(230f) Engineering Multifunctional Nanoparticles for Overcoming Drug Resistance In Multiple Myeloma

Multiple myeloma (MM), a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow (BM), is the second most common type of blood cancer in the U.S. Despite the recent advances in treatment strategies and the emergence of novel therapies, it still remains incurable due to the development of drug resistance with a median survival of 4-5 years. A major factor that contributes to development of drug resistance in MM is the interaction of MM cells with the BM microenvironment. It has been demonstrated that the adhesion of MM cells to the BM stroma via α4β1 integrins leads to cell adhesion mediated drug resistance (CAM-DR), which enables MM cells to gain resistance to drugs such as doxorubicin (Dox)–a 1^st line chemotherapeutic in the treatment of MM. The overall objective of this proposed project is to engineer “smart” nanoparticles that will deliver and exert the cytotoxic effects of the chemotherapeutic agents on MM cells, and at the same time do it in such a manner to overcome CAM-DR for improved patient outcome. To enable this, we engineered micellar nanoparticles that are (i) functionalized with α4β1-antagonist peptides as well as Dox conjugates, and (ii) designed to show the adhesion inhibitory and the cytotoxic effects in a temporal sequence. When the nanoparticles are delivered to the MM cells, as a first step they interact with the cell surface α4β1 integrins and inhibit MM cell adhesion to the stroma, thereby preventing development of CAM-DR. In the second step, Dox exerts its cytotoxic effects after cellular uptake, as the nanoparticles will be designed to require a low pH environment such as the endocytic vesicles, to release active Dox. This way, the “smart” nanoparticles act on the MM cells in a temporal fashion and prevent development of CAM-DR for improved patient outcome.