An Acrolein-Based Drug Delivery System Enables Tumor-Specific Sphingosine-1-Phosphate Targeting in Breast Cancer without Lymphocytopenia

PMCID: PMC12174973

PMID: 40528704

DOI: 10.1158/2767-9764.CRC-25-0023

Journal: Cancer research communications

Publication Date: 2025-6

Authors: Nagahashi M, Komatsu M, Urano S, Kuroiwa M, Takahashi Y, et al.

Key Points

• Pro-FTY selectively targets and inhibits breast cancer cells, including multidrug-resistant variants, using an acrolein-responsive drug delivery system
• Demonstrated 100% inhibition across 10 breast cancer cell lines, with IC50 values consistently between 10-30 μmol/L
• Offers a promising therapeutic strategy that maintains anti-cancer efficacy while avoiding lymphocytopenia and systemic immunosuppression

Summary

This preclinical study introduces a novel prodrug (pro-FTY) targeting sphingosine-1-phosphate (S1P) signaling in breast cancer, addressing a critical challenge of drug resistance and treatment-related immunosuppression. By developing a drug delivery system that specifically reacts with acrolein—a molecule overexpressed in cancer cells—researchers created a targeted therapy that inhibits cancer cell survival while avoiding lymphocytopenia, a significant limitation of current S1P-targeted treatments.

The research demonstrated pro-FTY's remarkable efficacy across multiple breast cancer cell lines, including multidrug-resistant variants, through comprehensive in vitro and in vivo experiments. Notably, the prodrug consistently inhibited cancer cell growth without affecting normal breast cells, and intravenous administration in mouse models significantly suppressed tumor growth. Mass spectrometry revealed selective drug activation within tumor tissues, with minimal systemic exposure, suggesting a potentially transformative approach to cancer treatment that minimizes adverse effects.