Dual Drug Encapsulation In A Novel Transethosomes For The Treatment Of Cutaneous Melanoma

Combination of dacarbazine(DAC)and tretinoin(all-trans retinoic acid,TRA),which can effectively reverse multidrug resistance(MDR),is applied to treat cutaneous melanoma.However,the active agents are difficult to across the stratum corneum into deep skin to play a therapeutic role.To overcome this problem,transethosomes(TES)were developed as the carriers to deliver drugs to and through the skin.The objective of this research was to develop and evaluate a dual drug-loaded dermal targeted vesicle for the treatment of cutaneous melanoma.TES were prepared according to the thin film hydration method and characterized in terms of appearance,morphology,and particle size.The results revealed that encapsulation efficiency values for TES were significantly higher than those of liposomes(LS).TES exhibited a smaller vesicle size with a higher negative charge,despite the same levels of phospholipid containing in the TES and LS.What’s more,it was known that TES were more uniform than LS by comparing the PDI values of different prescriptions.Skin permeation studies were carried out for different formulations and the results showed that the permeability of the active agents from TES was superior to that of LS.After 24 h,the mean amount of DAC permeated from TES was 4-5 fold higher than that from LS.In addition,the mean amount of drugs accumulated in the whole skin from TES was 2.5 fold higher than that from LS.Besides,drug distributions were validated by confocal laser scanning microscopy(CLSM),to visualize the distribution of calcein(hydrophilic)and rhodamine 6G(lipophilic)within the skin layers further confirm the skin targeting effect of TES.What’s more,the mechanism of the enhanced skin permeation was determined by fourier transform infrared spectroscopy(FTIR).The results of pharmacokinetics study showed that active agents could gradually penetrate into viable epidermis and dermis layers through transdermal absorption.TES group yielded higher plasma concentrations,larger plasma AUC,and higher relative bioavailability compared to the LS.The results of in vivo permeation study reflected that TES significantly enhanced the penetration of DAC and TRA.Furthermore,comparing with the normal skin,the vesicle treated skin did not show any infiltrated inflammatory cells,indicating the non-irritant and promising topical application of TES.In addition,the vesicular formulations were tested on B16-F10 cells.DAC/TRA-TES showed an improvement of the cytotoxic effect with respect to other formulations.The superior internalisation of TES was also detected by the extent and the time-dependent vesicular-cell interaction.In conclusion,this debut study laid the foundation for developing dual drug loaded vesicles and showed that TES could provide a promising tuning as a transdermal delivery system for the treatment of cutaneous melanoma.