(353a) Novel, Stimuli-Responsive Hydrogels Utilizing Ionic Interactions for the Controlled and Targeted Delivery of Nucleic Acid Nanospheres to Prevent Secondary Cataracts

Cataracts are the second leading cause of blindness worldwide. There are over 100 million cataract surgeries each year, and these cases are expected to double within the next ten years. Over 20% of adults and nearly all children develop secondary cataracts, or posterior capsule opacification (PCO), following cataract surgery. This vision impairing disorder is characterized by fibrosis, myofibroblasts that produce wrinkles in the lens capsule, and aggregates of differentiating lens epithelial cells. Currently, Nd:YAG laser therapy is used to treat PCO; however, laser therapy is not available worldwide and treatment may have adverse effects on surrounding ocular tissues. Thus, there is a considerable unmet need for more efficacious and convenient treatments to prevent PCO.

Our work focuses on engineering an innovative, two-part controlled release system to specifically deliver cytotoxic doxorubicin into the precursors of myofibroblasts targeted with the G8 monoclonal antibody (mAb). The first part utilizes novel, injectable, physically cross-linked, thermo-sensitive hydrogels formulated using biodegradable polymers for the extended and controlled release of nucleic acid nanocarriers. The second part refers to the drug consisting of the G8 mAb conjugated to 3DNA^® naocarriers intercalated with doxorubicin.

Injectable, stimuli-responsive gels were designed using poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)) (PLGA-PEG) triblock copolymer and poly(L-Lysine) (PLL). Novel, self-assembled gels that are optically clear at physiological temperatures were designed by varying the lactic acid (LA) to glycolic acid (GA) ratio, the PLGA/PEG ratio, the polymer solution composition, and the PLL concentration. Characterization studies included optical clarity, critical gelation temperature (CGT), and controlled and sustained drug release kinetics. These assessment utilized a microfluidic device designed to mimic the physiological flow rate of the human lens capsule.

Hydrogel formulations with LA/GA ratio of 15/1, at compositions between 14 and 25% (w/v), PLGA/PEG ratio of 2/1, and PLL concentrations between 10 and 40% (w/v) allowed for over 90% light transmittance, gel formation at 35 °C, and controlled release of 3DNA® conjugates for over four weeks. The release of 3DNA® conjugates was controlled through the multiple ionic interactions between 3DNA and PLL, as well as the degradation of PLGA-PEG-PLGA via the cleavage of ester bonds.

The physical and morphological states of this novel, thermosensitive hydrogel can be easily tailored for the purpose of modulating drug delivery utilizing nucleic acids. Our technology offers a more effective and efficient method of ocular therapy by providing controlled delivery of 3DNA conjugates designed to specifically target cells that cause PCO. Our US patent pending technology has high potential as a more efficacious delivery method for a wide range of other therapeutics to treat a number of ocular diseases.