Controlled Antibody Release from Degradable Thermoresponsive Hydrogels Cross-Linked by Diels–Alder Chemistry

Abstract

Amine-modified four- and eight-armed poloxamines were prepared and subsequently functionalized with maleimide or furyl groups. Aqueous solutions of these polymers exhibited an immediate gelation at a temperature above 37 °C. Concomitantly, Diels-Alder reactions gradually cross-linked and cured the gels. Different ratios between four- and eight-armed macromonomers were used to tune hydrogel stability and mechanical properties. In this way, hydrogel stability could be precisely controlled in the range of 14 to 329 days. Controlled release of the model antibody bevacizumab was achieved over a period of 7, 21, and 115 days. Release profiles were triphasic with a low burst; approximately 87% of the released antibody was intact and displayed functional binding. The hydrogels presented in this study are degradable, nontoxic, rapidly gelling, stable, and provide controlled antibody release. They can be tailored to match the demands of various applications and present an attractive platform for antibody delivery.

Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering

“…Then, the dual crosslinked hydrogels were fabricated via the Diels Alder click reaction between F127@ChS hydrogel and PEG with maleimido (PEG-AMI) acted as a crosslinker and used as scaffolds to load bone morphogenetic protein 4 (BMP-4), extracellular signaling molecule, for bone defect repair. In a recent study by Gregoritza et al (2017) [ 45 ], the 4- and 8-armed polyoxamines with maleimide or furyl groups were immediately formed the polyoxamine hydrogels with various ratios of 4- and 8-armed polyoxamines by thermal gelation at 37 °C. The gradual gelation by the Diels Alder reaction between maleimide and furyl groups was additionally involved, finally resulting in the physical and chemical crosslinked hydrogels.…”

Rational Design of Self-Healing Tough Hydrogels: A Mini Review

“…Diels-Alder reaction is one of the “click chemistry” which occurs between a diene and a dienophile (Gregoritza et al, 2017 ; Guaresti et al, 2018 ). Yang et al reported a self-healable cellulose nanocrystal-poly(ethylene glycol) (CNC-PEG) nanocomposite hydrogel via Diels-Alder reaction.…”

Improved Efficacy of Antibody Cancer Immunotherapeutics through Local and Sustained Delivery

“…Controlled diffusion—Affinity : Release rates from hydrogels are controlled by altering the protein's diffusion inside the hydrogel, which is influenced by hydrogel porosity . For example, controlling polymer branching and crosslink density in hydrogels extended the release of antibodies from ≈5 to 100 days . Self‐assembling peptide hydrogels have been used to study the release kinetics of different proteins such as lysozyme, bovine serum albumin (BSA), and IgG antibodies for over 40 days in vitro, where release rates are, in part, governed by the protein′s hydrodynamic radius .…”

“…[67] For example, controlling polymerb ranching andc rosslink density in hydrogels extended the release of antibodies from % 5t o 100 days. [68] Self-assembling peptide hydrogels have been used to study the releasek inetics of different proteins sucha sl ysozyme, bovine serum albumin( BSA), andI gG antibodies for over 40 days in vitro, where releaser ates are, in part, governed by the protein'sh ydrodynamic radius. [69] Peptide-basedh ydrogels can also protect physically entrapped proteins and sustain the releaseo fb rain-derived neurotrophic factor (BDNF)f or 28 days in vivo [70] and that of basic fibroblast growth factor (bFGF) for up to three weeks.…”