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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2024 Valsalakumari et al. This work is published and licensed by Dove Medical Press Limited.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.
Author(s): Valsalakumari R, Pandya AD, Prasmickaite L, Kvalvaag A, Myrann AG, Aslund AKO, Kjos MS, Fontecha-Cuenca C, Haroon HB, Ribeiro ARS, Horejs-Hoeck J, Moghimi SM, Morch Y, Skotland T, Sandvig K, Maelandsmo GM, Iversen TG
Publication type: Article
Publication status: Published
Journal: International Journal of Nanomedicine
Year: 2024
Volume: 2024
Issue: 19
Pages: 3009-3029
Online publication date: 26/03/2024
Acceptance date: 09/03/2024
Date deposited: 08/04/2024
ISSN (print): 1176-9114
ISSN (electronic): 1178-2013
Publisher: Dove Medical Press Ltd
URL: https://doi.org/10.2147/IJN.S450283
DOI: 10.2147/IJN.S450283
Data Access Statement: All data supporting the findings are shown in the paper and further queries can be directed to the corresponding author, if needed
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