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Hepatic arterial infusion with nanoliposomal irinotecan leads to significant regression of tumor size of colorectal liver metastases in a CC531 rat model

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Abstract

Long-term therapy for unresectable colorectal liver metastases remains challenging. Intraarterial treatments aim to avoid systemic adverse effects of chemotherapy. Nanoliposomal cytotoxic drugs manage to increase the drug concentration within the tumor while reducing toxicity in healthy tissue.  In this study we analyzed the effect of hepatic arterial infusion (HAI) with nanoliposomal irinotecan with or without the combination of embolization particles in a rat model for colorectal liver metastases. For the study 32 WAG/Rij rats received subcapsular tumor implantation with CC531 rat colonic adenocarcinoma cells. After ten days tumor size was assessed via ultrasound and animals underwent HAI. One group served as control receiving NaCl 0.9 % (Sham), the three treatment groups received either nanoliposomal irinotecan (HAI nal iri), Embocept® S (HAI Embo) or Embocept® S and nanoliposomal irinotecan (HAI Embo+nal iri). Three days after treatment animals were sacrificed after assessment of tumor size. As a result all treatment groups showed a significant reduction in tumor growth compared to Sham (p<0.05). Expression of the apoptosis marker caspase-3 was enhanced in HAI nal iri and HAI Embo+nal iri compared to Sham and HAI Embo and  even significantly enhanced after HAI Embo+nal iri in comparison to Sham (p<0.05). We were able to show that HAI with Embocept® S led to significantly reduced tumor growth while HAI with nanoliposomal irinotecan alone or in combination with Embocept® S even led to a reduction of tumor size. Thus, we demonstrate that intraarterial treatment with nanoliposomal irinotecan effectively inhibits tumor growth in a rat model of colorectal liver metastases and demands further investigation.

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Acknowledgements

The authors thank Birgit Jünemann who helped establishing the immunohistochemistry staining.

Funding

AK’s salary during the time of the study and part of the study itself was funded by the Else Kröner-Fresenius-Stiftung (EKFS), Bad Homburg v.d.H, Germany, due to a scholarship.

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Authors and Affiliations

  1. Department of General, Visceral and Pediatric Surgery, University Medical Center, Goettingen, Germany

    Anne Kauffels, Hannah Nowack, Melanie Spitzner, Thilo Sprenger, Michael Ghadimi & Jens Sperling

  2. Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital of Giessen, Rudolf-Buchheim-Str. 7, D-35292, Giessen, Germany

    Anne Kauffels & Thilo Sprenger

  3. Department of Internal Medicine, Asklepios Hospital, Schwalmstadt, Germany

    Hannah Nowack

  4. Institute of Pathology, University Medical Center, Goettingen, Germany

    Hanibal Bohnenberger

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Contributions

AK and JS are responsible for the study design and wrote the manuscript. AK carried out the animal experiments. HN and HB established and evaluated the immunohistochemistry staining and helped write the manuscript. HN carried out immunohistochemistry staining. MS carried out statistical analyses with professional support of the Department of Medical Statistics, designed the figures and helped write the manuscript. TS and MG helped write the mansucript and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Anne Kauffels.

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Ethics approval

All animal experiments were approved by the regional legislation on animal protection (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit) and was given the ethics approval number 14/1610.

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The manuscript does not contain any person’s data in any form.

Conflict of interest

AK’s salary during the time of the study was funded by the Else Kröner-Fresenius-Stiftung (EKFS), Bad Homburg v.d.H, Germany, due to a scholarship. All other authors declare no potential conflict of interest.

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Anne Kauffels-Sprenger and Hannah Nowack contributed equally.

Electronic supplementary material

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10585_2023_10209_MOESM1_ESM.jpg

Supplementary Material 1: Sup Fig. 1 (A) Hepatocellular vacuolisation score 0, HAI with nanaoliposomal irinotecan (HAI nal iri); (B) Hepatocellular vacuolisation score 3, HAI with nanoliposomal irinotecan and EmboCept® S (HAI nal iri + Embo); (C) Cytoplasmic clodding score 0, HAI with EmboCept® S (HAI Embo); (D) Cytoplasmic clodding score 3, HAI with EmboCept® S (HAI Embo).

10585_2023_10209_MOESM2_ESM.jpg

Supplementary Material 2: Sup Fig. 2 Data an representative examples of immunohistochemical analyses of tumor tissue of animals undergoing (A) HAI with NaCl 0.9% (Sham), (B) HAI with nanoliposomal irinotecan (HAI nal iri), (C) HAI with EmboCept® S (HAI Embo), or (D) HAI with nanoliposomal irinotecan and EmboCept® S (HAI nal iri + Embo). Images and data analyses of proliferating nuclear cell antibody (score 0 ≤ 1%, 1 = 1–10%, 2 = 10–30%, 3 = 30–50%, 4 ≥ 50% of PCNA-positive cells). Images and data analyses of caspase-3-positive cells (given as number per HPF). Images and data analyses of yH2AX-positive cells (given as number per HPF). Images and data analyses of PECAM positive vessels (given as number per HPF). Images and data analyses of HIF-1α positive cells (score 0 ≤ 1%, 1 = 1–5%, 2 = 5–10%, 3 = 10–50%, 4 > 50% of HIF-1α-positive cells or cytoplasmatic staining). Mean ± SEM; * p < 0.05 versus Sham.

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Kauffels, A., Nowack, H., Bohnenberger, H. et al. Hepatic arterial infusion with nanoliposomal irinotecan leads to significant regression of tumor size of colorectal liver metastases in a CC531 rat model. Clin Exp Metastasis 40, 235–242 (2023). https://doi.org/10.1007/s10585-023-10209-7

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