Nanoparticle Delivery of Therapeutic Agents in Neuroblastomas
Neuroblastoma (NB) is the most common and deadly solid tumor of childhood. Unfortunately, most patients have metastatic disease, and many progress relentlessly despite intensive multimodality therapy. Many cytotoxic agents used to treat high-risk NB have serious short- and long-term toxicities, and very few new agents are in the pipeline. Nanoparticles (NPs) are drug delivery vehicles (50-200 nm) that passively target tumors based on the enhanced permeability of tumor blood vessels, and retention due to poor venous/lymphatic return (EPR effect).
We hypothesize that NP delivery of chemotherapeutic agents will improve antitumor efficacy and decrease systemic toxicity, based on the EPR effect. Our aims are:
1) Develop NP formulations of two cytotoxic agents (irinotecan/SN38, etoposide) and two biological agents (fenretinide, PI-103) that are reformulated to remain in the NPs.
2) Test the efficacy of drug-loaded NPs on NB cells growing in culture.
3) Determine the optimum doses and schedules for these NPs in a mouse model of NB.
We will determine the optimum dose/schedule to achieve the best tumor control with the least toxicity. With irinotecan/SN38, we achieve equivalent tumor control with NPs delivering 1/10 the total dose compared to free drug, and we achieve better control (even cures) with only 20-40% the total dose. NP delivery of reformulated conventional agents produces dramatically improved efficacy and much less toxicity than free drug, and our NP formulations are completely biodegradable. This approach could be used for many different agents and could be applied to the treatment of any solid tumor in children or adults.