Synthesis of titanium dioxide nanotubes (TNT) conjugated with quercetin and its in vivo antitumor activity against skin cancer

Abstract

Cancer has a significant impact on public health around the world. Treating cancer by chemotherapy or radiotherapy has several side effects. In combinational cancer therapy, combining nanoparticles with chemotherapeutic and/or natural agents increases the synergistic therapeutic effects by reducing undesired side effects. In the pharmaceutical field, the use of quercetin was limited due to its partial solubility in aqueous solutions. Titanium dioxide nanotubes (TNT) have a higher surface area for carrier molecules with unique physical and chemical characteristics. We investigated the effect of quercetin, TNT, or conjugated TNT with quercetin (TNT–Qu) on the B16F10 murine melanoma model and two-stage chemical carcinogenesis model using 7, 12-Dimethylbenz (a) anthracene as a tumor initiator and Phorbol 12-myristate-13 acetate as a tumor promoter. The topical application of TNT–Qu enhanced the anti-tumor activity in comparison to quercetin or TNT alone. TNT–Qu treatment to the tumor-bearing mice significantly reduced the tumor growth than quercetin or TNT alone treatment. TNT–Qu inhibited tumor growth by regulating phospho-STAT3 levels in the tumor microenvironment. In the two-stage chemical carcinogenesis model, TNT–Qu treatment has no effect on skin color and delayed the mortality rate in tumor-bearing mice. The histopathological data supports that TNT–Qu treatment exhibited reduced squamous cell carcinoma and ameliorated to a large extent with very low epidermal hyperplasia compared with quercetin or TNT alone. TNT–Qu treatment restored the γδ T cells levels to the normal skin level. Furthermore, TNT–Qu significantly inhibited the blood vessel formation in chick chorioallantoic membrane assay. TNT conjugated with quercetin could thus be a promising combinational molecule for effectively treating skin cancer.