Despite advances in targeted drug delivery, one of the continuing problems in cancer therapy is the localization of the chemotherapeutic agent at the tumor site, in addition to monitoring the size and location of the tumor. To date these data have been inferred from indirect methods such as distribution studies in animal models and reduction in tumor size. Concurrent monitoring of the distribution of the delivery system and its role in reduction of tumor mass will be of prime interest in future advances in cancer treatment. To overcome this limitation, it is proposed in this small grant to develop polymer-directed nitroxides as selective MR contrast agents for tumor imaging. Upon preparation of polymer-directed nitroxides, efficacy of these compounds will be determined, measuring uptake in rabbit tumors by MRI. Specifically, we will synthesize and characterize a series of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer linked-nitroxides and HPMA copolymer linked-nitroxide biradicals. Nitroxides will be attached to the copolymer backbone via a non-biodegradable glycyl-glycine spacer. These compounds will be characterized by physicochemical methods to determine their average molecular weight, molecular weight distribution, and number of nitroxides attached, stability and relaxivity. Once completed, we will determine the ability of HPMA copolymer linkednitroxides and HPMA copolymer linked-nitroxide biradicals to be taken up by a tumor in a rabbit model. VX2 tumor cells will be implanted into the rabbit thigh muscle and MRI imaging experiments performed, when the tumor has reached the size of 5-10 ram. Results from these studies will pave the way for the development of novel HPMA copolymer-linked nitroxides for MR imaging of solid tumors and concurrent monitoring of targeted cancer chemotherapy.
