Bioactive polymer-peptide conjugates to attenuate inflammation and metastatic outgrowth of cancer

Metastasis is one of the major causes of cancer-related death, primarily due to the lack of effective therapeutics to prevent metastatic spread of cancer. In our research, we develop novel polymer conjugates based on an N-(hydroxypropyl)methacrylamide (HPMA) copolymer backbone and multiple copies of short peptides for targeting strategic molecules in the tumor microenvironment (TME) that supports the arrest, retention, transmigration and the metastatic outgrowth of cancer. Previously, we showed that targeting pathologically activated vascular endothelium for the delivery of drugs (Doxorubicin or proapoptotic peptide) prolongs the survival of mice with established melanoma lung metastases. Recently we demonstrated that a polymer that can target endothelial cell adhesion molecules (i.e., E-selectin) is biologically active without any drug attached and can control cancer cells dissemination to common sites of metastatic spread (e.g., lungs, liver, bones) in several tumor-bearing mice models. This approach was further shown to decrease excessive recruitment of leukocytes to sites of chronic inflammation (atherosclerosis, liver injury) in mice. Targeting cancer cell surface receptors (i.e., CD44) with a bioactive copolymer was also recognized as a strategy to control the invasion of cancer cells and inhibited breast cancer cells migration and colonization in the lungs of mice. While this work is still in progress, the approach of using “drug free” macromolecular therapeutics might depict a safe and specific treatment to modify the growth-supportive tumor microenvironment and offers great promise for the management of cancer and inflammation.