Colon-specific delivery of methotrexate using hyaluronic acid modified pH-responsive nanocarrier for the therapy of colitis in mice

Yingni Lv; Mengjiao Ren; Min Yao; Jiafeng Zou; Siqi Fang; Yanbing Wang; Minbo Lan; Yuzheng Zhao; Feng Gao

doi:10.1016/j.ijpharm.2023.122741

Colon-specific delivery of methotrexate using hyaluronic acid modified pH-responsive nanocarrier for the therapy of colitis in mice

Int J Pharm. 2023 Mar 25:635:122741. doi: 10.1016/j.ijpharm.2023.122741. Epub 2023 Feb 17.

Authors

Yingni Lv¹, Mengjiao Ren¹, Min Yao¹, Jiafeng Zou¹, Siqi Fang¹, Yanbing Wang¹, Minbo Lan², Yuzheng Zhao³, Feng Gao⁴

Affiliations

¹ Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China.
³ Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, 100000 Beijing, China.
⁴ Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: fgao@ecust.edu.cn.

PMID: 36804523
DOI: 10.1016/j.ijpharm.2023.122741

Abstract

Oral immunosuppressant methotrexate (MTX) is an effective method for the treatment of inflammatory bowel disease (IBD). To overcome the defects of clinical application of MTX, poly (lactic-co-glycolic acid) (PLGA), Eudragits® S100 (ES100), chitosan (CS) and hyaluronic acid (HA) were used to structure the MTX-loaded HA-CS/ES100/PLGA nanoparticles (MTX@hCEP). MTX@hCEP had a hydrodynamic particle size of approximately 202.5 nm, narrow size distribution, negative zeta potential (-18.7 mV), and smooth surface morphology. In vitro drug release experiments under simulated gastrointestinal conditions indicated that MTX@hCEP exhibited colonic pH-sensitive drug release properties. The cellular uptake capacity of hCEP nanoparticles was significantly enhanced in RAW 264.7 macrophages. Moreover, we further found that the MTX@hCEP also inhibited the proliferation and the secretion of pro-inflammatory cytokines in the LPS-stimulated macrophages. In vivo imaging results not only demonstrated that the accumulated in the colon of colitis mice, but also indicated the extended retention time of MTX in the colon. Additionally, MTX@hCEP alleviated inflammatory symptoms via decreasing the activities of myeloperoxidase and pro-inflammatory factors, promoting mucosal repair in vivo. Collectively, these results clearly demonstrated that MTX@hCEP with properties of colon-specific and macrophages targeting can be exploited as an efficient nanotherapeutic for IBD therapy.

Keywords: Active targeting; Colon-specific; Inflammatory bowel disease; Methotrexate; Oral nano drug delivery system; pH-sensitive.

MeSH terms

Animals
Colitis* / chemically induced
Colitis* / drug therapy
Drug Carriers / chemistry
Drug Delivery Systems / methods
Hyaluronic Acid / chemistry
Hydrogen-Ion Concentration
Inflammatory Bowel Diseases* / drug therapy
Methotrexate / pharmacology
Mice
Nanoparticles* / chemistry

Substances

Methotrexate
Hyaluronic Acid
Drug Carriers