Development of a hybrid micelle--hydrogel system for topical delivery of doxorubicin to skin cancer cells

Abstract

Objective(s): Topical delivery of anti-neoplastic agents could circumvent many drawbacks of chemotherapy in skin cancer. This study aims to develop a hybrid Hyaluronic acid-oleic acid (HA-C18) micelle--alginate hydrogel as a topical system for doxorubicin (DOX), enhancing skin penetration, providing controlled release, and localized therapy for skin cancer. Materials and Methods: DOX-loaded micelles (DOX-PMs) were prepared from the synthesized amphiphilic substance (HA-C18) and incorporated into an alginate hydrogel. Micelles were characterized for size, drug loading, and in vitro release behavior. pH and viscosity of the hydrogel were also evaluated. Ex vivo permeation through rat skin was investigated for DOX solution, DOX in hydrogel, and DOX-PMs-hydrogel. Finally, antitumor activity and flow cytometry analysis were also performed on the B16F10 cell line. Results: Size and drug loading of micelles were about 221.4±27 nm and 4.32±0.4%, respectively. pH values, and viscosity of hydrogel were 4.51±0.02, and 3.2 Pa.s, respectively. DOX was released in a burst and sustained manner after 72 hr. Results showed that micelles markedly enhanced DOX permeation, achieving a 2.1-fold increase over free drug and a 9.2-fold increase over hydrogel. DOX micelles exhibited lower cytotoxic activity against B16F10 cells compared to free DOX, due to the slower release from the micelles. Finally, in both quantitative and qualitative flow cytometry analyses, the cellular uptake was evident, and the uptake rate was lower than that of free DOX. Conclusion: The findings indicate that a hybrid micelle--hydrogel platform enables controlled delivery of DOX, enhancing topical efficacy in skin cancer while minimizing systemic exposure in a patient-compatible manner.