Abstract
Uncontrolled MAPK signaling is the main oncogenic driver in metastatic melanomas bearing mutations in BRAF kinase. These tumors are currently treated with the combination of BRAF/MEK inhibitors (MAPKi), but this therapy is plagued by drug resistance. In this context we recently discovered that several microRNAs are involved in the development of drug resistance. In particular miR-204-5p and miR-199b-5p were found to function as antagonists of resistance because their enforced overexpression is able to inhibit melanoma cell growth in vitro either alone or in combination with MAPKi. However, the use of miRNAs in therapy is hampered by their rapid degradation in serum and biological fluids, as well as by the poor intracellular uptake. Here, we developed lipid nanoparticles (LNPs) encapsulating miR-204-5p, miR-199b-5p individually or in combination. We obtained LNPs with mean diameters < 200 nm and high miRNA encapsulation efficiency. These formulations were tested in vitro on several melanoma cell lines sensitive to MAPKi or rendered drug resistant. Our results show that LNPs encapsulating combinations of the two oncosuppressor miRNAs are highly efficient in impairing melanoma cell proliferation and viability, affect key signaling pathways involved in melanoma cell survival, and potentiate the efficacy of drugs inhibiting BRAF and MEK. These results warrant further assessment of the anti-tumor efficacy of oncosuppressor miRNAs encapsulating LNPs in in vivo tumor models.
Highlights
Melanoma is the most severe malignant form of skin cancer and is characterized by high propensity to spread to other parts of the body [1]
lipid nanoparticles (LNPs) used in this study are characterized by a PEGylated lipid that is not present in the lipofectamine and that makes the nanoparticles stealth in the blood circulation
It is worthy of note that, in the case of LNP4, a mix of different miRNA sequences (50% miR-204-5p and 50% miR-199b-5p) was encapsulated, maintaining a very high miRNA loading
Summary
Melanoma is the most severe malignant form of skin cancer and is characterized by high propensity to spread to other parts of the body [1]. Targeted therapy was conceived following the discovery that about 50% of patients bear activating mutations in the BRAF oncogene in their tumors [4] For these patients BRAF and MEK inhibitors in combination have become the gold standard of first-line therapy because this approach showed superiority over monotherapy with BRAF inhibitor to contain the development of drug resistance and to improve time to recurrence and overall survival [5,6,7]. For BRAF wild-type melanomas, the therapeutic approach is the use of first-line therapy immune checkpoint inhibitors (ICI) with antibodies against PD-1/PD-L1, either alone or in combination with anti CTLA4 antibodies [8,9,10] Both targeted therapy and immunotherapy have improved metastatic melanoma patients’ survival, drug resistance, either innate or acquired, severely limits their efficacy [11,12,13]
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