(283c) 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.