| Description |
The extracellular matrix (ECM) is intricately involved in most aspects of cell life and survival. During tumorigenesis, tumor growth, and metastasis, there are extensive changes to the ECM which are correlated with and causative of tumor progression. This offers opportunities for both targeting and treatment of cancer. Strategies for tumor drug delivery of chemotherapeutics that target upregulated cell surface receptors, in order to improve site-specific activity and reduce off-target effects, are limited by most inter- and intra-tumor heterogeneity, as well as the need to traverse a dense stromal barrier. By targeting the tumor outside the tumor cells, this work sought to overcome these limitations. During tumor progression, there is an increased expression of ECM-degrading enzymes, which leads to an increased availability of denatured collagen. Capitalizing on this, this work focused on developing collagen-targeted copolymer-peptide conjugates which target tumors by binding to denatured collagen. The strategy employed water soluble N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to collagen hybridizing peptides (CHP). This body of work optimized the conjugates, characterized their collagen binding and folding properties, and demonstrated their tumor localization in three cancer models: breast cancer, osteosarcoma, and pancreatic ductal adenocarcinoma. Appendix A describes preliminary studies that optimized the HPMA copolymer- CHP conjugates (HPMA-CHP), which led to conjugates used in the main chapters of this dissertation. Chapter 1 provides a general introduction which broadly describes the purpose iv of this work. Chapter 2 provides a literature background on harnessing the ECM towards drug delivery and treatment strategy. Chapter 3 describes the synthesis and characterization of HPMA-CHP conjugates, their binding and folding properties, and their in vivo tumor localization in a murine model of breast cancer. Successful results in this breast cancer model led to expanding this to murine models of osteosarcoma (Chapter 4) and pancreatic ductal adenocarcinoma (Chapter 5). Chapter 6 summarizes the conclusions of this work and future directions. Appendices B, C, and D provide supplementary data to accompany these animal experiments. Lastly, the remaining appendices describe some of the simultaneous work in polymer conjugates that was conducted along with the main body of this dissertation. |
