Liposomal Vardenafil and Linagliptin Combined with Irinotecan for Synergistic Colorectal Cancer Therapy

  • Pharm Res. 2025 Jun;42(6):935-945. doi: 10.1007/s11095-025-03876-6.
Xian Zhao  #  1 ,  Ruijie Xu  #  2 ,  Yuanyuan Zhai  #  2 ,  Yi Wang  3 ,  Yuxin Zhang  4 ,  Yuan Tian  2 ,  Fengguo Xu  5 ,  Pei Zhang  6
Affiliations
  • 1. Department of Pharmacy, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, 210008, China.
  • 2. State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China.
  • 3. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
  • 4. Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, 210008, China.
  • 5. State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China. [email protected].
  • 6. State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China. [email protected].
  • # Contributed equally.
PMID: 40473893 DOI: 10.1007/s11095-025-03876-6
Abstract

Background: Irinotecan (CPT-11) is a standard first-line chemotherapy treatment for colorectal Cancer (CRC). However, its clinical application is often comprised by gastrointestinal toxicity and limited therapeutic efficacy. Our previous study has revealed that the combination of Vardenafil (Vard) and Linagliptin (Linag) significantly alleviated CPT-11-induced intestinal toxicity in both in vitro and in vivo models. It remains unclear whether this combination can synergistically enhance the Anticancer activity of CPT-11.

Methods: The in vitro synergism of Vard, Linag, and CPT-11 was assessed using cell viability assays on CRC cell lines, including HCT116, SW620, and HT29. An in vivo xenograft mouse model was established to evaluate the drug efficacy of both the original and liposomal forms of Vard and Linag combined with CPT-11. Additionally, untargeted metabolomics was utilized to explore the potential mechanisms underlying the observed synergistic effects.

Results: In vitro, the combination of Vard and Linag synergistically enhanced the Anticancer activity of CPT-11 in CRC cell lines. In vivo, liposomal formulations of Vard and Linag tended to accumulate at the tumor site, improving drug targeting and synergistically enhancing the Anticancer efficacy of CPT-11. Untargeted metabolomics analysis revealed that this synergistic effect was probably mediated through the regulation of lysophospholipid metabolism.

Conclusion: Liposomal Vard and Linag combined with CPT-11 demonstrated a synergistic anti-CRC effect, offering valuable insights into novel combination therapies in CRC treatment.

Keywords
Colorectal cancer; Linagliptin; Liposome; Synergistic effect; Vardenafil.
Products