Rationally Engineered 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 the α₄β₁ integrin (a.k.a. Very Late Antigen-4, VLA-4) leads to cell adhesion mediated drug resistance (CAM-DR), which enables MM cells to gain resistance to drugs such as doxorubicin (Dox)–a 1st line chemotherapeutic in the treatment of MM.

In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4 antagonist peptides and Dox conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities, while Dox was conjugated to the nanoparticles through a hydrazone bond. When the nanoparticles are delivered to the MM cells, as a first step they interact with the cell surface VLA-4 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 are designed to require a low pH environment, such as the endocytic vesicles, to release active Dox.

Our studies have shown that the nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ~10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM.