The field of gene therapy, which aims to treat patients by modulating gene expression, has come to fruition and has landed several landmark FDA approvals. The full potential of polymer-based delivery systems has yet to be realized, however, due to the fact that most polymeric transfection reagents are either too inefficient or too toxic for use in the clinic. Developments in carbohydrate-based cationic polymers, termed glycopolymers, for enhanced nonviral gene delivery will be described. As ubiquitous components of biological systems, carbohydrates are a rich class of compounds that can be harnessed to improve the biocompatibility of non-native polymers, such as linear polyaminesused for promoting transfection. We have developed a new class of carbohydrate-based polymers called poly(glycoamidoamine)s (PGAAs) by integrating linear monosaccharides with polyamines via step-growthpolymerization to drastically improve the biocompatibility of the polymer without sacrificing its ability to transfect cells. Systematic modifications of the structural components of the PGAA system revealed structure-activity relationshipsimportant to its function, including its ability to degrade in situ. Expanding upon the development of step-growth glycopolymers, monosaccharides and disaccharides, such as glucose and trehalose, were functionalized as vinyl-based monomers for the formation of diblock copolymers via radical addition-fragmentation chain-transfer (RAFT)polymerization. Upon complexation with plasmid DNA, the carbohydrate-containing block creates a hydrophilic shell that promotes colloidal stability as effectively as PEG functionalization. An N-acetyl-D-galactosamine variant of this diblock polymer yields colloidally stable particles that show increased receptor-mediated uptake by liver hepatocytes in vitro and promotes liver targeting in mice. The aforementioned series of glycopolymers use carbohydrates to promote effective and safe delivery of nucleic acid cargo into a variety of human cells types by promoting vehicle degradation, tissue-targeting, colloidal stabilization, and stability towards lyophilization to extend shelf life.

Nonviral gene delivery with cationic glycopolymers

ACS Spring Meeting 2021

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