Targeted nanomedicine design for melanoma brain metastasis combining BRAF and MEK inhibitors

Cutaneous melanoma is the most lethal of all skin cancers due to its ability to metastasize to the liver, lungs, bones and brain. Brain metastases dramatically lower the prognosis with a median overall survival (OS) of 4 months¹. BRAF mutations occur at approximately 50% of the patients and are associated with enhanced cell proliferation and survival. FDA-approved Dabrafenib (DBF), a BRAF inhibitor (BRAFi), and Trametinib (TRM), a MEK inhibitor (MEKi), were shown to improve progression-free survival (PSF) and OS compared to standard chemotherapy. However, the effect was limited to about 5 months due to acquired resistance. In order to overcome resistance, a combination of MEKi with BRAFi was examined and demonstrated longer PFS. However, adverse events related to the combination of the two low molecular weight drugs reside². Nanomedicine can be harnessed to deliver the two drugs simultaneously to the tumor site enhancing their synergistic effect. Additionally, it can reduce adverse events through preferred extravasation-dependent accumulation at the tumor site. Nevertheless, as the enhanced permeability and retention phenomenon varies between both patient and tumor types, ligand-receptor-mediated nanoparticles (NPs) may improve NPs accumulation at the tumor site. We have developed a microfluidic method to prepare nano-sized Poly lactic-co-glycolic acid (PLGA) NPs loaded with DBF and TRM. In addition, as P-selectin was shown to be expressed on activated endothelial cells and on tumor cells³, PLGA carboxylic acid end groups were modified in order to target P-selectin and therefore enhance the internalization and accumulation of NPs on both compartments, the melanoma cells and the activated endothelial cells at the tumor site. The nano-sized (≈100 nm) NPs showed encapsulation efficacy of 60% and drug loading of 10% for DBF and 1% for TRM exerting the appropriate ratio for synergism. Our P-selectin-targeted NPs inhibited melanoma cell growth on our unique multicellular 3D melanoma spheroids in vitro models.

References:

1. Davies, M.A., et al. Cancer 117, 1687-1696 (2011).
2. Davies, M.A., et al. The Lancet Oncology 18, 863-873 (2017).
3. Ferber, S., et al. eLife 6(2017).