RAFT Synthesis of Reactive Multifunctional Triblock‐Copolymers for Polyplex Formation

Abstract

Reversible addition–fragmentation chain transfer polymerization with a low‐temperature initiator can be used to synthesize multifunctional block copolymers for polyplex formation. Utilizing three methacrylate monomers (triethylene glycol methyl ether methacrylate (MEO3MA), pyridyldisulfideethyl methacrylate (PDSM), N,N‐dimethylethylenediamine methacrylate (DMAEMA)) and an azide bearing chain transfer agent for polymerization, the resulting triblock‐copolymers possess two orthogonally reactive functionalities (a block with reactive disulfide side chains and an azide end‐group) and two additional functional blocks for i) solubilization and ii) polyplex formation. Thereby, the MEO3MA block provides solubility in aqueous media and the DMAEMA block, having a tertiary amine in the side chain, allows polyplex formation with polyanionic biomacromolecules like DNA or RNA. Due to the reactive disulfide block the polyplexes can be (reversibly) crosslinked with dithiols. Because of the manifold of possibilities to modify the pDNApolyplexes, this polymers system is an interesting candidate for active‐targeting and codelivery approaches.

Post‐Polymerization Modifications to Prepare Biomedical Nanocarriers with Varying Internal Structures, their Properties and Impact on Protein Corona Formation

“…These polymers provided ideal complexation and intracellular release behavior for mRNA delivery. [93] Additionally, triblock-copolymers were recently designed, [94,97] which provide an additional short thiol-reactive block for further functionalization after pDNA polyplex formation. This third block is based on pyridyldisulfide ethyl methacrylates, which were functionalized by thiols as soft nucleophiles, [94,96,98] while rather hard nucleophiles like amines were applied for the cationic domains through conversion of the polymeric reactive esters.…”

Closing the Gap between Experiment and Simulation─A Holistic Study on the Complexation of Small Interfering RNAs with Polyethylenimine

“…Besides their advantages when it comes to loading capacity where a drug-to-excipient ratio of 1 or higher can be achieved, − polymeric systems offer tremendous tunability and easy scalability of production processes. Polyethylenimine (PEI), polyamidoamine (PAMAM), polylysine (PLL), poly­(β-amino ester) (PBAE), or spermines are among the most frequently studied materials. − Modified or block copolymers became popular to add extra features such as improved stability, targeting with ligands, or shielding. − PEI as one of the first and most commonly used polycations for RNA delivery shows high loading capacity and transfection efficiency in vitro , , but its high cation density and resulting toxicity , impedes the translation of PEI into application in human.…”

Engineering poly- and micelleplexes for nucleic acid delivery – A reflection on their endosomal escape

“…With the decision for the primary encapsulation agent, further modifications of the system are possible. Those not only refer to whether or not to introduce hydrophobic moieties but may also include the incorporation of targeting ligands or membrane penetrating peptides [ [39] , [40] , [41] , [42] , [43] ].…”