Development of dual arv-825 and nintedanib-loaded pegylated nano-liposomes for synergistic efficacy in vemurafnib-resistant melanoma

Yige Fu, Aishwarya Saraswat, Zenghui Wei, Manas Yogendra Agrawal, Vikas V. Dukhande, Sandra E. Reznik, Ketan Patel

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number1005
JournalPharmaceutics
Volume13
Issue number7
DOIs
StatePublished - Jul 2021
Externally publishedYes

Keywords

  • ARV-825
  • Combination therapy
  • Nintedanib
  • PEGylated nanoliposomes
  • Proteolysis targeting chimera
  • Synergistic interaction
  • Vemurafenib-resistant melanoma

ASJC Scopus subject areas

  • Pharmaceutical Science

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