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

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2024 Apr 2

PMID 38562610

Authors

Remya Valsalakumari

Abhilash D Pandya

Lina Prasmickaite

Audun Kvalvaag

Anne Grethe Myrann

Andreas K O Aslund

Marianne Steinsvik Kjos

Cristina Fontecha-Cuenca

Hajira B Haroon

Ana R S Ribeiro

Jutta Horejs-Hoeck

S Moein Moghimi

Yrr Morch

Tore Skotland

Kirsten Sandvig

Gunhild Mari Maelandsmo

Tore Geir Iversen

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Entry of nanoparticles into cells and tissues: status and challenges.

Sandvig K, Iversen T, Skotland T Beilstein J Nanotechnol. 2024; 15:1017-1029.

PMID: 39161463 PMC: 11331539. DOI: 10.3762/bjnano.15.83.

References

Valsalakumari R, Yadava S, Szwed M, Pandya A, Maelandsmo G, Torgersen M . Mechanism of cellular uptake and cytotoxicity of paclitaxel loaded lipid nanocapsules in breast cancer cells. Int J Pharm. 2021; 597:120217. DOI: 10.1016/j.ijpharm.2021.120217. View

Bahl A, Wilson W, Ball J, Renninson E, Dubey S, Bravo A . Concept: A randomised multicentre trial of first line chemotherapy comparing three weekly cabazitaxel versus weekly paclitaxel in HER2 negative metastatic breast cancer. Breast. 2022; 66:69-76. PMC: 9530955. DOI: 10.1016/j.breast.2022.09.005. View

Menjivar R, Nwosu Z, Du W, Donahue K, Hong H, Espinoza C . Arginase 1 is a key driver of immune suppression in pancreatic cancer. Elife. 2023; 12. PMC: 10260021. DOI: 10.7554/eLife.80721. View

Reichel D, Tripathi M, Perez J . Biological Effects of Nanoparticles on Macrophage Polarization in the Tumor Microenvironment. Nanotheranostics. 2019; 3(1):66-88. PMC: 6328304. DOI: 10.7150/ntno.30052. View

Fumoleau P, Trigo J, Isambert N, Semiond D, Gupta S, Campone M . Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours. BMC Cancer. 2013; 13:460. PMC: 3854123. DOI: 10.1186/1471-2407-13-460. View

Wu L, Ficker M, Christensen J, Simberg D, Trohopoulos P, Moghimi S . Dendrimer end-terminal motif-dependent evasion of human complement and complement activation through IgM hitchhiking. Nat Commun. 2021; 12(1):4858. PMC: 8357934. DOI: 10.1038/s41467-021-24960-6. View

Fusser M, Overbye A, Pandya A, Morch Y, Borgos S, Kildal W . Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles improve treatment efficacy in a patient derived breast cancer xenograft. J Control Release. 2018; 293:183-192. DOI: 10.1016/j.jconrel.2018.11.029. View

Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P . A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res. 2007; 13(13):3989-98. DOI: 10.1158/1078-0432.CCR-07-0078. View

Youn Y, Bae Y . Perspectives on the past, present, and future of cancer nanomedicine. Adv Drug Deliv Rev. 2018; 130:3-11. DOI: 10.1016/j.addr.2018.05.008. View

10.

Schwarz H, Gornicec J, Neuper T, Parigiani M, Wallner M, Duschl A . Biological Activity of Masked Endotoxin. Sci Rep. 2017; 7:44750. PMC: 5357793. DOI: 10.1038/srep44750. View

11.

Michelini S, Barbero F, Prinelli A, Steiner P, Weiss R, Verwanger T . Gold nanoparticles (AuNPs) impair LPS-driven immune responses by promoting a tolerogenic-like dendritic cell phenotype with altered endosomal structures. Nanoscale. 2021; 13(16):7648-7666. PMC: 8087175. DOI: 10.1039/d0nr09153g. View

12.

Liu Q, Yang C, Wang S, Shi D, Wei C, Song J . Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. Cell Commun Signal. 2020; 18(1):51. PMC: 7106599. DOI: 10.1186/s12964-020-00557-2. View

13.

Steggerda S, Bennett M, Chen J, Emberley E, Huang T, Janes J . Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer. 2017; 5(1):101. PMC: 5735564. DOI: 10.1186/s40425-017-0308-4. View

14.

Bergamaschi A, Hjortland G, Triulzi T, Sorlie T, Johnsen H, Ree A . Molecular profiling and characterization of luminal-like and basal-like in vivo breast cancer xenograft models. Mol Oncol. 2009; 3(5-6):469-82. PMC: 5527532. DOI: 10.1016/j.molonc.2009.07.003. View

15.

Valencia P, Hanewich-Hollatz M, Gao W, Karim F, Langer R, Karnik R . Effects of ligands with different water solubilities on self-assembly and properties of targeted nanoparticles. Biomaterials. 2011; 32(26):6226-33. PMC: 3146392. DOI: 10.1016/j.biomaterials.2011.04.078. View

16.

Cao X, Li B, Chen J, Dang J, Chen S, Gunes E . Effect of cabazitaxel on macrophages improves CD47-targeted immunotherapy for triple-negative breast cancer. J Immunother Cancer. 2021; 9(3). PMC: 7986678. DOI: 10.1136/jitc-2020-002022. View

17.

Wibroe P, Anselmo A, Nilsson P, Sarode A, Gupta V, Urbanics R . Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes. Nat Nanotechnol. 2017; 12(6):589-594. DOI: 10.1038/nnano.2017.47. View

18.

Klymchenko A, Roger E, Anton N, Anton H, Shulov I, Vermot J . Highly lipophilic fluorescent dyes in nano-emulsions: towards bright non-leaking nano-droplets. RSC Adv. 2017; 2(31):11876-11886. PMC: 5726488. DOI: 10.1039/C2RA21544F. View

19.

Lee N, Kim S, Park C . Immune cell targeting nanoparticles: a review. Biomater Res. 2021; 25(1):44. PMC: 8690904. DOI: 10.1186/s40824-021-00246-2. View

20.

Almansour N . Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022; 9:836417. PMC: 8824427. DOI: 10.3389/fmolb.2022.836417. View