Neutral Polymeric Micelles for RNA Delivery
Lundy, Brittany Bradshaw
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Small interfering RNA (siRNA) is a therapeutic gene silencing strategy that has generated substantial interest in the scientific community, but it remains a challenge to produce a robust and nontoxic systemic delivery system capable of efficient in vivo intracellular siRNA delivery. Due to the complexity of this problem, an efficient delivery system requires multiple functional components including a cell targeting moiety, siRNA binding region, and an endosomal escape component, all of which must be independently functional when combined. Based upon these requirements, we developed a rationally designed siRNA carrier possessing the above properties that form the basis for successful siRNA-polymer conjugates systemic delivery in vivo. We engineered a biocompatible, neutral, pH-responsive multifunctional micellar system using reversible addition fragmentation chain transfer (RAFT) polymerization. By incorporating biotin and pyridyl disulfide functionalities into the polymer, we were able to directly link streptavidin antibody conjugates and conjugate thiolated siRNA for multi-functional delivery platform. In this work, we explored several advanced cell targeting moieties including antibody and carbohydrate strategies, and furthermore we demonstrated that this modular siRNA delivery platform has the capability to overcome various delivery limitations on both cellular and systemic levels. Finally, we demonstrated proof-of-principle therapeutic efficacy by sensitizing ovarian cancer cells to carboplatin after Bcl-xL gene silencing with the trastuzumab-targeted siRNA conjugates. The polymer-siRNA conjugates developed in this work may prove to a useful approach for future clinical delivery of siRNA therapeutics in a variety of disease states.
- Bioengineering