Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype. (7th November 2022)

• Record Type: Journal Article
• Authors: Soni, Shreya S.; D'Elia, Arielle M.; Alsasa, Abdulrahman; Cho, Sylvia; Tylek, Tina; O'Brien, Erin M.; Whitaker, Ricardo; Spiller, Kara L.; Rodell, Christopher B.
• Is Part Of: Biomaterials science. Volume 10:Number 24(2022)
• Page Start: 6951
• Page End: 6967
• Publication Date: 2022-11-07
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/d2bm01113a
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : Polymer-nanoparticle hydrogels are assembled by guest–host interactions that also enable drug encapsulation. Surface erosion of celastrol-loaded nanoparticles from injectable hydrogels enables macrophage-targeted delivery to modulate cell phenotype. Abstract : Injectable hydrogels may be pre-formed through dynamic crosslinks, allowing for injection and subsequent retention in the tissue by shear-thinning and self-healing processes, respectively. These properties enable the site-specific delivery of encapsulated therapeutics; yet, the sustained release of small-molecule drugs and their cell-targeted delivery remains challenging due to their rapid diffusive release and non-specific cellular biodistribution. Herein, we develop an injectable hydrogel system composed of a macrophage-targeted nanoparticle (cyclodextrin nanoparticles, CDNPs) crosslinked by adamantane-modified hyaluronic acid (Ad-HA). The polymer-nanoparticle hydrogel uniquely leverages cyclodextrin's interaction with small molecule drugs to create a spatially discrete drug reservoir and with adamantane to yield dynamic, injectable hydrogels. Through an innovative two-step drug screening approach and examination of 45 immunomodulatory drugs with subsequent in-depth transcriptional profiling of both murine and human macrophages, we identify celastrol as a potent inhibitor of pro-inflammatory (M1-like) behavior that furthermore promotes a reparatory (M2-like) phenotype. Celastrol encapsulation within the polymer-nanoparticle hydrogels permitted shear-thinning injection and sustained release of drug-laden nanoparticles that targeted macrophages to modulate cell behavior for greater than two weeks in vitro . The modular hydrogel system is a promising approach to locally modulate cell-specific phenotype in a range of applications for immunoregenerative medicine.