Photodynamic Therapy of Melanoma By Engineered Titanium Dioxide Nanoparticles

Metastatic melanoma has a very poor prognosis, and conventional chemotherapy treatment causes severe toxic response to healthy cells due to lack of selectivity in targeting the tumor cells. The advancement of nanotechnology has opened up avenues for the use of engineered nanoparticles for diagnosis, imaging and targeted treatment of cancer. In this work, we hypothesize that engineered hybrid titanium dioxide (TiO₂) nanoparticles (NPs) that possesses tumor targeting peptide ligands and tunable photoactivity will result in a superior cancer therapeutic strategy. TiO₂ NPs make them attractive materials for photodynamic therapy of cancer due to their a) tunable size and photoemissive properties b) efficient photoactivity to induce cytotoxicity c) conjugation with targeting ligands and ability to carry drug payloads. Peptides are excellent targeting agents due to a) high potency and selectivity in targeting cancer cells b) tunable physiochemical properties due to high chemical diversity c) enhanced tumor penetration, higher stability and lower antigenicity. We have investigated the toxicity of two size variants of TiO₂ NPs (5 and 25 nm) on normal human cells and cancer cells. Our results, indicated that NPs were not cytotoxic to cells in concentration range tested (0.01 - 100 µg/mL).  A dose - dependent phototoxicity of UV irradiation was observed and cell death was predominant when UV intensity was greater than 20 J/cm². UV photoactivated 25 nm particles show enhanced cytotoxic effect compared with 5 nm particles in normal and cancerous cells. Photoactivity measurements indicated 25 nm particles had a higher photocatalytic activity than 5 nm particles. Transferrin receptor mediated pathway was selected for targeting cancer cells. Flow cytometry analysis indicated transferrin receptor was overexpressed in melanoma cells by 2 – 3 fold compared to the normal dermal fibroblasts and keratinocytes. We have designed peptide ligands to target the transferrin receptor overexpressed on cancer cells. These results provide us the opportunity to employ transferrin receptor mediated targeting of melanoma cancer cells using photoactivated titanium dioxide nanoparticles.