Surface-Decorated Nanocarrier as a Targeted Drug Delivery Cargo to Folate Receptor-Overexpressing Cells for Enhancing Anti-cancer and Anti-inflammatory Activity
Yomna Adel Gabr *
Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia, Egypt.
Germeen N. S. Girgis
Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia, Egypt.
Hassan Mohamed EL-Sabbagh
Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia, Egypt.
*Author to whom correspondence should be addressed.
Abstract
Aims: Folate receptor (FR) is overexpressed in most cancer cells and activated macrophages entailed in rheumatoid arthritis (RA). The aim of the current study was the fabrication of FR-targeted nanocarrier loaded with methotrexate (MTX) to magnify its therapeutic efficacy and limit its toxicity.
Methodology: Folic acid-chitosan (FA-CS) conjugate was synthesized and characterized. MTX loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were prepared, optimized and coated with different concentrations of FA-CS conjugate. The selected FA-CS coated MTX NPs formulation (F10) was evaluated via in vitro and in vivo studies.
Results: F10 had satisfactory encapsulation efficiency (76.2%), homogenous particle size (278.6 nm) and positive zeta potential (34.0 mV) and displayed biphasic drug release pattern in different pH media. Further characterization of F10 cinched MTX incorporation in the polymeric matrix of the targeted nanocarrier. In vitro cytotoxicity assay to FR-positive and FR-negative cancer cells revealed the improved anticancer effect of F10 to FR-positive cancer cells, which was absent in FR-negative cells, compared to free MTX or uncoated MTX NPs (F2). F10 showed appropriate storage stability at refrigerated temperature up to 3 months. Moreover, oral administration of F10 in the treatment of complete Freund’s adjuvant (CFA)-induced RA in BALB/c mice conferred prodigious therapeutic outcomes and declined systemic toxicity compared to oral treatment with conventional pure MTX or commercial MTX tablets.
Conclusion: The fabricated targeted nanocarrier could enhance the anticancer activity of MTX to FR-overexpressing cancer cells and could be a promising novel approach for oral administration of MTX in the treatment of RA or other inflammatory conditions associated with FR-overexpressing activated macrophages.
Keywords: Methotrexate, folic acid-chitosan conjugate, PLGA nanoparticles, oral drug delivery, complete Freund’s adjuvant-induced arthritis
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