Project 5: Nanotherapeutics: Multifunctional Nanoparticles for Drug Delivery

Investigators:

The primary goal of this CCNE project is to develop a new class of self-assembled and biodegradable nanoparticles for delivery and targeting of cytotoxic chemotherapeutic drugs to solid tumors. The use of nanoparticles for drug delivery and targeting is one of the most advanced, exciting, and clinically important applications of nanotechnology. Recent advances have led to the FDA approval of albumin-conjugated paclitaxel or TaxolTM (Abraxane), a "binary" nanoparticle for treatment of taxane-refractory breast cancer. Research by this CCNE team has developed a more sophisticated "ternary" nanoparticle structure by linking both a hydrophobic cancer drug (TaxolTM) and a tumor-targeting ligand (folic acid or FA) to a hydrophilic and biodegradable polymer (Heparin). The antitumor activity of this ternary nanoparticle (Heparin-FA-Taxol) is nearly 17 times higher than the free drug in the xenograft tumor models. These results have raised new possibilities in developing targeted nanoparticle drugs for cancer therapy. In this project, we propose to develop several series of multifunctional nanoparticle therapeutics by using three taxane drugs (paclitaxel, docetaxel, and epothilone B), two targeting ligands (e.g., folic acid and a single-chain antibody fragment against EGFR), and biodegradable carriers (e.g., heparin). Initial studies will focus on the Heparin-FA-TaxolTM nanoparticle because of our extensive experience with this conjugate and its excellent drug delivery and targeting properties. Other combinations will also be explored, and will be critically evaluated and compared with free drugs in both in-vitro and in-vivo systems. Promising nanoparticles will be further evaluated by the CCNE Assessment Committee for the possibility of moving toward preclinical toxicology, pharmacokinetic, and pharmacodynamic studies. To this end, we propose to test the hypotheses that tumor targeted novel therapeutic nanoparticles will improve (i) delivery and tumor specific distribution of anticancer drugs, (ii) will provide novel pharmacokinetic and pharmacodynamic properties, leading to much improved therapeutic indeces for common anticancer drugs.