Water Soluble Polymers to Target Tumor-Associated Extracellular Matrix for Delivery of MMP Inhibitors

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Project Summary/Abstract. Breast cancer is among the most frequently diagnosed cancers. It accounts for nearly a quarter of all cancer diagnoses worldwide every year. Metastasis typically occurs early in breast cancer, and it is the most significant cause of mortality. The current treatment and staging for breast cancer are based on the TNM prognostic markers: tumor size (T), presence of lymph nodes (N), and metastasis (M). Increasing evidence indicates that breast cancer development is correlated with significant changes in the extracellular matrix (ECM). An important change is the excess accumulation and deposition of collagen, termed desmoplasia, which results in increased linearity of fibrous protein in the tumor-associated ECM, as well as stiffening of the matrix. These changes are highly correlated with and, based on increasing evidence, causative of metastasis. A key player that is responsible for this restructuring of the ECM is matrix metalloproteinases (MMPs), a zinc-dependent family of proteases which break down proteins in the ECM. There have been efforts to therapeutically combat this propensity for metastasis through the use of MMP inhibitors as a form of cancer therapy. One highly promising investigational drug is Batimastat, an MMP inhibitor which progressed through Phases I, II, and III clinical trials, before being eliminated due to poor solubility and problematic routes of administration. The key limiting factor of Batimastat was in delivery. To improve this, this study proposes to develop a water-soluble polymer as a vehicle for delivery of Batimastat. N- (2-hydroxypropyl)methacrylamide (HPMA) copolymers are water soluble, non-toxic, non-immunogenic, multifunctional polymer platforms, which have been studied extensively for drug delivery. Collagen mimetic peptide (CMP) is collagen-resembling peptide that was rationally designed to bind to denatured collagen in the same hallmark triple helical form as endogenous collagen. As collagen is the most abundant protein in mammals and is the most concentrated molecule in the ECM, the presence of excessive denatured collagen in the remodeling tumor-associated ECM provides an excellent opportunity for tumor-selective targeting. We hypothesize that through the incorporation of CMP as a targeting moiety in the side chains of HPMA copolymers, we can improve the delivery and efficacy of the therapeutic, Batimastat as well as imaging agents. To test this hypothesis the following Specific Aims will be pursued:  1) to design and characterize a multifunctional HPMA-CMP conjugate with the ability to bind to tumor-associated ECM; 2) to characterize the ability of the polymer conjugate systems to modulate tumor cell migration and invasion, [collagen remodeling, and MMP activity] in vitro; and 3) to evaluate the ability of the polymer conjugate to accumulate in tumor regions and affect tumor growth [and metastasis].