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

Abstract

Remya Valsalakumari,1– 3 Abhilash D Pandya,3,* Lina Prasmickaite,3,* Audun Kvalvaag,1,2 Anne Grethe Myrann,1,2 Andreas KO Åslund,4 Marianne Steinsvik Kjos,4 Cristina Fontecha-Cuenca,5,6 Hajira B Haroon,5 Ana RS Ribeiro,7 Jutta Horejs-Hoeck,7,8 S Moein Moghimi,5,9,10 Ýrr Mørch,4 Tore Skotland,1,2 Kirsten Sandvig,1,2,11 Gunhild Mari Mælandsmo,3,12 Tore Geir Iversen1,2 1Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway; 2Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway; 3Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway; 4Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim, 7034, Norway; 5School of Pharmacy, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK; 6Department of Biomedical Science, University of Padova, Padova, Italy; 7Department of Biosciences and Medical Biology, Paris Lodron University Salzburg, Salzburg, 5020, Austria; 8Cancer Cluster Salzburg, Salzburg, 5020, Austria; 9Faculty of Health and Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; 10Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Center, Aurora, CO, USA; 11Department of Biosciences, University of Oslo, Oslo, 0316, Norway; 12Department of Medical Biology, University of Tromsø, Tromsø, 9019, Norway*These authors contributed equally to this workCorrespondence: Tore Geir Iversen, Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway, Tel [phone], Email [email protected]: 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. Keywords: poly(alkyl cyanoacrylate), cabazitaxel, breast cancer, patient-derived xenograft, tumor microenvironment

Keywords

• poly(alkyl cyanoacrylate)
• cabazitaxel
• breast cancer
• patient derived xenograft
• tumor microenvironment