Thermally Targeted Delivery of a c-Myc Inhibitory Peptide In Vivo Using Elastin-Like Polypeptide

摘要

Although surgical resection with adjuvant chemotherapy and/or radiotherapy are used to treat breast tumors, normal tissue tolerance, development of metastases, and inherent tumor resistance to radiation or chemotherapy can hinder a successful outcome. Therefore, it is necessary to consider alternative targeted therapeutic approaches for adjuvant therapy that would significantly reduce undesired side effects in normal tissues. This proposal describes a thermally responsive polypeptide (CPP-ELP-H1) that inhibits breast cancer cell proliferation by blocking the activity of the oncogenic protein c-Myc. The objective of the proposed research is to demonstrate that these genetically engineered polypeptides can be targeted to the tumor site by applying local hyperthermia and can inhibit tumor growth in an animal model. During the course of this training program, we have used fluorescently labeled polypeptides to demonstrate that thermal targeting can, in fact, be used to enhance the accumulation of an ELP-based c-Myc inhibitory polypeptide at the tumor site. We have defined the plasma clearance and biodistribution of the Bac-ELP1-H1 polypeptide, and we have used in vivo imaging to demonstrate tumor deposition and thermal targeting of the polypeptide in real time. We have also collected tumor reduction data using a lead c-Myc inhibitory polypeptide, and determined that treatment of mice with this polypeptide combined with thermal targeting resulted in a 70% inhibition of tumor volumes.