Injectable\nGranular Hydrogels Enable Avidity-Controlled\nBiotherapeutic\nDelivery

Abstract

Protein therapeutics\nrepresent a rapidly growing class\nof pharmaceutical\nagents that hold great promise for the treatment of various diseases\nsuch as cancer and autoimmune dysfunction. Conventional systemic delivery\napproaches, however, result in off-target drug exposure and a short\ntherapeutic half-life, highlighting the need for more localized and\ncontrolled delivery. We have developed an affinity-based protein delivery\nsystem that uses guest–host complexation between β-cyclodextrin\n(CD, host) and adamantane (Ad, guest) to enable sustained localized\nbiomolecule presentation. Hydrogels were formed by the copolymerization\nof methacrylated CD and methacrylated dextran. Extrusion fragmentation\nof bulk hydrogels yielded shear-thinning and self-healing granular\nhydrogels (particle diameter = 32.4 ± 16.4 μm) suitable\nfor minimally invasive delivery and with a high host capacity for\nthe retention of guest-modified proteins. Bovine serum albumin (BSA)\nwas controllably conjugated to Ad via EDC chemistry without affecting\nthe affinity of the Ad moiety for CD (<i>K</i>_D = 12.0 ± 1.81 μM; isothermal titration calorimetry).\nThe avidity of Ad–BSA conjugates was directly tunable through\nthe number of guest groups attached, resulting in a fourfold increase\nin the complex half-life (<i>t</i>_1/2 = 5.07\n± 1.23 h, surface plasmon resonance) that enabled a fivefold\nreduction in protein release at 28 days. Furthermore, we demonstrated\nthat the conjugation of Ad to immunomodulatory cytokines (IL-4, IL-10,\nand IFNγ) did not detrimentally affect cytokine bioactivity\nand enabled their sustained release. Our strategy of avidity-controlled\ndelivery of protein-based therapeutics is a promising approach for\nthe sustained local presentation of protein therapeutics and can be\napplied to numerous biomedical applications.