title: Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery.
abstract: The objective of this study was to investigate the combined influence of independent variables in the preparation of folic acid-chitosan-methotrexate nanoparticles (FA-Chi-MTX NPs). These NPs were designed and prepared for targeted drug delivery in tumor. The NPs of each batch were prepared by coaxial electrospray atomization method and evaluated for particle size (PS) and particle size distribution (PSD). The independent variables were selected to be concentration of FA-chitosan, ratio of shell solution flow rate to core solution flow rate, and applied voltage. The process design of experiments (DOE) was obtained with three factors in three levels by Design expert software. Box-Behnken design was used to select 15 batches of experiments randomly. The chemical structure of FA-chitosan was examined by FTIR. The NPs of each batch were collected separately, and morphologies of NPs were investigated by field emission scanning electron microscope (FE-SEM). The captured pictures of all batches were analyzed by ImageJ software. Mean PS and PSD were calculated for each batch. Polynomial equation was produced for each response. The FE-SEM results showed the mean diameter of the core-shell NPs was around 304 nm, and nearly 30% of the produced NPs are in the desirable range. Optimum formulations were selected. The validation of DOE optimization results showed errors around 2.5 and 2.3% for PS and PSD, respectively. Moreover, the feasibility of using prepared NPs to target tumor extracellular pH was shown, as drug release was greater in the pH of endosome (acidic medium). Finally, our results proved that FA-Chi-MTX NPs were active against the human epithelial cervical cancer (HeLa) cells.
authors.affiliation: Department of Pharmaceutical Engineering, Faculty of Engineering, University of Tehran, Tehran, Iran.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Naghibi Beidokhti
authors.affiliation: Medical Plants Research Center, Institute of Medical Plants, ACECR, Karaj, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Ghaffarzadegan
authors.affiliation: Medical Plants Research Center, Institute of Medical Plants, ACECR, Karaj, Iran.
authors.forename: Sasan
authors.initials: S
authors.lastname: Mirzakhanlouei
authors.affiliation: Pasteur Institute of Iran, National Cell Bank of Iran, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Ghazizadeh
authors.affiliation: Medical Biomaterial Research Center, Tehran University of Medical Sciences, Tehran, Iran. Drorkoosh@tums.ut.ac.ir.|Department of Pharmaceutics, Tehran University of Medical Sciences, Tehran, Iran. Drorkoosh@tums.ut.ac.ir.
authors.forename: Farid Abedin
authors.initials: FA
authors.lastname: Dorkoosh
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005492:Folic Acid / Q000008:administration & dosage / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size
chemical_list: D004337:Drug Carriers; D048271:Chitosan; D005492:Folic Acid; D008727:Methotrexate
keywords: box-Behnken design; coaxial electrospray; folic acid-chitosan nanoparticles; methotrexate; optimization