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Paul J. Davis, Thangirala Sudha, Shaker A Mousa

TARGETED DELIVERY OF GENERIC CHEMOTHERAPEUTIC AGENTS TO SOLID TUMORS VIA SYSTEMIC NANOTETRAC (NANO-DIAMINO-TETRAC). Paul J. Davis, Thangirala Sudha, Shaker A Mousa Albany Medical College, Albany, NY; Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences.

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Paul J. Davis, Thangirala Sudha, Shaker A Mousa

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  1. TARGETED DELIVERY OF GENERIC CHEMOTHERAPEUTIC AGENTS TO SOLID TUMORS VIA SYSTEMIC NANOTETRAC (NANO-DIAMINO-TETRAC) Paul J. Davis, Thangirala Sudha, Shaker A Mousa Albany Medical College, Albany, NY; Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences

  2. Integrin avb3 is a structural protein of the plasma membrane; it is generously expressed by tumor cells and dividing endothelialcells. • The extracellular domain of this integrin contains a receptor for thryoid hormone and a thyroid hormone derivative, tetraiodo-thyroacetic acid (tetrac).

  3. At the integrin, thyroid hormone (T4, T3) is pro-angio-genic and anti-apoptotic by multiple mechanisms, thus supporting tumor cell survival and vascular support for cancer cells. • Tetrac at the integrin is anti-angiogenic, pro-apoptotic and radiosensitizing.

  4. The covalent bonding of tetrac to a diaminopropane linker and the latter to a poly(lactic-co-gly-colic acid) (PLGA) nanoparticle yields a molecular delivery system targeted to cancer cells and dividing endothelial cells. • We have loaded cancer chemotherapeutic agents into the nanoparticle for delivery/release in tumors.

  5. Chemical structure of Nano-diamino-tetrac (NDAT, Nanotetrac)

  6. The cancer treatment agents tested were cisplatin, paclitaxel and doxorubicin.

  7. A B C B Effective chemotherapeutic drug loading of PLGA Dynamic light scattering (DLS) monitoring: Cis, Pac, Dox

  8. The xenografts were bladder carcinoma (cisplatin), pancreatic carcinoma (pacli-taxel) and breast cancer (doxo-rubicin).

  9. Tumor-targeted chemothera-peutic agent delivery reduces risk of systemic drug-induced side effects.

  10. Cisplatin neurotoxicity is prevented with tumor-targeted drug delivery

  11. SUMMARY • Payloads of cisplatin, paclitaxel or doxorubicin in the PLGA nanopartcle of Nanotetrac (NDAT, Nano-diamino-tetrac) were successfully delivered to relevant solid tumor xenografts. • Tumor uptake of these generic chemotherapeutic agents via NDAT was up to 7-fold greater than with drugs administered by conventional routes.

  12. SUMMARY 2 • Increases in tumor uptake of chemotherapeutic agents via Nano-diamino-tetrac validates NDAT targeting of tumors via integrin avb3. • Appropriate reduction in tumor size was achieved via NDAT delivery. • Systemic toxicity of cisplatin (hindlimb neuropathy) was eliminated by payload delivery.

  13. Figure 2 A B C

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