title: Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate.
abstract: Folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-FOL) decorated methotrexate (MTX)-conjugated nanoparticles were developed for targeted delivery of MTX to folate receptor-expressed tumor cells. The synthesis of TPGS-FOL followed 3-step process. Firstly, the terminal hydroxyl group of TPGS was converted to sulfonyl chloride using mesyl chloride in comparison with nosyl and tosyl chlorides. The highest conversion efficiency and yield were obtained by mesyl chloride due to the formation of higher reactive intermediate in a presence of triethylamine. Secondly, the substitution of sulfonyl group by sodium azide produced considerably high yield with conversion efficiency of over 90%. Lastly, the coupling reaction of azido-substituted TPGS and propargyl folamide by click reaction resulted in 96% conjugation efficiency without polymer degradation. To fabricate the folate receptor-targeted nanoparticles, 10 and 20%mol MTX-conjugated PEGylated poly(ϵ-caprolactone) nanoparticles were decorated with TPGS-FOL. The size and size distribution of MTX-conjugated nanoparticles relatively increased with %MTX. The MTX release from the nanoparticles was accelerated in acidic medium with an increase of %MTX but retarded in physiological pH medium. The decoration of TPGS-FOL onto the nanoparticles slightly enlarged the size and size distribution of the nanoparticles; however, it did not affect the surface charge. The cytotoxicity and cellular uptake of MCF-7 cells demonstrated that 10% MTX-conjugated nanoparticles and FOL-decorated nanoparticles possessed higher toxicity and uptake efficiency than 20% MTX-conjugated nanoparticles and undecorated nanoparticles, respectively. The results indicated that FOL-10% MTX-conjugated nanoparticles exhibited potential targeted delivery of MTX to folate receptor-expressed cancer cells.
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand. Electronic address: varaporn.jun@mahidol.ac.th.
authors.forename: Varaporn Buraphacheep
authors.initials: VB
authors.lastname: Junyaprasert
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand.
authors.forename: Sirithip
authors.initials: S
authors.lastname: Dhanahiranpruk
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand.
authors.forename: Jiraphong
authors.initials: J
authors.lastname: Suksiriworapong
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand.
authors.forename: Kittisak
authors.initials: K
authors.lastname: Sripha
authors.affiliation: Department of Microbiology, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand.
authors.forename: Primchanien
authors.initials: P
authors.lastname: Moongkarndi
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008727:Methotrexate / Q000008:administration & dosage* / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D066007:Toxicokinetics; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D014810:Vitamin E; D011092:Polyethylene Glycols; D005492:Folic Acid; C014225:tocophersolan; D008727:Methotrexate
keywords: Folic acid; MCF-7 breast cancer cells; Methotrexate; PEGylated poly(ε-caprolactone); Targeted nanoparticles; d-α-Tocopheryl polyethylene glycol 1000 succinate