Chitosan-Carboxymethyl-5-Fluorouracil-Folate Conjugate Particles: Microwave Modulated Uptake by Skin and MelanomaCells.

Abstract

5-Fluorouracil delivery profiles in the form of chitosan-folate submicron particles through skin and melanoma cells invitro were examined using microwaves as the penetration enhancer. The invivo pharmacokinetic profile of 5-fluorouracil was also determined. Chitosan-carboxymethyl-5-fluorouracil-folate conjugate was synthesized and processed into submicron particles by spray-drying technique. The size, zeta potential, morphology, drug content, and drug release, as well as skin permeation and retention, pharmacokinetics, invitro SKMEL-28 melanoma cell line cytotoxicity, and intracellular trafficking profiles of drug/particles, were examined as a function of skin/melanoma cell treatment by microwaves at 2,450 MHz for 5+ 5 minutes. The level of skin drug/particle retention invitro and invivo increased in skin treated by microwaves. This was facilitated by the drug conjugating to chitosan and microwaves fluidizing both the protein and lipid domains of epidermis and dermis. The uptake of chitosan-folate particles by melanoma cells was mediated via lipid raft route. It was promoted by microwaves, which fluidized the lipid and protein regimes of the cell membrane, and this increased drug cytotoxicity. Invivo pharmacokinetic study indicated skin treatment by microwave-enhanced drug retention but not permeation. The combination of microwaves and submicron particles synergized skin drug retention and intracellular drug delivery.