A Water-Soluble Pro-Drug of Acetaminophen Has Increased Intracellular Delivery of Active Drug and Anti-Cancer Activity in Triple-Negative Breast Cancer and Pancreatic Ductal Adenocarcinoma
11 affiliations
- 1Department of Veterans Affairs, Richmond, VA 23249, USA
- 2Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA
- 3Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine, Suwanee, GA 30024, USA
- 4Department of Pharmacology, Toxicology and Therapeutics, University of Kansas, Kansas, KS 66160, USA
- 5Department of Microbiology and Immunology, VCU School of Medicine, Richmond, VA 23298, USA
- 6VCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
- 7Department of Pediatrics, VCU School of Medicine, Richmond, VA 23298, USA
- 8Department of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
- 9Department of Cellular, Molecular and Genetic Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- 10Department of Ophthalmology, Department of Biomedical Engineering, Department of Pediatrics, Center for Pharmaceutical Engineering, Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298, USA
- 11Department of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA 23298, USA
Abstract
Background/Objectives. Triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are two of the deadliest adult cancers. High-dose acetaminophen (AAP) has anti-cancer activity when given in conjunction with CYP2E1 inhibitors to block liver toxicity. However, the administration of high doses of AAP presents practical challenges stemming from limited water solubility, making it difficult to create a concentrated treatment solution in limited volume. Propacetamol (PROP) is a water-soluble AAP pro-drug that has been used clinically as an IV AAP formulation for analgesia. Methods. We sought to investigate the pharmacokinetics, safety and anti-cancer activity of PROP in comparison to AAP using transplantable syngeneic models of TNBC and PDAC. Results. In vivo, PROP was rapidly converted to AAP within minutes of administration. PROP demonstrated enhanced effectiveness in suppressing tumor growth in the TNBC and PDAC syngeneic murine tumor models compared to AAP. The enhanced efficacy of PROP appears to stem from increased cellular uptake, leading to intracellular AAP concentrations that are 2.7-fold higher within 5 min compared to cells treated with unmodified AAP. PROP demonstrated enhanced modulation of intracellular JAK/STAT signaling, a key mediator of AAP anti-cancer activity, using both murine and humanized models. STAT3 and STAT6 inhibition by PROP led to modulation of macrophage polarization, likely contributing to its anti-TNBC and anti-PDAC activity. While parenteral administration is the preferred route of administration for PROP in anti-cancer indications, we also evaluated the safety and efficacy of oral PROP in comparison to AAP. High-dose PROP demonstrated improved safety following oral administration compared to AAP in the BALB/c murine model while maintaining anti-cancer activity in vivo. Conclusions. PROP, an AAP pro-drug, demonstrates enhanced intracellular delivery of AAP and in vivo anti-cancer activity compared to unmodified AAP, setting the stage for investigation as an anti-cancer drug across different indications.
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BibTeX
@article{bryan2026watersoluble,
title = {{A Water-Soluble Pro-Drug of Acetaminophen Has Increased Intracellular Delivery of Active Drug and Anti-Cancer Activity in Triple-Negative Breast Cancer and Pancreatic Ductal Adenocarcinoma}},
author = {Allyn Bryan and Rudra Pangeni and Jephte Y. Akakpo and Alex Wendling and Madison Isbell and Rebecca K. Martin and George Weistroffer and Hartmut Jaeschke and Diane Ingabire and Won S. Lee and Anthony C. Faber and Stacey M. Bagby and Todd M. Pitts and Joseph Landry and Bhaumik Patel and Qingguo Xu and Alexander Neuwelt},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203390},
url = {https://www.mdpi.com/2072-6694/18/20/3390},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Water-Soluble Pro-Drug of Acetaminophen Has Increased Intracellular Delivery of Active Drug and Anti-Cancer Activity in Triple-Negative Breast Cancer and Pancreatic Ductal Adenocarcinoma
AU - Allyn Bryan
AU - Rudra Pangeni
AU - Jephte Y. Akakpo
AU - Alex Wendling
AU - Madison Isbell
AU - Rebecca K. Martin
AU - George Weistroffer
AU - Hartmut Jaeschke
AU - Diane Ingabire
AU - Won S. Lee
AU - Anthony C. Faber
AU - Stacey M. Bagby
AU - Todd M. Pitts
AU - Joseph Landry
AU - Bhaumik Patel
AU - Qingguo Xu
AU - Alexander Neuwelt
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203390
UR - https://www.mdpi.com/2072-6694/18/20/3390
AB - Background/Objectives. Triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are two of the deadliest adult cancers. High-dose acetaminophen (AAP) has anti-cancer activity when given in conjunction with CYP2E1 inhibitors to block liver toxicity. However, the administration of high doses of AAP presents practical challenges stemming from limited water solubility, making it difficult to create a concentrated treatment solution in limited volume. Propacetamol (PROP) is a water-soluble AAP pro-drug that has been used clinically as an IV AAP formulation for analgesia. Methods. We sought to investigate the pharmacokinetics, safety and anti-cancer activity of PROP in comparison to AAP using transplantable syngeneic models of TNBC and PDAC. Results. In vivo, PROP was rapidly converted to AAP within minutes of administration. PROP demonstrated enhanced effectiveness in suppressing tumor growth in the TNBC and PDAC syngeneic murine tumor models compared to AAP. The enhanced efficacy of PROP appears to stem from increased cellular uptake, leading to intracellular AAP concentrations that are 2.7-fold higher within 5 min compared to cells treated with unmodified AAP. PROP demonstrated enhanced modulation of intracellular JAK/STAT signaling, a key mediator of AAP anti-cancer activity, using both murine and humanized models. STAT3 and STAT6 inhibition by PROP led to modulation of macrophage polarization, likely contributing to its anti-TNBC and anti-PDAC activity. While parenteral administration is the preferred route of administration for PROP in anti-cancer indications, we also evaluated the safety and efficacy of oral PROP in comparison to AAP. High-dose PROP demonstrated improved safety following oral administration compared to AAP in the BALB/c murine model while maintaining anti-cancer activity in vivo. Conclusions. PROP, an AAP pro-drug, demonstrates enhanced intracellular delivery of AAP and in vivo anti-cancer activity compared to unmodified AAP, setting the stage for investigation as an anti-cancer drug across different indications.
SN - 2072-6694
ER -