Developing Targeted Therapeutic Nanosystems to Treat Metastatic Colon Cancer The long-term goal of this research is to create a nanostructure that can target colon cancer including its metastases, while delivering a therapeutic agent. In this project, we seek to develop a nanosystem that can target Claudin-1, a transmembrane protein overexpressed in colon cancer and its metastases. The project will test the hypothesis that fiber-like nanostructures can be used to target Claudin-1 efficiently. The project consists of three aims. The first specific aim focuses on the synthesis and characterization of peptide amphiphiles that can form nanostructures in water. Diverse nanostructures, micelles and fibers, will be prepared and characterized using transmission electron microscopy and atomic force microscopy among other approaches. Toxicity, binding affinity and cell internalization of a library of nanostructures containing the Claudin-1 targeting peptide will be assessed. Computational tools to modify the claudin-1 targeting peptide will be used to guide optimization of nanostructure targeting. The in vivo targeting efficacy of selected systems will then be examined. The encapsulation efficiency of different anticancer drugs inside the nanocarriers that demonstrate the best performance (based on toxicity, stability and cell binding) will be assessed. Finally, the dose-dependent toxicity of drugs encapsulated in selected nanostructures against colon tumor cells will be evaluated in comparison to free drug alone.
|Fan, Wei; Zhang, Wenting; Alshehri, Sameer et al. (2018) Increasing time on target: utilization of inhibitors of cysteine cathepsins to enhance the tumor retention of receptor-targeted agents. Chem Commun (Camb) 54:11268-11271|