Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies and significantly reduces tumor sensitivity to radiation and chemotherapy. Therefore, it is of great importance to develop therapies that target specifically to hypoxic microenvironments and effectively eliminate tumors without damage of normal tissue and recurrence of cancer cells. Nanoparticle-based photothermal ablation therapy assisted by near infrared (NIR) laser has arisen as one of most promising new medical strategies for this endeavor. Gold nanorods (GNR) are of particular interest in this regard because of their small and adjustable size, strong optical tunability as well as inertness. Base on that, we performed a series of preliminary studies that successfully prepared and characterized a novel nanoconstruct composed of GNR and anti-carbonic anhydrase IX (CAIX) antibody, which is a viable biomarker for tumor hypoxia. Herein we propose to test our hypothesis that this nanoconstruct-based photothermal ablation will effectively eliminate tumors in hypoxic microenvironments without damage to normal tissue.
The first aim i s to conduct in vitro cellular binding, uptake and photothermal destruction studies. It will determine if this approach will have specific binding to CAIX-overexpressed human colon tumor HT29 cells and will effectively destruct cancer cells at the laser condition that normal cells remain intact.
The second aim i s to study pharmacokinetics and biodistribution of targeted and nontargeted GNR (with and without anti-CAIX) in animals bearing HT29 xenografts. It will elucidate if higher accumulation of GNR at tumor hypoxia can be achieved with the aid of anti-CAIX antibody.
The third aim i s to perform in vivo photothermal ablation on animals bearing HT29 xenografts. It will reveal whether this therapy can target on hypoxic regions, effectively kill cancer cells and improve the survival rate of tumored animals. In general, these studies will validate the feasibility of applying this GNR/anti-CAIX-based photothermal ablation therapy to treat tumor hypoxia and improve clinical outcome.
The proposed GNR/anti-CAIX nanoconstruct-based photothermal therapy could serve as an alternative or complementary approach for standard cancer treatment to eliminate residual or recurrent tumor cells, especially within the hypoxic areas that are resistant to traditional therapies. This therapy can have widespread utilization in many different cancer types that overexpress CAIX. Such a class solution to the vexing problem of hypoxic therapy resistance would likely be a significant contribution to cancer treatment.
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