Session Speaker
Nanopolymers and Phosphodiesterase Type 5 Inhibitors for Drug Delivery Into The Brain To Treat Primary Tumors and Metastases
Ljubimova JY, Hu J, Inoue S, Patil R, Ding H, Portilla, H, Holler E, Black KL
USA


Malignant brain tumors have the highest mortality compared with other tumors. 20-40% of patients with systemic cancer develop central nervous system metastases. The most difficult problem in brain tumor treatment is drug delivery through blood/tumor brain barrier.

Phosphodiesterase Type 5 (PDE5) inhibitors facilitated high molecular weight molecule (antibody) delivery in preclinical models of brain metastasis. After co-treatment with PDE5 inhibitors and Herceptin, mice with brain metastases of high HER-2 expressing tumors (lung cancer CRL5904 and breast cancer BTB-474) demonstrated significantly greater survival than mice with metastases of low HER-2 expressing breast cancer BT-MBM-435. Co-treatment induced much stronger tumor cell apoptosis in vivo than Herceptin alone. PDE5 inhibitors could increase Herceptin effects through stimulation of caveolae endocytosis. Nanoconjugate Polycefin was designed and synthesized that penetrates blood tumor barrier. Its biodegradable, nontoxic and non-immunogenic polymalic acid platform carries covalently bound two different monoclonal antibodies for targeting brain tumor barrier and human tumor cells, and several antisense/siRNAs to block molecular markers as combination cancer therapy. Preclinical studies demonstrate significant increase of survival (p<0.01) and tumor size reduction in treatment mouse group (4 mm³), versus control group (47 mm³; p<0.001). Successful drug delivery using intravenous nanoconjugate gives a hope for new glioma treatment strategy.