Vitamin D3-based conjugates for topical treatment of psoriasis: synthesis, antiproliferative activity, and cutaneous penetration studies.
OBJECTIVE
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 gamma-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.
Ben-Shabat
Shimon
S
The Institutes for Applied Research and the School of Pharmacy, Ben-Gurion University of the Negev, 84105 Beer Sheva, Israel. sbs@bgu.ac.il
Benisty
Rachel
R
Wormser
Uri
U
Sintov
Amnon C
AC
D000287:Administration, Topical; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000031:analogs & derivatives; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D066298:In Vitro Techniques; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D013552:Swine
D006131:Growth Inhibitors; D002762:Cholecalciferol