Vitamin D₃-based conjugates for topical treatment of psoriasis: Synthesis, antiproliferative activity, and cutaneous penetration studies

Purpose. The goals of the experiments reported in this paper were to explore skin bioavailability and cell growth inhibitory activity of new vitamin D₃-based conjugates studied as a potential drug complex for psoriasis. Methods. Conjugation was made between polyunsaturated fatty acids (PUFAs), such as linolenic acid or γ-linolenic acid, and calcipotriol-a vitamin D₃ analogue clinically used for topical treatment of psoriasis. These complexes were prepared by coupling the corresponding fatty acid with calcipotriol in the presence of dicyclohexyl-carbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) to obtain an ester bond. Results. The conjugates were capable of enhancing the penetration of the vitamin into the skin as well as inhibiting proliferation of keratinocytes in cultures. The antiproliferative activity even increased after simulating the full hydrolysis of the conjugates. In vitro skin penetration studies revealed that the conjugates penetrated into the skin at higher levels relative to calcipotriol alone. It was also demonstrated that the conjugate containing n-3 fatty acid penetrated into the skin at higher levels as compared to the conjugate containing n-6 PUFA. High-performance liquid chromatography analysis has shown that after penetration, a major portion of calcipotriol-PUFA conjugate was first converted mainly into another isomer form, presumably by transesterification, and only then it was hydrolyzed to form apparently high local concentrations of both calcipotriol and PUFA. Conclusions. The unique biotransformation that occurred after penetration into the skin indicates that these conjugates are mutual prodrugs that are able to be bioprocessed in the skin and fully converted to the parent therapeutic agents.