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UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies

  • 0Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Molecules (basel, Switzerland) +

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February 24, 2024

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February 24, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Legubicin, a novel albumin-binding prodrug, shows promising anti-cancer potential. This study details its favorable pharmacokinetics and tumor distribution compared to doxorubicin.

Area Of Science

  • Pharmacology
  • Drug Development
  • Analytical Chemistry

Background

  • Legubicin is a novel prodrug of doxorubicin with albumin-binding and legumain-activating properties.
  • Understanding its in vivo behavior is crucial for its development as an anti-cancer therapeutic.

Purpose Of The Study

  • To develop and validate a UHPLC-MS/MS method for quantifying legubicin and its metabolites.
  • To investigate the in vivo pharmacokinetics and tissue distribution of legubicin in rats and tumor-bearing mice.
  • To compare legubicin's profile with doxorubicin.

Main Methods

  • A validated UHPLC-MS/MS method was used to determine legubicin, Leu-DOX, and DOX levels.
  • Analysis was performed in plasma, tumor, and tissue samples from rats and tumor-bearing mice.
  • Pharmacokinetic and tissue distribution studies were conducted following intravenous administration.

Main Results

  • The UHPLC-MS/MS method demonstrated excellent selectivity, sensitivity, recovery, and short run times.
  • Legubicin circulated primarily in a protein-bound form, exhibiting higher AUC, lower clearance, and reduced distribution.
  • Compared to doxorubicin, legubicin increased tumor drug exposure while decreasing cardiac and renal drug levels.

Conclusions

  • Legubicin exhibits favorable pharmacokinetic and tissue distribution profiles, with enhanced tumor targeting.
  • The developed UHPLC-MS/MS method is suitable for analyzing legubicin and its metabolites.
  • Legubicin shows potential as an effective anti-cancer drug candidate with an improved therapeutic index.

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