(719e) Novel in-Situ Forming Gels Utilizing Novel Complexation Strategies for Sustained Delivery of Antibody-Targeted Nanocarriers to Treat Posterior Capsule Opacification

Over 100 million cataract surgeries are performed worldwide, with projected cases doubling within the next ten years. Approximately 50% of all cataract surgery patients develop posterior capsule opacification (PCO), a fibrotic disease arising from contractile forces exerted by myofibroblasts during the wound healing response resulting in loss of vision. Currently, there are no commercially available treatments to prevent PCO and treatment is a considerable unmet need. With the expected increase in cataract surgery cases, we have developed a prophylactic treatment strategy that can be delivered at the time of surgery.

Our group has engineered novel biomimetic gels to specifically deplete the cells responsible for the fibrotic response that characterizes PCO. Gels contain polycations and polyanions of varying molecular weight with poly(D,L-lactic-co-glycolic acid)-b- poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers. For the first time, release has been shown to be finely controlled by number and type of non-covalent interactions leading to release durations over 5 months of antibody-targeted, nucleic acid-based nanocarriers loaded with cytotoxic doxorubicin compared to only 28 day release provided by unmodified gels. Additional gel properties such as the lactic acid (LA) to glycolic acid (GA) ratio, the PLGA/PEG ratio, polymer solution composition, and homopolymer MW and concentration were varied.

The gels have shown groundbreaking results both in vivo and in vitro, showing great specificity for myofibroblast precursors with minimal off-target effects. Characterization studies included optical clarity, critical gelation temperature (GT) and sustained drug release kinetics. These hydrogels are in situ forming, nontoxic and optically clear at 37° C, and therefore, could be irrigated over the lens capsule at the time of surgery. A threshold concentration of myofibroblasts on the lens capsule necessary to cause visual impairment was established for the first time using an ex vivo model. Our findings from cell studies under dynamic flow show that extending delivery of a low dose of DNA-based nanocarriers by exploiting long-chain non-covalent interactions led to targeted depletion of over 90% of myofibroblasts and progenitor cells. We have also shown that treatment with nanocarriers in gel led to decreased myofibroblast contraction and wrinkling within 25 days in an in vivo mouse model, compared to a bolus dose of nanocarriers. This system has the potential to impact every cataract surgery patient, decreasing the incidence of PCO and associated complications. Moreover, this gel can be adapted to deliver various other types of therapeutics into the eye.