Preclinical Efficacy of Cabazitaxel Loaded Poly(2-alkyl cyanoacrylate) Nanoparticle Variants.

Autor:	Valsalakumari R; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway.; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway., Pandya AD; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway., Prasmickaite L; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway., Kvalvaag A; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway., Myrann AG; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway., Åslund AKO; Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim, 7034, Norway., Kjos MS; Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim, 7034, Norway., Fontecha-Cuenca C; School of Pharmacy, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.; Department of Biomedical Science, University of Padova, Padova, Italy., Haroon HB; School of Pharmacy, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK., Ribeiro ARS; Department of Biosciences and Medical Biology, Paris Lodron University Salzburg, Salzburg, 5020, Austria., Horejs-Hoeck J; Department of Biosciences and Medical Biology, Paris Lodron University Salzburg, Salzburg, 5020, Austria.; Cancer Cluster Salzburg, Salzburg, 5020, Austria., Moghimi SM; School of Pharmacy, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.; Faculty of Health and Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Center, Aurora, CO, USA., Mørch Ý; Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim, 7034, Norway., Skotland T; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway., Sandvig K; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway.; Department of Biosciences, University of Oslo, Oslo, 0316, Norway., Mælandsmo GM; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Department of Medical Biology, University of Tromsø, Tromsø, 9019, Norway., Iversen TG; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway.
Jazyk:	angličtina
Zdroj:	International journal of nanomedicine [Int J Nanomedicine] 2024 Mar 26; Vol. 19, pp. 3009-3029. Date of Electronic Publication: 2024 Mar 26 (Print Publication: 2024).
DOI:	10.2147/IJN.S450283
Abstrakt:	Background: Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect. Methods: Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry. Results: In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment. Conclusion: We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response. Competing Interests: Dr Ýrr Mørch reports NaDeNo Nanoscience is a SINTEF-spin off established in 2022 commercializing PACA-encapsulated cabazitaxel nanoparticles (currently in pre-clinical phase). In addition, Dr Ýrr Mørch has a patent WO 2014/191502 issued to NaDeNo Nanoscience AS, a patent WO 2019/185685 pending to NaDeNo Nanoscience AS. The authors declare that they have no other competing interests. (© 2024 Valsalakumari et al.)
Databáze:	MEDLINE
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