The Effect of Lipophilicity of a Novel Oxaliplatin Derivative on the Ex-vivo Skin Penetration and Efficacy

The increased lipophilicity of a novel oxaliplatin derivative was evaluated on enhanced skin permeation of the molecule via human skin, although its molecular weight is quite high, 713 Da. The lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)]/OPA was prepared by conjugating oxaliplatin with palmitate and acetate moieties to improve performance and facilitate incorporation into polymeric nanoparticles. OPA NPs prepared by solvent displacement method containing OPA, PLGA, Tween 80, MCT, Lipoid E80 and Solutol^® HS 15. The cytotoxicity, skin permeation, and lesional activity using non-melanoma skin cancer cells, BCC/SCC and actinic keratosis (AK) cells was tested in-vitro. The mean particle diameter of the OPA NPs was 120 nm with PDI less than 0.15 and optimal encapsulation yields was approximately 95%. TEM and HPLC confirmed the excellent stability of the lyophilized powder with 2% Hydroxypropyl-β-cyclodextrin. OPA and OPA NPs exhibited pronounced cytotoxic effect in MTT Assay against SCC and AK cells compared to Oxaliplatin and 5-FU. In-vitro permeability study of OPA in Castor oil, MCT, NPs was conducted using Franz diffusion cell through human skin and the amount of Platinum distributed in different layers of the skin after 24h was measured using ICP-MS. It was observed that the amounts of Pt deposited in the epidermis and dermis layers following a single dose of 100 µg OPA in various formulations, including NPs were significant, well above the estimated therapeutic concentration of 1μg Pt/g. The effect of OPA compared to Aldara^® 5% (imiquimod) and 5-FU (Efudix^®) was evaluated on ex-vivo tumor lesion samples of patients. Resazurin assay for 96 h confirmed that OPA was much more effective than 5-FU and Aldara^® Cream in reducing BCC/SCC Cell viability.