Anticancer activity and Microemulsion formulation for Transdermal delivery of Temozolomide Hexyl ester

Abstract

Temozolomide (TMZ) has been shown to possess excellent activity against malignant melanoma (skin cancer) in phase II and III clinical trials equal to alternative skin cancer drug, dacarbazine via oral administration. However, for the treatment of skin disorders, delivery of this agent directly to the skin would be advantageous. The previous studies suggest that temozolomide hexyl ester (TMZ-HE) derivative demonstrated the promising permeability by means of permeability coefficient (Kp) and flux values (Jss). This derivative was also completely hydrolysed by esterase enzymes within the skin, and generated biological active TMZA during the permeation test on viable rat and human skin. In this study, the cytotoxicity test of TMZ-HE was thus carried out comparing with TMZA and TMZ. TMZ-HE demonstrated an equal cytotoxicity against the cancer cell lines (IC₅₀) as TMZ and TMZA and significantly inhibited tumour growth in hairless mice inoculated with human melanoma comparing to untreated group as a control (P<0.05). Finally, topical formulation development of TMZ-HE was also studied. Microemulsion (ME) systems containing Vitamin E-TPGS (VE-TPGS) as a surfactant, oleic acid (OA) or isopropyl myristate (IPM) as an oil phase and isopropyl alcohol (IPA) as co-surfactant where appropriate were prepared. The permeation studies were performed on silicone membrane and hairless mouse skin. Kp and Jss values of TMZ-HE from ME preparations were significantly higher than neat OA and IPM as control formulation (up to 7-fold).