Controlled Polymerization of Poly[N-[2(dimethylamino)ethyl] acrylamide (pDMAEAM) using RAFT techniques Esther Udobang 1,3 , Sébastien Perrier 1,2,3 1 Department of Chemistry, University of Warwick, UK, 2 Warwick Medical School, University of Warwick, UK, 3 Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Australia Gene therapy has become a prominent tool in biomedical science for genetic modification as well as the treatment of a myriad of incommunicable diseases and genetic disorders. The therapies are driven by transfection of specific nucleotides through viral or non-viral vectors.A crucial determinant of the gene transfection efficacy is morphology and structural composition of the carrier for safe delivery of the nucleic acid and therapeutic efficacy. Polymeric vectors are favoured over their lipid non-viral counterparts due to tunability, low immunogenicity and ease of production 1,2 . Cationic polymers are generally favoured in gene therapy research for their electrostatic condensation with the negatively charged therapeutic DNA or RNA. These polymers enhance cellular uptake due to their destabilizing properties which promote endosomal escape. The synthetic polycations commonly used are amine based and pH responsive under physiological and endosomal conditions. Polyethyleneimine (PEI) has been the gold standard for polymeric vectors due to its high transfection capabilities. But the high charge density has contributed to its increased cytotoxicity and cell death. Polymeric vectors designed from poly[ N -[2(dimethylamino)ethyl]acrylamide pDMAEAM, synthesized via RAFT are promising systems for DNA/RNA delivery. They have been studied for their protonable tertiary amine which possesses high buffering activity, useful for endosomal escape and more efficient gene transfection. We conduct experimental modelling of RAFT polymerizations of polymers with tertiary amine functionalities to investigate the optimal conditions for polymerizing pDMAEAM. These polymerizations are done in aqueous and non-aqueous conditions, and we examine the effect of tertiary amine on the control over polymerisation. We observed low conversions and poor dispersity when varying conditions of polymerization of DMAEAM when compared to other acrylamide monomers, and we observe that the tertiary amine has a negative effect on the radical formation and is especially detrimental to the RAFT agent. References 1. Ita, K. (2020). Polyplexes for gene and nucleic acid delivery: Progress and bottlenecks. European Journal of Pharmaceutical Sciences , 150 , 105358. 2. Burgevin, F., Hapeshi, A., Song, J.-I., Omedes-Pujol, M., Christie, A., Lindsay, C., & Perrier, S. (2023). 3. Cationic star copolymers obtained by the arm first approach for gene transfection. Chem. , 10.1039.D3PY00352C.
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