Evaluation of the Synthesis and Skin Penetration Pathway of Folate-Conjugated Polymeric Micelles for the Dermal Delivery of Irinotecan and Alpha-Mangostin

Background/Objectives: The present study aimed to synthesize folate-conjugated poloxamers and develop polymeric micelles for the dermal delivery of irinotecan and alpha-mangostin for the treatment of melanoma using poloxamer 188 and poloxamer 184, which have never been synthesized with folate before. Methods: Poloxamer 188 and poloxamer 184 were synthesized with folate by esterification. The in vitro skin penetration enhancement of irinotecan- and alpha-mangostin-loaded folate-conjugated polymeric micelles was evaluated. The skin penetration pathway of folate-conjugated polymeric micelles was investigated by colocalization of multiple fluorescently labeled particles using confocal laser scanning microscopy (CLSM). Results: Folate-conjugated poloxamer 188 and poloxamer 184 were successfully synthesized. The prepared irinotecan- and alpha-mangostin-loaded folate-conjugated polymeric micelles from poloxamer 188 and poloxamer 184 had particle sizes of approximately 180 and 150 nm, respectively, indicating a positive charge with a narrow size distribution which could be easily taken up into cells. An in vitro skin penetration study revealed that folate-conjugated polymeric micelles from poloxamer 184 significantly enhanced the skin penetration of irinotecan and alpha-mangostin to a greater extent than the solution. CLSM visualization revealed that folate-conjugated polymeric micelles penetrated through the skin by the transfollicular pathway as the major penetration pathway, whereas penetration by the intercluster pathway, transcellular pathway and intercellular pathway constituted a minor pathway. Conclusions: Folate-conjugated poloxamer 184 polymeric micelles are promising candidates for the dermal delivery of anticancer drugs by the transfollicular pathway as the major skin penetration pathway.