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    Contents lists available at ScienceDirect
    Journal of Controlled Release
    journal homepage:
    Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles PX-478 improve T treatment efficacy in a patient derived breast cancer xenograft
    Markus Fussera, Anders Øverbyeb,1, Abhilash D. Pandyaa,1, Ýrr Mørchc, Sven Even Borgosc, Wanja Kildald, Sofie Snipstadc,e, Einar Sulheimc,e, Karianne Giller Fletena,
    Hanne Arenberg Askautrudd, Olav Engebraatena,f, Kjersti Flatmarka,f, Tore Geir Iversenb, Kirsten Sandvigb,g, Tore Skotlandb, ,1, Gunhild M. Mælandsmoa,h,1 a Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway b Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway c Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim, Norway d Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway e Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway f Institute for Clinical Medicine, The Medical Faculty, University of Oslo, Oslo, Norway g Department of Biosciences, University of Oslo, Oslo, Norway h Department of Pharmacy, University of Tromsø, Tromsø, Norway
    Poly(alkyl cyanoacrylate) nanoparticles
    Breast cancer
    Macrophage infiltration
    Cell toxicity
    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 spec-trometry 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 ca-bazitaxel-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.
    Abbreviations: AUC, Area under the curve; CBZ, cabazitaxel; EPR, enhanced permeability and retention; i.v., intravenously; LC, liquid chromatography; LNs, lymph nodes; LOQ, limit of quantification; PACA, poly(alkyl cyanoacrylate); PBCA, poly(n-butyl cyanoacrylate); PDI, polydispersity index; PDX, patient-derived xenograft; PEBCA, poly(2-ethyl-butyl cyanoacrylate); PEG, polyethylene glycol; POCA, poly(octyl cyanoacrylate); MS, mass spectrometry; NPs, nanoparticles; TAMs, tumor-associated macrophages.