Molecular pharmacokinetic mechanism of quercetin-encapsulated polymeric micelles in alleviating cisplatin-induced nephrotoxicity and enhancing antineoplastic effects

Tangna Hao; Xiaokui Huo; Zhen Li; Changyuan Wang; Sha Wu; Anni Song; Fengyu Zhang; Kexin Liu

doi:10.3389/fphar.2025.1590688

Molecular pharmacokinetic mechanism of quercetin-encapsulated polymeric micelles in alleviating cisplatin-induced nephrotoxicity and enhancing antineoplastic effects

Front Pharmacol. 2025 Jun 9:16:1590688. doi: 10.3389/fphar.2025.1590688. eCollection 2025.

Authors

Tangna Hao^{1

2

3}, Xiaokui Huo⁴, Zhen Li⁵, Changyuan Wang^{2

6}, Sha Wu³, Anni Song³, Fengyu Zhang³, Kexin Liu^{1

2

6}

Affiliations

¹ Institute of Integrative Medicine, Dalian Medical University, Dalian, China.
² Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China.
³ Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
⁴ Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China.
⁵ College of Pharmacy, Dalian Medical University, Dalian, China.
⁶ Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.

Abstract

Introduction: Cisplatin (DDP), a platinum-based chemotherapy drug, shows broad antineoplastic activity, however, its clinical use is limited by dose-dependent nephrotoxicity, a major challenge in cancer therapy. The purpose of this study was to investigate the mechanism by which quercetin-polyethylene glycol-polycaprolactone (Que-PEG-PCL) micelles simultaneously enhance the cytotoxicity of DDP against cancer cells and reduce its nephrotoxicity.

Methods: Rodent models and HEK293 cells were used to evaluate the renoprotective effects of Que-PEG-PCL micelles. Pharmacokinetics focused on OCT2-mediated renal DDP disposition. Antitumor activity was assessed in CT26 cells and syngeneic tumors. Key assessments included oxidative stress, apoptosis, renal markers, and histopathology.

Results: Que-PEG-PCL reduced DDP-induced nephrotoxicity, lowering creatinine and BUN to 42% and 38%. It also reduced oxidative stress and improved antioxidant activity. DDP plasma exposure increased to 323%, with renal clearance reduced to 14%, due to OCT2 inhibition. In a CT26 syngeneic model, combination therapy inhibited tumor volume by 84% compared to control group.

Discussion: Que-PEG-PCL enhanced DDP's therapeutic window by limiting renal accumulation and promoting tumor cell apoptosis. This dual-action strategy provides a novel approach for improving the clinical efficacy of DDP-based cancer therapy.

Keywords: antitumor potency; cisplatin; nephrotoxicity; polymeric micelles; quercetin.