Mix-and-match nanodendrons for detection and treatment of breast cancer metastases
Scherer, Randy Lee Ray
INTERDISCIPLINARY MATERIALS SCIENCE MIX-AND-MATCH NANODENDRONS FOR DETECTION AND TREATMENT OF BREAST CANCER METASTASES RANDY LEE RAY SCHERER Dissertation under the direction of Professor Lynn M. Matrisian This project used nanotechnology to develop imaging and treatment agents for cancer. There is an overwhelming need to selectively identify and eliminate small clusters of abnormal cells to reduce early mortality due to metastatic disease. In this dissertation, new nanomaterials that utilize matrix metalloproteinases (MMPs), in particular MMP7 and MMP9, to sensitively and selectively detect tumors using optical imaging and target therapeutics to tumor sites using a prodrug design were described. MMPs play essential roles in many aspects of biology, including cell proliferation, differentiation, apoptosis, and migration through degradation of both matrix and non-matrix substrates. These processing enzymes have clear links to cancer and tumor progression, in which proteolysis of the extracellular matrix is required to accommodate increased growth, migration, and invasion of tumor cells. We focused on designing polymer-based agents to image MMP activity in murine models of cancer, and created a prodrug version of Paclitaxel to improve delivery and reduce the toxic side effects of this chemotherapeutic. We developed two generations of proteolytic optical beacon nanoreagents. The first targeted MMP7 in models of human colon cancer. The initial beacon, PB-M7NIR, was the first dendrimeric near-infrared fluorescent probe designed for the in vivo detection and imaging of MMP7 activity. Intravenous administration of PB-M7NIR allowed for the selective visualization and localization of MMP7 activity in whole animals and in tissue sections and was sensitive enough to detect tumors 1mm in diameter. The second beacon, NDPB, was the first near-infrared dendron probe designed to detect MMP9 activity in vivo. This beacon was capable of selectively imaging MMP9 activity in mouse models of human breast cancer, and was successfully linked together with the prodrug Paclitaxel dendron to image delivery of therapy. The prodrug Paclitaxel dendron performed better than albumin-conjugated paclitaxel (Abraxane) therapy in a mouse model of breast cancer and indicated a trend towards reducing peripheral neuropathic side-effects of Paclitaxel. Studies performed in this dissertation provided proof-of-principle approaches to further the development of personalized medicine by allowing simultaneous delivery and optical monitoring of prodrug delivery using techniques that can be modified for translation into humans.