A major challenge the application of nanotechnology to cancer therapy is targeting of the nanomaterials specifically to the tumor itself. Although both arsenic and platinum based drugs used in cancer therapy have displayed significant response in certain tumor types, their therapeutic applications are limited by serious systemic toxicities, limited bioavailability to the tumor site and development of drug resistance by tumor cells. We propose to address these challenges by preferentially targeting an arsenic-cisplatin nanoparticulate formulation encapsulated in liposomal vesicles called "nanobins" to the tumor site using the anti-angiogenic peptide, anginex. This peptide specifically binds to galectin-1, a tumor endothelial cell specific antigen that is induced in response to radiation. The novel nanobin formulation developed by our collaborator (O'Halloran) to be used in the present project utilizes a gradient of cisplatin ions to facilitate stable coencapsulation of Arsenic trioxide. The inclusion of the arsenic compound in the nanovesicle is expected to make the tumor targeted delivery more active against solid tumors by causing vascular damage and by overcoming resistance of tumor cells to conventional chemotherapy. The 33 amino acid, small peptide, anginex, will be the galectin-1 targeting agent to deliver arsenic and platinum drugs co-encapsulated in a single liposomal vesicle to the irradiated tumor site. It is expected that targeted delivery of liposomal cytotoxic payloads like the dual-drug nanobins via the anginex peptide to radiation-induced galectin-1 in the tumor-vasculature will increase the therapeutic ratio of such novel strategies developed against solid tumors.
Preferential target and delivery to the tumor site is capable of overcoming the limitation of acute systemic cytotoxicity and short half-life in circulation of therapeutic payloads. Targeted nanoparticle delivery of therapeutic molecules has the potential to provide safer and more effective therapies for cancer applications. Our central hypothesis is that dual drug delivery of Arsenic and cisplatin based nanoparticles via anginex, targeted to radiation-induced tumor-vasculature associated Galectin-1 will improve the therapeutic potential for combination therapy strategies against solid tumors. The development of targeting ligands, such as anginex, for conjugation to drug loaded nanoparticles will serve as a model for highly selective, radiation therapy-amplified drug delivery.
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