Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles improve treatment efficacy in a patient derived breast cancer xenograft

Markus Fusser, Anders Overbye, Abhilash D. Pandya, Ýrr Mørch, Sven Even Borgos, Wanja Kildal, Sofie Snipstad, Einar Sulheim, Karianne Giller Fleten, Hanne Arenberg Askautrud, Olav Engebraten, Kjersti Flatmark, Tore Geir Iversen, Kirsten Sandvig, Tore Skotland, Gunhild Mari Mælandsmo

Research output: Contribution to journalArticle

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Abstract

The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of free drug in the basal-like patient-derived xenograft and resulted in complete remission of 6 out of 8 tumors, whereas free drug gave complete remission only with 2 out of 9 tumors. To investigate the different efficacies obtained with nanoparticle-encapsulated versus free cabazitaxel, mass spectrometry quantification of cabazitaxel was performed in mice plasma and selected tissue samples. Nanoparticle-encapsulated drug had a longer circulation time in blood. There was approximately a three times higher drug concentration in tumor tissue 24 h after injection, and two times higher 96 h after injection of nanoparticles with drug compared to the free drug. The tissue biodistribution obtained after 24 h using mass spectrometry analyses correlates well with biodistribution data obtained using IVIS® Spectrum in vivo imaging of nanoparticles labeled with the fluorescent substance NR668, indicating that these data also are representative for the nanoparticle distribution. Furthermore, immunohistochemistry was used to estimate infiltration of macrophages into the tumor tissue following injection of nanoparticle-encapsulated and free cabazitaxel. The higher infiltration of anti-tumorigenic versus pro-tumorigenic macrophages in tumors treated with the nanoparticles might also contribute to the improved effect obtained with the nanoparticle-encapsulated drug. Tumor infiltration of pro-tumorigenic macrophages was four times lower when using nanoparticles containing cabazitaxel than when using particles without drug, and we speculate that the very good therapeutic efficacy obtained with our cabazitaxel-containing particles may be due to their ability to reduce the level of pro-tumorigenic macrophages in the tumor. In summary, encapsulation of cabazitaxel in poly(2-ethyl-butyl cyanoacrylate) nanoparticles seems promising for treatment of breast cancer.

Original languageEnglish (US)
Pages (from-to)183-192
Number of pages10
JournalJournal of Controlled Release
Volume293
DOIs
StatePublished - Jan 10 2019

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Cyanoacrylates
Heterografts
Nanoparticles
Breast Neoplasms
Pharmaceutical Preparations
Macrophages
Neoplasms
Injections
cabazitaxel
Mass Spectrometry
Blood Circulation Time
Adipose Tissue

Keywords

  • Biodistribution
  • Breast cancer
  • Cabazitaxel
  • Cell toxicity
  • Macrophage infiltration
  • Poly(alkyl cyanoacrylate) nanoparticles

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles improve treatment efficacy in a patient derived breast cancer xenograft. / Fusser, Markus; Overbye, Anders; Pandya, Abhilash D.; Mørch, Ýrr; Borgos, Sven Even; Kildal, Wanja; Snipstad, Sofie; Sulheim, Einar; Fleten, Karianne Giller; Askautrud, Hanne Arenberg; Engebraten, Olav; Flatmark, Kjersti; Iversen, Tore Geir; Sandvig, Kirsten; Skotland, Tore; Mælandsmo, Gunhild Mari.

In: Journal of Controlled Release, Vol. 293, 10.01.2019, p. 183-192.

Research output: Contribution to journalArticle

Fusser, Markus ; Overbye, Anders ; Pandya, Abhilash D. ; Mørch, Ýrr ; Borgos, Sven Even ; Kildal, Wanja ; Snipstad, Sofie ; Sulheim, Einar ; Fleten, Karianne Giller ; Askautrud, Hanne Arenberg ; Engebraten, Olav ; Flatmark, Kjersti ; Iversen, Tore Geir ; Sandvig, Kirsten ; Skotland, Tore ; Mælandsmo, Gunhild Mari. / Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles improve treatment efficacy in a patient derived breast cancer xenograft. In: Journal of Controlled Release. 2019 ; Vol. 293. pp. 183-192.
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AU - Sulheim, Einar

AU - Fleten, Karianne Giller

AU - Askautrud, Hanne Arenberg

AU - Engebraten, Olav

AU - Flatmark, Kjersti

AU - Iversen, Tore Geir

AU - Sandvig, Kirsten

AU - Skotland, Tore

AU - Mælandsmo, Gunhild Mari

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N2 - The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of free drug in the basal-like patient-derived xenograft and resulted in complete remission of 6 out of 8 tumors, whereas free drug gave complete remission only with 2 out of 9 tumors. To investigate the different efficacies obtained with nanoparticle-encapsulated versus free cabazitaxel, mass spectrometry quantification of cabazitaxel was performed in mice plasma and selected tissue samples. Nanoparticle-encapsulated drug had a longer circulation time in blood. There was approximately a three times higher drug concentration in tumor tissue 24 h after injection, and two times higher 96 h after injection of nanoparticles with drug compared to the free drug. The tissue biodistribution obtained after 24 h using mass spectrometry analyses correlates well with biodistribution data obtained using IVIS® Spectrum in vivo imaging of nanoparticles labeled with the fluorescent substance NR668, indicating that these data also are representative for the nanoparticle distribution. Furthermore, immunohistochemistry was used to estimate infiltration of macrophages into the tumor tissue following injection of nanoparticle-encapsulated and free cabazitaxel. The higher infiltration of anti-tumorigenic versus pro-tumorigenic macrophages in tumors treated with the nanoparticles might also contribute to the improved effect obtained with the nanoparticle-encapsulated drug. Tumor infiltration of pro-tumorigenic macrophages was four times lower when using nanoparticles containing cabazitaxel than when using particles without drug, and we speculate that the very good therapeutic efficacy obtained with our cabazitaxel-containing particles may be due to their ability to reduce the level of pro-tumorigenic macrophages in the tumor. In summary, encapsulation of cabazitaxel in poly(2-ethyl-butyl cyanoacrylate) nanoparticles seems promising for treatment of breast cancer.

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