Issue 24, 2022

Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage 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.

Graphical abstract: Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype

Supplementary files

Article information

Article type
Paper
Submitted
15 Jūl. 2022
Accepted
19 Okt. 2022
First published
21 Okt. 2022
This article is Open Access
Creative Commons BY-NC license

Biomater. Sci., 2022,10, 6951-6967

Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype

S. S. Soni, A. M. D'Elia, A. Alsasa, S. Cho, T. Tylek, E. M. O'Brien, R. Whitaker, K. L. Spiller and C. B. Rodell, Biomater. Sci., 2022, 10, 6951 DOI: 10.1039/D2BM01113A

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