The use of small RNAs to directly perturb the proteins that drive cancer development and progression presents an exciting approach to treat cancer. Carriers are required to transport small RNA drugs into cancer cells. Unfortunately, existing carriers have largely worked only in normal hepatocytes and are not capable of effectively targeting cancer cells in vivo. That need is coupled with a desire to simultaneously image and track tumor cells, particularly in the context of metastasis. We recently overcame this challenge by developing dendrimer nanoparticles (DNPs) that can potently deliver siRNAs/microRNAs to tumor cells in aggressive genetic models of cancer with very low toxicity. A large library of &gt;1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. Lead dendrimers were potent (EC50 &lt; 0.02 mg/kg siFVII) in dose response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven liver tumors. Delivery of let-7g miRNA mimic (1 mg/kg, once per week) inhibited tumor growth and dramatically extended survival.2 To improve upon this system, we have now developed multi-component theranostic DNPs that are capable siRNA-mediated gene silencing with simultaneous "turn on" fluorescence activation in tumors (Figure 1). PEGylated pH-activatable dyes have been employed to permit general activation in tumors due to the decreased pH of the tumor microenvironment. These DNPs localize to various xenograft tumors after intravenous delivery, “turn on”, and enable silencing of luciferase reporter gene expression at low doses. I will present our work towards the chemical synthesis of dendrimers and pH-responsive probes, as well as efforts to optimize the biophysical properties of DNPs for theranostic gene silencing coupled to cancer imaging.

Multi-component theranostic dendrimer nanoparticles (DNPs) capable of gene delivery and turn on activation in tumors

252nd National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.