Faculty, Staff and Student Publications
Publication Date
1-3-2024
Journal
Molecular Therapy
Abstract
Metastatic melanoma poses significant challenges as a highly lethal disease. Despite the success of molecular targeting using BRAFV600E inhibitors (BRAFis) and immunotherapy, the emergence of early recurrence remains an issue and there is the need for novel therapeutic approaches. This study aimed at creating a targeted delivery system for the oncosuppressor microRNA 126 (miR126) and testing its effectiveness in combination with a phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor for treating metastatic melanoma resistant to BRAFis. To achieve this, we synthesized chitosan nanoparticles containing a chemically modified miR126 sequence. These nanoparticles were further functionalized with an antibody specific to the chondroitin sulfate proteoglycan 4 (CSPG4) melanoma marker. After evaluation in vitro, the efficacy of this treatment was evaluated through an in vivo experiment using mice bearing resistant human melanoma. The co-administration of miR126 and the PI3K/AKT inhibitor in these experiments significantly reduced tumor growth and inhibited the formation of liver and lung metastases. These results provide evidence for a strategy to target an oncosuppressive nucleic acid sequence to tumor cells while simultaneously protecting it from plasma degradation. The system described in this study exhibits encouraging potential for the effective treatment of therapy-resistant metastatic melanoma while also presenting a prospective approach for other forms of cancer.
Keywords
Humans, Animals, Mice, Melanoma, Proto-Oncogene Proteins c-akt, Phosphatidylinositol 3-Kinases, Signal Transduction, Cell Line, Tumor, Phosphoinositide-3 Kinase Inhibitors, MicroRNAs, nanoparticles; miR126; melanoma; PI3K/AKT inhibitors; anti-CSPG4, drug resistance; metastasis; dabrafenib; microRNAs; chitosan
DOI
10.1016/j.ymthe.2023.11.021
PMID
37990493
PMCID
PMC10787166
PubMedCentral® Posted Date
11-21-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Nanotechnology Commons, Oncology Commons