Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue
Abstract
Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell-layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10-100 μM) to pharmacological levels (>1 mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100 μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue.
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Subpopulations of KRAS or BRAF mutant colorectal cancer cells that survive pro-oxidant killing in vivo may remain sensitive to ascorbate via reduced HIF1 signalling and/or TET enzyme activation.
“For example, subpopulations of KRAS or BRAF mutant CRC cells that were not completely killed via the pro-oxidant mechanism in vivo — potentially owing to their distance from blood vessels, poor perfusion101 or resistance to ROS — may still be affected by ascorbate therapy via inhibition of HIF1 signalling and/or activation of TET enzymes.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [101]
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Self-citationPraditi, C., Bozonet, S. M., Dachs, G. U., & Vissers, M. C. M. (2023) · Antioxidants · doi:10.3390/antiox12111929 · Cited by 6 · see citing works
“Hypoxia may prolong the availability of ascorbate in a cell culture medium, as shown previously in ascorbate supplementation on HT29 cells [28].”
BackgroundInfluentialSelf-citationMathematical Model for Tissue-Level Hypoxic Response in Microfluidic Environment
Morshed, A. Z., & Dutta, P. (2017) · Journal of Biomechanical Engineering · doi:10.1115/1.4037915 · Cited by 5 · see citing works
“Ascorbate diffusivity in tissue 2:13 10 11 m(2)/s [20]”
BackgroundAscorbate and Tumor Cell Iron Metabolism: The Evolving Story and Its Link to Pathology
Bae, D.-H., Azad, M. G., Kalinowski, D. S., Lane, D. J. R., Jansson, P. J., & Richardson, D. R. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7903 · Cited by 6 · see citing works
“The delivery of Asc to poorly vascularized tumor tissue has been observed to be limited with normal dietary plasma Asc levels (10–100 l M ), using a three-dimensional cellular diffusion model (113).”
Is “Mega-Dose” IV Vitamin C Required for Septic and Critical Coronavirus Disease 2019 Patients?
Carr, A. C. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000004873 · Cited by 5 · see citing works
Burgess, E. R., Praditi, C., Phillips, E., Vissers, M. C. M., Robinson, B. A., Dachs, G. U., & Wiggins, G. A. R. (2024) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30658 · Cited by 4 · see citing works
“In contrast, we have previously proposed that high ‐ dose ascorbate infusions are required to overcome the perfusion and diffusion barriers of solid cancers [68], without the need for cytotoxicity.”
Self-citationAng, A. D., Vissers, M. C. M., Burgess, E. R., Currie, M. J., & Dachs, G. U. (2021) · Antioxidants · doi:10.3390/antiox10030430 · Cited by 3 · see citing works
“HIF activation is exacerbated when ascorbate availability is limited, and restricted access of ascorbate due to poor vascularity in solid tumours has been shown to be correlated with active HIF in tumour tissues [33–35].”
Self-citationAscorbic acid: still controversial when used against cancer resistance?
Islam, M. T. (2017) · Drugs & Therapy Perspectives · doi:10.1007/s40267-017-0475-x · Cited by 2 · see citing works
“[19] suggested that the distribution of AA in tumor tissue is heterogeneous, thus supraphysiological plasma AA concentrations ([ 100 lM) are required to achieve effective”
BackgroundVitamin C: Current Concepts in Human Physiology
Carr, A. C., & Natarajan, R. (2018) · MDPI eBooks · doi:10.3390/books978-3-03897-295-2 · Cited by 1 · see citing works
Kraft, K. (2023) · Zeitschrift für Komplementärmedizin · doi:10.1055/a-2119-9588 · Cited by 1 · see citing works
Akram, T., Luchtel, R. A., Dubey, V., Seal, S., Aggarwal, R. K., Sai, H., & Shenoy, N. K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.21.655101 · Cited by 1 · see citing works
Update 2021: Vitamin C und Zink bei COVID-19
Vollbracht, C., Friedrichsen, H.-P., & Gröber, U. (2021) · Zeitschrift für Orthomolekulare Medizin · doi:10.1055/a-1397-5441
“Nur durch Infusion lassen sich hohe Wirkspiegel im Blut und damit eine schnelle und effiziente Versorgung des Gewebes erreichen [11].”
Background
- Authors
- Kuiper, C., Vissers, M. C. M., & Hicks, K. O.
- Affiliations
- University of Otago (NZ)
- University of Auckland (NZ)
- Corresponding author
- Kuiper, Caroline
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 77
- Pages
- 340-352
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2014202252
- Cited by
- 45
- References
- 55
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 8 · 2020: 2 · 2019: 6 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 1
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- ResearchSpace (University of Auckland) (submittedVersion)
- Funders
- Bright Future Top Achiever Doctoral Scholarship by the Tertiary Education Commission, New Zealand
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- vitamin C, tissue diffusion, tumor hypoxia, solid tumors, paracellular transport, mannitol, 3D tissue models, pharmacokinetics, tumor vascularization, ascorbate uptake, intravenous infusion
- MeSH terms
- Ascorbic Acid, Biological Transport, Coenzymes, Diffusion, Humans, Kinetics, Mannitol, Models, Biological, Tissue Distribution, Urea, HT29 Cells
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