2024 AIChE Annual Meeting
(338g) Novel Injectable Thermoresponsive Hydrogels for Sustained Release of Antibody-Targeted DNA Nanocarriers As a Prophylactic Treatment for Secondary Cataracts
Cataracts are the second leading cause of blindness worldwide, with over 100 million cataract surgeries performed annually. Over 30% of adults and nearly all children develop secondary cataracts or clouding of the lens capsule following cataract surgery.Secondary cataracts, also known as posterior capsule opacification (PCO), originate from the differentiation of Myo/Nog cells into myofibroblasts, which contract and wrinkle the lens capsule. Current treatment strategies are insufficient and pose severe adverse effects; thus, a prophylactic treatment strategy delivered during cataract surgery is a considerable unmet need. Previous studies in a rabbit model suggest that a bolus dose of doxorubicin intercalated in DNA nanoconjugates containing the G8 monoclonal antibody (3DNA/Dox/G8), irrigated around the intraocular lens during cataract surgery resulted in the targeted depletion of myofibroblast precursors with minimal off-target effects. However, these studies reported only a short delay in the progression of PCO, instead of overall prevention.
To provide extended release of nanocarriers, injectable stimuli-responsive gels were designed using FDA-approved poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)) (PLGA-PEG-PLGA) triblock copolymers and Poly-L-Lysine (PLL). PLL polycations provide multiple non-covalent complexation interactions between the homopolymer and 3DNA conjugates within the nanogel to control release. The addition of oppositely charged homopolymers forming co-assembled supramolecular hydrogels provided a novel platform for extended release exploiting non-covalent complexation interactions (US Patent pending, US20200038323A1). Incorporating cationic PLL chains of molecular weight in the 30-70kDa range into self-assembled PLGA-PEG-PLGA matrices controlled the release of negatively charged DNA-based nanocarriers for over 3 months. Our group has shown targeting specificity and cellular depletion sufficient to have therapeutic effects against PCO in vitro, in 28 days.
Our findings suggest that extended delivery of a low dose of 3DNA nanocarriers can have therapeutically relevant effects in the prevention of PCO. This system has the potential to impact every cataract surgery patient, decreasing the incidence of PCO and associated complications. Moreover, this gel formulation can be adapted to deliver various other types of therapeutics into the eye.
To provide extended release of nanocarriers, injectable stimuli-responsive gels were designed using FDA-approved poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)) (PLGA-PEG-PLGA) triblock copolymers and Poly-L-Lysine (PLL). PLL polycations provide multiple non-covalent complexation interactions between the homopolymer and 3DNA conjugates within the nanogel to control release. The addition of oppositely charged homopolymers forming co-assembled supramolecular hydrogels provided a novel platform for extended release exploiting non-covalent complexation interactions (US Patent pending, US20200038323A1). Incorporating cationic PLL chains of molecular weight in the 30-70kDa range into self-assembled PLGA-PEG-PLGA matrices controlled the release of negatively charged DNA-based nanocarriers for over 3 months. Our group has shown targeting specificity and cellular depletion sufficient to have therapeutic effects against PCO in vitro, in 28 days.
Our findings suggest that extended delivery of a low dose of 3DNA nanocarriers can have therapeutically relevant effects in the prevention of PCO. This system has the potential to impact every cataract surgery patient, decreasing the incidence of PCO and associated complications. Moreover, this gel formulation can be adapted to deliver various other types of therapeutics into the eye.