Structural optimization of diblock polymers that undergo thermo-responsive nanoparticle self-assembly for intravitreal drug delivery

Certain diseases of the eye require frequent intravitreal injections to sustain active drug concentrations due to the limited volume (≤50 µL) of solution that can be administered each injection. Drug delivery systems have been evaluated to reduce dosing frequency but achieving (i) high concentrations with low viscosity (<100 cP) and (ii) narrow range of particle size (∼20–70 nm) to prolong drug activity without affecting vision remain major challenges. To address these challenges, we synthesized a combinatorial library of thermo-responsive polymer-drug conjugates with diblock architecture and assessed how various parameters (monomer unit composition, block length, drug density and attachment site) affect properties impacting ocular injection suitability. Our screens identified a lead composition, p[(N-isopropylmethacyrlamide)–co-(N-benzylmethacrylamide)]-b-p(N-(2-hydroxypropyl)methacrylamide with 20 mol% N-benzylmethacrylamide (p[(NIPMAM)–co-(BnMAM)]-b-p(HPMA)), that exists as unimers at room temperature that can be highly concentrated (200 mg/mL) and injected at low viscosity but self-assemble into 20–70 nm particles upon injection into vitreous humor at body temperature. Furthermore, covalent attachment of representative small molecule, peptide- and protein-based drugs had minimal to no impact on thermoresponsive and hydrodynamic behavior highlighting the versatility of the lead composition as a platform for delivering a broad range of different drug molecules.