Thursday, April 25, 2024
4/25/2024
Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a major challenge in public health. Preliminary studies conducted by our group suggest that carvedilol, a ß-adrenergic receptor antagonist (ß-blocker), may be repurposed for prevention of skin cancer: (1) carvedilol blocked epidermal growth factor (EGF)- and ultraviolet B (UVB)-induced neoplastic transformation of the non- cancerous mouse epidermal JB6 Cl 41-5a cells; among 15 commonly prescribed ¿-blockers, carvedilol showed the highest inhibitory activity on cell transformation; (2) both topical and oral administration of carvedilol inhibited chemical carcinogen-induced skin hyperplasia and H-ras mutation in mice with the topical route showing better effect; (3) topical application of carvedilol prevented UVB-induced skin damage, inflammation, formation of cyclobutane pyrimidine dimers, and development of squamous cell carcinoma in mice; (4) Although exact anticancer mechanisms are unknown, carvedilol predominantly inhibits EGF- and UVB-induced NF-¿B and AP-1 transactivation, key factors mediating skin carcinogenesis. These data revealed the potential of carvedilol as a novel anticancer agent. However, systemic absorption of carvedilol can cause cardiovascular effects such as bradycardia and hypotension which is undesirable for a cancer prevention purpose. Thus, we hypothesize that a nano delivery system for carvedilol based on flexible liposomes (transfersomes) targeting only the skin can be used as a cancer preventative therapy. Evaluation of a pilot formulation in vitro indicated that this formulation resulted in a higher skin retention of carvedilol and lower permeation compared with free carvedilol in acetone. Preliminary studies further confirmed that topical administration of transfersomal carvedilol had negligible effect on blood pressure compared with oral carvedilol treatment in mice. Clinically used carvedilol is a racemic mixture of ß-blocking S-carvedilol and non-ß-blocking R-carvedilol. The R-carvedilol enantiomer showed similar cancer preventive activity as the racemic mixture in our studies, indicating that ß- blockage is not required for the cancer preventive activity. Therefore, in this application, R-carvedilol-loaded transfersomes will be prepared and characterized in vitro (Aim 1). The optimized topical formulation will be examined for skin deposition and permeation, organ distribution, and cardiovascular effects in mice (Aim 2), and further characterized for chemopreventive activity on UV-induced skin carcinogenesis in mice (Aim 3). Since R-carvedilol does not lower heart rate or blood pressure but does block cardiac ryanodine receptors, with the skin targeting transfersomal formulation, we anticipate that the cardiovascular side effects will not be a concern for repurposing R-carvedilol for skin cancer prevention.
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