(109g) Photocleavable Polyplexes As Dynamic Carriers for Controlled Nucleic Acid Delivery

Nucleic acid unpackaging has been widely identified as a key hurdle towards the successful clinical application of gene therapies. Many current delivery systems employ cationic polymers such as polyethylenimine to strongly bind and compact the nucleic acid and create stable polyplexes, which protect the nucleic acid from enzymatic degradation.  However, these polyplex-based approaches offer limited control over the timing and specificity of nucleic acid delivery. Recent strategies to address this issue include the design of materials that release the nucleic acid cargo in response to specific intracellular cues such as a change in pH. An appealing alternative approach is the design of materials that are responsive to external stimuli and can be used to control the timing and specific location of delivery.

In this work, we present a novel block copolymer-based carrier that allows added tunability in the delivery system and decoupling of shielding and complexation requirements in the carrier by incorporating nonfouling and cationic blocks. A photocleavable segment in the cationic block allows for user-controlled release of the nucleic acid at a subcellular target, through light-induced hydrolysis and charge reversal.  Furthermore, a poly(ethylene glycol) block provides a stealth coating during delivery that is removed in response to the light trigger.  Here we report the synthesis of this photocleavable block copolymer and the assembly into stable polyplexes with nucleic acids.  Additionally, we demonstrate robust cellular uptake and light-responsive cleavage of this polymer system, laying a platform for enhancing the efficiency of nucleic acid delivery.