(64c) Targeted Nanocarriers for the Delivery of Novel Metastatic Melanoma Chemotherapeutics

There are currently two major problems with treating metastatic melanoma. First, it is difficult to deliver a therapeutic concentration of traditional chemotherapeutics without lethal side effects on the patient. The second problem is that there is a large void in the knowledge of genetic mutations that contribute to the disease state which has led to a paucity of targeted chemotherapeutics for metastatic melanoma. This work proposes a potential therapeutic solution that acknowledges both of these issues.

The first task was to identify a target that was specific to metastatic melanoma cells. A significant fraction of metastatic melanomas express gain-of-function mutations in the ErbB4 receptor tyrosine kinase. In previous work, our lab has shown that mutant versions of naturally-occurring ligands for ErbB4 function as partial agonists at ErbB4. The partial agonists stimulate ErbB4 tyrosine phosphorylation, fail to stimulate ErbB4 coupling to cellular proliferation, and inhibit agonist induced ErbB4 coupling to cellular proliferation. The discovery of these partial agonists led to the development of a series of high throughput screening assays to screen a library of small molecules that would potentially function as partial agonists at ErbB4. A sandwich-ELISA (Enzyme Linked Immunosorbent Assay) was developed to identify molecules that stimulate ErbB4 tyrosine phosphorylation. An MTT proliferation assay was used in the development of assays to identify molecules that fail to stimulate ErbB4 coupling and to identify molecules that inhibit agonist induced ErbB4 coupling. The top candidate molecules identified from the screening assays were used to coat the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles that contain traditional metastatic melanoma chemotherapeutics. In vitro studies were performed to determine the targeting abilities of these partial agonist coated nanoparticles, as well as, whether the partial agonists retained their functionality once bound to the surface of the PLGA nanoparticles.