopolymers enable rapid degradation and cargo release under acidic conditions, such as at tumor microenvironments, within lysosomal/phagosomal compartments inside phagocytic cells, or at sites of inflammation. One such acid-sensitive biopolymer, acetalated dextran (Ace-DEX), has tunable degradation rates and pH-neutral degradation byproducts consisting of dextran, acetone, and ethanol. By studying the degradation profiles of Ace-DEX MPs with varying cyclic acetal coverage (CAC) and dextran molecular weight (MW), we concluded that MPs composed of low CAC or high MW polymer degraded the fastest at both pH 7.4 and 5.0. To further understand the properties of this unique polymer, we encapsulated a model drug resiquimod, which is a toll-like receptor (TLR) 7/8 agonist, into Ace-DEX MPs of different polymer CAC and dextran MW. It was observed that resiquimod was released faster from MPs of lower CAC or higher MW. By evaluating the activation of RAW macrophages cultured with different types of resiquimod-loaded Ace-DEX MPs, we found that MPs of lower CAC or higher MW promoted greater nitrite production and resulted in more robust cell activation. Our results indicate we can precisely control the degradation profile, release kinetics, and bioactivity of encapsulated cargos by altering CAC and MW, furthering Ace-DEX MPs' novelty as a drug carrier.