Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease

Authors
Park, ByeongminHan GeonheeJin, Do YoungGil kicheolDongwon ShinLee, Jong WonPark, Jung YeonJang, HochungPark, DaehoLee, SangminKim, KwangmeyungYang, YoosooKim, YongjuKim, Jun-SeobKim, Sun HwaShim, Man Kyu
Issue Date
2024-06
Publisher
American Chemical Society
Citation
ACS Nano, v.18, no.25, pp.16297 - 16311
Abstract
While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine’s pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.
Keywords
DRUG-DELIVERY; NANOPARTICLES; COLITIS; THERAPY; 5-AMINOSALICYLIC ACID; mucoadhesive; intestinalmacrophages; inflammatory bowel disease; oral delivery; mesalamine; prodrug nanoassembly
ISSN
1936-0851
URI
https://pubs.kist.re.kr/handle/201004/150083
DOI
10.1021/acsnano.4c05544
Appears in Collections:
KIST Article > 2024
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