Abstract
Systemic chemotherapy with the anticancer agent cisplatin is approved for advanced non-melanoma skin cancer (NMSC), but topical treatment is limited by insufficient cutaneous penetration. We studied the impact of ablative fractional laser (AFL) exposure on topical cisplatin’s pharmacokinetics and biodistribution in skin, using microscopic ablation zones reaching the mid- (MAZ-MD; 620 μm depth) and deep dermis (MAZ-DD; 912 μm depth) (λ = 10,600 nm, 196 MAZ/cm2). Assessed in an in vitro Franz cell model after 0.5-, 4-, 24 h topical exposure (n = 8), cisplatin delivery was greatly accelerated by AFL, shown by quantitative- and imaging-based inductively coupled plasma-mass spectrometry (ICP-MS). After 30 minutes, cisplatin concentrations were 91.5, 90.8 and 37.8 μg/cm3 in specific 100-, 500, and 1500 μm skin layers respectively, contrasting to 8.08, 3.12, 0.64 μg/cm3 in non-laser-exposed control skin (p < .001; control vs MAZ-MD). Supported by element bioimaging, the greatest relative increases occurred in the deep skin compartment and at later time points. After 24 h, cisplatin concentrations thus rose to 1829, 1732 and 773 μg/cm3, representing a 25-, 103- and 447-fold enhancement in the 100, 500, and 1500 μm deep skin layers versus corresponding controls (p < .001; MAZ-MD). A significant difference in cutaneous uptake using MAZ-MD and MAZ-DD was not shown at any time point, though deeper laser channels resulted in increased transdermal cisplatin permeation (p ≤ .015). In conclusion, AFL is a rapid, practical and existing skin treatment that may provide greatly enhanced uptake of topical cisplatin for treatment of superficial and deep skin cancer.
Highlights
Since its approval in 1978, cisplatin (300.1 g/mol) has remained one of the most successful and versatile anticancer agents in oncology
Systemic chemotherapy with the anticancer agent cisplatin is approved for advanced non-melanoma skin cancer (NMSC), but topical treatment is limited by insufficient cutaneous penetration
We studied the impact of ablative fractional laser (AFL) exposure on topical cisplatin’s pharmacokinetics and biodistribution in skin, using microscopic ablation zones reaching the mid- (MAZ-MD; 620 lm depth) and deep dermis (MAZ-DD; 912 lm depth) (k 1⁄4 10,600 nm, 196 MAZ/cm2)
Summary
Since its approval in 1978, cisplatin (300.1 g/mol) has remained one of the most successful and versatile anticancer agents in oncology. Used as both mono- and combination therapy, the drug represents a cornerstone treatment of epithelial cancers of the head and neck, lungs, testes, ovaries and bladder (Chabner et al, 2015). Cisplatin is first activated by hydrolysis inside the cell, subsequently forming intra- and interstrand crosslinks with DNA. An effective treatment using topical cisplatin would be far less toxic, but is limited by insufficient penetration into the skin likely due to the agents’ poor lipophilicity (reported range of experimental LogP: -2.55 À -2.19) (Leo et al, 1995, Ghezzi et al, 2004)
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