Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study: idarubicin dose selection, tissue response and survival

Nyman, Sofi Sennefelt; Åhlström, Håkan; Creusen, Angeliki Dimopoulou; Dahlgren, David; Hedeland, Mikael; Heindryckx, Femke; Johnson, Ulf; Khaled, Jaafar; Kullenberg, Fredrik; Nyman, Rickard; Rorsman, Fredrik; Sheikhi, Reza; Simonsson, Ulrika S. H.; Sjögren, Erik; Wanders, Alkwin; Lennernäs, Hans; Barbier, Charlotte

doi:10.1136/bmjopen-2022-065839

Cited by 2 publications

(1 citation statement)

References 32 publications

(63 reference statements)

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“…The combination of tumor cell uptake and in silico modelling will be an important tool to develop dose planning strategies for locoregional therapies, such as TACE in HCC, that aim to avoid strategies resulting in tumor tissue areas with sub-therapeutic drug exposure. For instance, such in vitro and in silico models are planned to be used in an on-going phase II study in patients with HCC as it is expected to improve the understanding of interactions between local pharmacology, tumor targeting, HCC pathophysiology, hypoxia, metabolomics and molecular mechanisms of drug resistance [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells

Degerstedt,

O’Callaghan,

Clavero

et al. 2023

Drug Deliv. and Transl. Res.

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Novel tumor-on-a-chip approaches are increasingly used to investigate tumor progression and potential treatment options. To improve the effect of any cancer treatment it is important to have an in depth understanding of drug diffusion, penetration through the tumor extracellular matrix and cellular uptake. In this study, we have developed a miniaturized chip where drug diffusion and cellular uptake in different hydrogel environments can be quantified at high resolution using live imaging. Diffusion of doxorubicin was reduced in a biomimetic hydrogel mimicking tissue properties of cirrhotic liver and early stage hepatocellular carcinoma (373 ± 108 µm2/s) as compared to an agarose gel (501 ± 77 µm2/s, p = 0.019). The diffusion was further lowered to 256 ± 30 µm2/s (p = 0.028) by preparing the biomimetic gel in cell media instead of phosphate buffered saline. The addition of liver tumor cells (Huh7 or HepG2) to the gel, at two different densities, did not significantly influence drug diffusion. Clinically relevant and quantifiable doxorubicin concentration gradients (1–20 µM) were established in the chip within one hour. Intracellular increases in doxorubicin fluorescence correlated with decreasing fluorescence of the DNA-binding stain Hoechst 33342 and based on the quantified intracellular uptake of doxorubicin an apparent cell permeability (9.00 ± 0.74 × 10–4 µm/s for HepG2) was determined. Finally, the data derived from the in vitro model were applied to a spatio-temporal tissue concentration model to evaluate the potential clinical impact of a cirrhotic extracellular matrix on doxorubicin diffusion and tumor cell uptake. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells

Degerstedt,

O’Callaghan,

Clavero

et al. 2023

Drug Deliv. and Transl. Res.

Self Cite

View full text Add to dashboard Cite

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Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells

Degerstedt

O’Callaghan

Clavero

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Novel tumor-on-a-chip approaches are increasingly used to investigate tumor progression and potential treatment options. To improve the effect of any cancer treatment it is important to have an in depth understanding of drug diffusion, penetration through the tumor extracellular matrix and cellular uptake. In this study, we have developed a miniaturized chip where drug diffusion and cellular uptake in different hydrogel environments can be quantified at high resolution using live imaging. Diffusion of doxorubicin was reduced in a biomimetic hydrogel mimicking tissue properties of cirrhotic liver and early stage hepatocellular carcinoma (373 ± 108 µm2/s) as compared to an agarose gel (501 ± 77 µm2/s, p = 0.019). The diffusion was further lowered to 256 ± 30 µm2/s (p = 0.028) by preparing the biomimetic gel in cell media instead of phosphate buffered saline. The addition of liver tumor cells (Huh7 or HepG2) to the gel, at two different densities, did not significantly influence drug diffusion. Clinically relevant and quantifiable doxorubicin concentration gradients (1–20 µM) were established in the chip within one hour. Intracellular increases in doxorubicin fluorescence correlated with decreasing fluorescence of the DNA-binding stain Hoechst 33342, and based on the quantified intracellular uptake of doxorubicin an apparent cell permeability (9.00 ± 0.74 x 10− 4 µm/s for HepG2) was determined. Finally, the data derived from the in vitro model were applied to a spatio-temporal tissue concentration model to evaluate the potential clinical impact of a cirrhotic extracellular matrix on doxorubicin diffusion and tumor cell uptake.

show abstract

Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study: idarubicin dose selection, tissue response and survival

Cited by 2 publications

References 32 publications

Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells

Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells

Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells

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