Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel.
In this study, the ability of nanocarriers containing protein transduction domains (PTDs) of various classes to improve cutaneous paclitaxel delivery and efficacy in skin tumor models was evaluated. Microemulsions (MEs) were prepared by mixing a surfactant blend (polyoxyethylene 10 oleoyl ether, ethanol and propylene glycol), monocaprylin, and water. The PTD transportan (ME-T), penetratin (ME-P), or TAT (ME-TAT) was added at a concentration of 1 mM to the plain ME. All MEs displayed nanometric size (32.3-40.7 nm) and slight positive zeta potential (+4.1 mV to +6.8 mV). Skin penetration of paclitaxel from the MEs was assessed for 1-12 hours using porcine skin and Franz diffusion cells. Among the PTD-containing formulations, paclitaxel skin (stratum corneum + epidermis and dermis) penetration at 12 hours was maximized with ME-T, whereas ME-TAT provided the lowest penetration (1.6-fold less). This is consistent with the stronger ability of ME-T to increase transepidermal water loss (2.4-fold compared to water) and tissue permeability. The influence of PTD addition on the ME irritation potential was assessed by measuring interleukin-1α expression and viability of bioengineered skin equivalents. A 1.5- to 1.8-fold increase in interleukin-1α expression was induced by ME-T compared to the other formulations, but this effect was less pronounced (5.8-fold) than that mediated by the moderate irritant Triton. Because ME-T maximized paclitaxel cutaneous localization while being safer than Triton, its efficacy was assessed against basal cell carcinoma cells and a bioengineered three-dimensional melanoma model. Paclitaxel-containing ME-T reduced cells and tissue viability by twofold compared to drug solutions, suggesting the potential clinical usefulness of the formulation for the treatment of cutaneous tumors.
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Dominique
D
Pepe
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Vanessa Fm
VF
Carvalho
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Melissa
M
McCall
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Débora P
DP
de Lemos
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Luciana B
LB
Lopes
D000279:Administration, Cutaneous; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000737:chemistry*; D004655:Emulsions / Q000737:chemistry; D019004:Galanin / Q000494:pharmacology*; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000494:pharmacology*; D010539:Permeability; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D034421:Sus scrofa; D014862:Wasp Venoms / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004655:Emulsions; D011993:Recombinant Fusion Proteins; D014862:Wasp Venoms; C110068:transportan; D019004:Galanin; D017239:Paclitaxel
microemulsion; nanocarriers; paclitaxel; protein transduction domains; skin; transdermal