Olaparib-Cediranib Hybrid as Dual PARP-VEGFR3 Inhibitor Elicits Antitumor Efficacy: Rational Design, Synthesis, Biological Evaluation and Construction of a Charge Convertible pH Responsive Nanoformulation

  • Bioorg Chem. 2025 Oct:165:109035. doi: 10.1016/j.bioorg.2025.109035.
Mandeep Rana  1 ,  N VijayKamasewara Rao  1 ,  Zih-Yao Yu  2 ,  Ram Sharma  1 ,  Jacob Mathew  3 ,  Yu-Wen Chen  2 ,  Sung-Bau Lee  2 ,  Ankush Bansode  4 ,  Tai-Ju Hsu  2 ,  Ajmer Singh Grewal  5 ,  Chun Hsu Pan  2 ,  Santosh Guru  4 ,  Kunal Nepali  6
Affiliations
  • 1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
  • 2. Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 3. Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan.
  • 4. Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
  • 5. Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Near Guru Nanak Khalsa College, Yamuna Nagar, 135001, Haryana, India.
  • 6. 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: [email protected].
PMID: 41056654 DOI: 10.1016/j.bioorg.2025.109035
Abstract

Tempted by the clinical outcomes attained with the combination of poly(ADP-ribose) polymerase (PARP) and vascular endothelial growth factor receptor (VEGFR) inhibitors, a compendium of dual PARP-VEGFR inhibitory assemblages based on structural commonalities of Olaparib (PARP Inhibitor) and Cediranib (VEGFR Inhibitor) was furnished. The aforementioned efforts culminated into a strikingly potent antitumor agent 18 exerting remarkable cell growth inhibitory effects [IC50 = 0.37 μM (HL60); 0.56 μM (A549); 0.80 μM (MDA-MB-231)] through a balanced inhibition of PARP and VEGFR. Specifically, 18 displayed magnificent PARP1, PARP2, and VEGFR3 inhibitory profiles with an IC50 value of 0.0763 nM, 0.0366 nM, and 4.25 nM, respectively. Further, a charge-convertible polymer-based nanoformulation (18-PEG-PLL/DMMA nanoparticles) for targeted drug delivery of 18 was developed. Encouragingly, the nanoformulation demonstrated a cytotoxicity-devoid profile towards normal cells owing to its pH-sensitive behavior and manifested selective cell growth inhibition against solid tumor cells, possibly due to the EPR effect.

Keywords
Leukemia; Lung cancer; Nanoformulation; PARP inhibitors; VEGFR inhibitors.
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