Major non-viral polymeric vectors studied for gene therapy are based on polyethylene imine (PEI) because of its high condensation ability and superior transfection efficiencies. Typically high molecular weight (MW) and branched PEI is used to electrostatically condense DNA and produce polyplex nanoparticles in the range of 10-100 nm capable of adsorptive endocytosis. To overcome the stability and low plasma half-life of PEI/DNA polyplex, the hydrophilic polyethylene glycol (PEG) is often utilized to decorate the polyplex surface resulting in “stealth” core-shell micelles. The major drawback of PEI is high cytotoxicity associated with high charge density, which directly relates to the MW. We have developed a new gene delivery system, three layered micelles (3LM) using low MW linear PEI and biodegradable polylactides (PLLA/PDLA). For localized gene delivery DNA can be encapsulated within a gel forming polymer system; the vector is then implanted or injected within a close proximity to the target site. The 3LM is further formulated into a physical hydrogel by the stereocomplexation mechanism of enantiomeric PLA’s to study as an injectable local delivery system.<br/>The dual encapsulation mechanism by electrostatic interaction and solvent condensation to form 3LM allowed large-sized DNA to be efficiently loaded into compact nano-sized particles using low MW low-cytotoxic PEI. The folate-conjugated 3LM showed pH-responsive DNA release, significantly lower cytotoxicity, and successful targeting in activated macrophage and ovarian cancer cells achieving statistically higher transfection. Upon addition of an stereoisomeric micelle solutions to the 3LM, chain exchange between these two micelle population led to co-crystallization of PDLA/PLLA leading to network formation and eventual gelation occurred at ~37°C. Further structural analyses and gene delivery studies indicated that 3LM/hydrogel systems are promising systemic and local delivery systems.

Targeted three-layered micelles and injectable hydrogels for systemic and local gene delivery systems

2019 Spring National Meeting

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