Development of peptide drug conjugates for cancer therapy

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Abstract The ultimate goal of this project is to develop and commercialize peptide drug conjugates to treat life- threatening triple negative breast cancer. Triple negative breast cancer (TNBC) is a high aggressive subtype of breast cancer with poor survival. TNBC patients do not respond well to currently available clinical therapies, including targeted therapy. Chemotherapy is commonly used to treat TNBC. We will develop novel peptide conjugates of chemotherapeutics for highly efficient and tumor-specific delivery of the anticancer drugs into triple negative breast cancer. Various drug delivery systems, including nanosized delivery systems, have been tested for delivery of anticancer therapeutics for treating TNBC. However, these delivery systems are unable to provide efficient drug delivery in solid tumors due to the physical barrier of dense tumor extracellular matrix (ECM). Previously, we have designed and developed a small peptide targeted MRI contrast agent ZD2-N3-Gd(HP-DO3A) (MT218) to target an ECM oncoprotein extradomain B fibronectin (EDB-FN) for accurate detection of TNBC. MT218 is able to deliver the contrast agent at micromolar concentrations in aggressive tumors, including TNBC, resulting in robust signal enhancement for accurate detection of triple negative breast cancer in mice with MRI. Currently, MT218 is in phase II clinical development for cancer diagnosis. In this project, we will design and develop ZD2 peptide targeted drug conjugates for efficacious treatment of TNBC. The specific aims are: 1) to synthesize and characterize a peptide drug conjugate to treat triple negative breast cancer; 2) to determine in vivo therapeutic efficacy of the drug conjugate to treat TNBC in mouse models. After further demonstrating the feasibility of the peptide drug conjugate in tumor models, including a PDX model, in this phase 1 SBIR project, we will then further perform comprehensive preclinical assessment of its physicochemical properties, pharmaceutical properties, and therapeutic efficacy for further clinical development. The peptide drug conjugate has a great potential to achieve highly efficient, tumor-specific drug delivery and efficacious treatment of triple negative breast cancer and to improve the quality of the life and survival of the patients.