Green Synthesized Honokiol Transfersomes Relieve the Immunosuppressive and Stem-Like Cell Characteristics of the Aggressive B16F10 Melanoma

Abstract

Background: Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study. Methods: TFs were prepared using the modified scalable heating method. A three-factor, three-level Box-Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell-activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively). Results: The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the "do not eat me" signal -CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix-depleting enzyme, produced detrimental effects. Conclusion: HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.

Advancements in nanoparticle-based treatment approaches for skin cancer therapy

“…Honokiol/ transferosomes/ melanoma [ 340 ] , melittin/ lipoosmes/ melanoma [ 341 ] , berberine/ transniosomes/ skin cancer [ 342 ] , protein kinase C inhibitor, BRD4 PROTAC/ liposomes/ melanoma [ 343 ] , hispolon, doxorubicin/ liposomes/ melanoma [ 344 ] , phenylethylresorcinol/ liposomes, transferosomes, invasomes/ melanoma [ 345 ] , brucine/ ethosomes/ melanoma [ 346 ] , berberine chloride, evodiamine/ ethosomes/ melanoma [ 347 ] , 5-fluorouracil/ ethosomes/ melanoma [ 348 ] , doxorubicin, Au, TRP-2, polyinosinic:polycytidylic acid/ liposomes, chitosan, poly(lactide-co-glycolic acid)/ melanoma [ 349 ] are few more investigations of nanovesicles that endowed excellent anti-skin cancer efficacy.…”

Transferosomes as a transdermal drug delivery system: Dermal kinetics and recent developments

“…Honokiol is a natural chemical compound that demonstrates anticancer effects against melanoma cells. Ezzeldean et al effectively fabricated transferosomes loaded with honokiol using a heating method with lecithin and the edge activator sodium deoxycholate (Ezzeldeen et al, 2021). They noted that the increase in the edge activator (sodium deoxycholate) produced reduced vesicle elasticity due to the bulkiness of the steroid-like structure of the sodium deoxycholate and less deformable vesicles (Salama et al, 2012).…”

The application prospects of honokiol in dermatology

“…And alleviated the immunosuppressive characteristics of melanoma cells via the downregulation of TGF-β signaling. 48 Methoxylated honokiol enhanced the inhibitory activities against inflammatory biomarkers such as COX-2, and could be a candidate for treating inflammatory skin disorders. 3 Moreover, the methoxylation of honokiol significantly enhanced skin absorption and exposition amounts, but the transdermal penetration across the skin decreased, indicated the feasibility of using methoxylated permeants for dermal but not transdermal.…”

“…It could overcome the physiological barriers of the stratum corneum and the anomalous tumor microenvironment. And alleviated the immunosuppressive characteristics of melanoma cells via the downregulation of TGF‐β signaling 48 . Methoxylated honokiol enhanced the inhibitory activities against inflammatory biomarkers such as COX‐2, and could be a candidate for treating inflammatory skin disorders 3 .…”