Macrophage-mediated controlled release of cysteine protease inhibitor from PLGA-PEG/hydroxyapatite microspheres for targeting cathepsin S in Alzheimer's disease
Journal
European Polymer Journal
Journal Volume
214
ISSN
0014-3057
Date Issued
2024-06
Author(s)
I-Hsuan Yang
Che-Yung Kuan
Sheng-Long Zhang
Zhi-Yu Chen
Chi-Han Li
Ya-Jyun Liang
Wei-Ting Kuo
Chia-Ting Chang
Jason Lin
Hsing-Pang Hsieh
Jang-Yang Chang
DOI
10.1016/j.eurpolymj.2024.113151
Abstract
The cause of Alzheimer's disease (AD) remains unknown; however, studies have indicated the increased expression of cathepsin S (CTSS) in AD brains. Cathepsin S acts as a β-secretase, prompting the release of amyloid-β peptides and stimulating microglial cell activation, causing microglial migration, and contributing to neuroinflammation and disease progression. In this study, CT001, an inhibitor of the cysteine protease CTSS, was encapsulated in poly(lactic-co-glycolic acid)-polyethylene glycol microspheres combined with hydroxyapatite microspheres (CPPMs/HAMs) to achieve a constant and long-term drug release for AD. The results showed that CPPMs/HAMs had a uniform diameter of approximately 1 μm, enabling macrophage endocytosis and facilitating sustained CT001 release into the bloodstream, ultimately reaching the brain for AD treatment. The developed CPPMs/HAMs demonstrated excellent anti-inflammatory properties and mitigated CTSS expression in an in vitro inflammation microglial model. Intramuscular administration of CPPMs/HAMs improved learning and memory in AD mice during behavioral assessments. Furthermore, CPPMs/HAMs reduced CTSS expression, amyloid-beta accumulation, and deposition in vivo. This study demonstrated the potential of CT001 delivered via CPPMs/HAMs as a promising approach for managing AD in patients.
Subjects
Alzheimer's disease
Amyloid-β peptides
Cathepsin S
Hydroxyapatite
PLGA-PEG
SDGs
Publisher
Elsevier BV
Description
Article number 113151
Type
journal article