Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma

Abstract

A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A modified hydration method with citric acid was used to improve the loading of both the molecules in liposomes. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency for both the drugs and was found to be physically stable for a month at 4 °C. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and down-regulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroids with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma.

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

“…In antiretroviral drug-loaded PEG-polylactic-co-glycolic acid polymer nanoparticles in pancreatic cancer two-dimensional cell culture and three-dimensional multicellular tumor spheroids, the model can continue to explain that BRD4 shows a good anticancer effect and can effectively treat pancreatic cancer [ 46 ]. Experimental results have also shown excellent synergistic effects of dual ARV-825 and nintedanib-loaded PEGylated nanoliposomes in melanoma, providing a new approach for the treatment of vemurafenib-resistant melanoma [ 47 ]. Experiments with ARV-825-loaded nanoliposomes in lung cancer and hepatocellular carcinoma have shown that nano-fusion leads to better tumor penetration and lethality [ 48 , 49 ].…”

Research Trend and Detailed Insights into the Molecular Mechanisms of Food Bioactive Compounds against Cancer: A Comprehensive Review with Special Emphasis on Probiotics

“…Researchers have been trying to develop novel drug delivery systems to improve the site-specific targeting of the bioactive compounds along with their enhanced efficacy. The use of nanotechnology and thus nanoformulations has been extensively explored [ 256 , 257 , 258 , 259 ]. Below are a few examples of novel drug delivery methods to enhance the efficacy of phytocompounds.…”

Nintedanib‐αVβ3 Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma

“…Remarkably, several recent studies on melanoma treatment have demonstrated that the efficacy of MAPK‐targeting therapies, [16,17] and immunotherapies [18] are significantly improved by the co‐administration of nintedanib, thus emphasizing the role of this small molecule in TME normalization.…”

“…[14] Nintedanib, a small-molecule tyrosine kinase inhibitor, clinically approved as an antifibrotic drug, inhibits the accumulation and activation of fibroblasts so too their transition into myofibroblasts, as well as the deposition of the ECM. [15] Remarkably, several recent studies on melanoma treatment have demonstrated that the efficacy of MAPK-targeting therapies, [16,17] and immunotherapies [18] are significantly improved by the co-administration of nintedanib, thus emphasizing the role of this small molecule in TME normalization.…”