2. Academic Validation
  3. Leveraging a rationally designed veliparib-based anilide eliciting anti-leukemic effects for the design of pH-responsive polymer nanoformulation

Leveraging a rationally designed veliparib-based anilide eliciting anti-leukemic effects for the design of pH-responsive polymer nanoformulation

  • Eur J Med Chem. 2024 May 17:273:116507. doi: 10.1016/j.ejmech.2024.116507.
Amandeep Thakur 1,  Yi-Hsuan Chu 2,  N Vijayakameswara Rao 3,  Jacob Mathew 3,  Ajmer Singh Grewal 4,  Prabhita Prabakaran 5,  Santosh Guru 6,  Jing Ping Liou 7,  Chun-Hsu Pan 8,  Kunal Nepali 9
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 2 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei City, 110, Taiwan.
  • 3 Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106335, Taiwan.
  • 4 Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Near Guru Nanak Khalsa College, Yamuna Nagar, 135001, Haryana, India.
  • 5 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore, India.
  • 6 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 8 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: panch@tmu.edu.tw.
  • 9 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: nepali@tmu.edu.tw.
PMID: 38776806 DOI: 10.1016/j.ejmech.2024.116507
Abstract

Careful recruitment of the components of the HDAC inhibitory template culminated in veliparib-based anilide 8 that elicited remarkable cell growth inhibitory effects against HL-60 cell lines mediated via dual modulation of PARP [(IC50 (PARP1) = 0.02 nM) and IC50 (PARP2) = 1 nM)] and HDACs (IC50 value = 0.05, 0.147 and 0.393 μM (HDAC1, 2 and 3). Compound 8 downregulated the expression levels of signatory biomarkers of PARP and HDAC inhibition. Also, compound 8 arrested the cell cycle at the G0/G1 phase and induced Autophagy. Polymer nanoformulation (mPEG-PCl copolymeric micelles loaded with compound 8) was prepared by the nanoprecipitation technique. The mPEG-PCL diblock copolymer was prepared by ring-opening polymerization method using stannous octoate as a catalyst. The morphology of the compound 8@mPEG-PCL was examined using TEM and the substance was determined to be monodispersed, spherical in form, and had an average diameter of 138 nm. The polymer nanoformulation manifested pH-sensitive behaviour as a greater release of compound 8 was observed at 6.2 pH as compared to 7.4 pH mimicking physiological settings. The aforementioned findings indicate that the acidic pH of the tumour microenvironment might stimulate the nanomedicine release which in turn can attenuate the off-target effects precedentially claimed to be associated with HDAC inhibitors.

Keywords

Anilides; Antitumor; Cancer; Cell cycle; HDAC inhibitors; Hydroxamic acid; Leukemia; PARP inhibitors; Scaffolds.

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