Addition of poly (propylene glycol) to multiblock copolymer to optimize siRNA delivery

Dai, Zhi; Arévalo, Maria T; Li, Junwei; Zeng, Mingtao

While viral vectors have proven effective in delivering siR-NAs processed from short hairpin-RNAs or micro-RNA mimics, concerns arise over the immunogenic potential and possibility of mutation of these viruses. 2, 13 Although cationic liposomes can protect siRNA from nucleases and easily penetrate cells membranes, they are considered too toxic for systemic delivery. 1 However, cationic polymers are an appealing alternative for nucleic acid delivery as they can bind and condense nucleic acids into stable nanoparticles. 1 Furthermore, cationic polymers allow for synthetic modification of structures to enhance transfection efficiencies and reduce cytoxicity. [14] [15] [16] Assembly of multiblock copolymer structures is a recent and popular approach for nucleic acid delivery. Common cationic polymers used for this purpose include poly-L-lysine (PLL) 15, [17] [18] [19] [20] and polyethylenimine (PEI). [21] [22] [23] [24] In addition, polyethylene glycol (PEG) 15, [17] [18] [19] [20] [21] 23, 24 is often introduced to improve solubility of the nanoparticle complex, increase biocompatibility, and reduce toxicity to cells. 14, 15 Of note, micelle formation of copolymer blocks with nucleic acids is viewed favorably as it has been met with some success for nucleic acid delivery. 17, 18, 22, 23, 25, 26 In a micelle-siRNA complex, the hydrophobic polymer segments form the particle core, while the cationic polymer segments complex with nucleic acid chains to form the particle shell. 18 Herein, we describe the design, synthesis, and evaluation of several copolymers based on PEG, poly(propylene glycol) PPG, and PLL blocks for siRNA delivery. It was hypothesized that the amphiphilic nature of particles formed by block combinations of these polymers would readily allow for micelle-complex formation with siRNA. We report on the structural and functional characterization of these polymers when complexed with siR-NAs, and the feasibility of using these copolymers for safe and efficient siRNA delivery.