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

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).

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.

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.

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

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

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

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

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

Cisplatin neurotoxicity is prevented with tumor-targeted drug delivery

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.

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.

Figure 2 A B C