posted on 2024-02-15, 09:29authored byArielle
M. D’Elia, Olivia L. Jones, Gabriela Canziani, Biplab Sarkar, Irwin Chaiken, Christopher B. Rodell
Protein therapeutics
represent a rapidly growing class
of pharmaceutical
agents that hold great promise for the treatment of various diseases
such as cancer and autoimmune dysfunction. Conventional systemic delivery
approaches, however, result in off-target drug exposure and a short
therapeutic half-life, highlighting the need for more localized and
controlled delivery. We have developed an affinity-based protein delivery
system that uses guest–host complexation between β-cyclodextrin
(CD, host) and adamantane (Ad, guest) to enable sustained localized
biomolecule presentation. Hydrogels were formed by the copolymerization
of methacrylated CD and methacrylated dextran. Extrusion fragmentation
of bulk hydrogels yielded shear-thinning and self-healing granular
hydrogels (particle diameter = 32.4 ± 16.4 μm) suitable
for minimally invasive delivery and with a high host capacity for
the retention of guest-modified proteins. Bovine serum albumin (BSA)
was controllably conjugated to Ad via EDC chemistry without affecting
the affinity of the Ad moiety for CD (KD = 12.0 ± 1.81 μM; isothermal titration calorimetry).
The avidity of Ad–BSA conjugates was directly tunable through
the number of guest groups attached, resulting in a fourfold increase
in the complex half-life (t1/2 = 5.07
± 1.23 h, surface plasmon resonance) that enabled a fivefold
reduction in protein release at 28 days. Furthermore, we demonstrated
that the conjugation of Ad to immunomodulatory cytokines (IL-4, IL-10,
and IFNγ) did not detrimentally affect cytokine bioactivity
and enabled their sustained release. Our strategy of avidity-controlled
delivery of protein-based therapeutics is a promising approach for
the sustained local presentation of protein therapeutics and can be
applied to numerous biomedical applications.