Thiourea Modified Doxorubicin: A Perspective pH-Sensitive Prodrug

Area of Science:

• Medicinal Chemistry
• Drug Delivery
• Oncology

Background:

• Tumor microenvironments exhibit acidic pH, offering a target for selective drug delivery.
• Prodrug strategies aim to improve drug efficacy and reduce systemic toxicity.
• Thiourea modification offers a novel pathway for creating pH-sensitive drug conjugates.

Purpose of the Study:

• To develop and validate a novel thiourea-based prodrug strategy for pH-sensitive drug release.
• To synthesize dual prodrugs capable of releasing both a cytotoxic agent and a biologically active moiety.
• To evaluate the efficacy and cellular uptake of a doxorubicin prodrug in prostate cancer cells.

Main Methods:

• Acid-catalyzed cyclization of thioureas to 2-thiohydantoins.
• Synthesis of dual prodrugs using azidothymidine, doxorubicin, and albutoin.
• Förster Resonance Energy Transfer (FRET) model for concept validation.
• In vitro cytotoxicity assays on prostate cancer cells (PC3) at varying pH.
• Cellular and nuclear accumulation studies.

Main Results:

• The acid-catalyzed cyclization of thioureas to 2-thiohydantoins was successfully demonstrated.
• Dual prodrugs were synthesized, releasing active components in acidic conditions.
• The doxorubicin prodrug exhibited reduced cytotoxicity at neutral pH but comparable toxicity to free doxorubicin in acidic conditions.
• Significantly higher cellular and nuclear accumulation of the doxorubicin prodrug was observed in PC3 cells compared to free doxorubicin.

Conclusions:

• Thiourea modification is a viable strategy for developing pH-sensitive prodrugs.
• These prodrugs can selectively release therapeutic agents in the acidic tumor environment.
• The doxorubicin prodrug demonstrates improved tumor cell uptake, suggesting potential for enhanced therapeutic outcomes.