Functionalized block co-polymer pro-drug nanoparticles with anti-cancer efficacy in 3D spheroids and in an orthotopic triple negative breast cancer model

Taresco, Vincenzo; Abelha, Thais F.; Cavanagh, Robert J.; Vasey, Catherine E.; Anane-Adjei, Akosua B.; Pearce, Amanda K.; Monteiro, Patr�cia F.; Spriggs, Keith A.; Clarke, Philip; Ritchie, Alison; Martin, Stewart; Rahman, Ruman; Grabowska, Anna M.; Ashford, Marianne B.; Alexander, Cameron

Abstract

Amphiphilic block co-polymers composed of poly(ethylene glycol)-co-poly(lactide)-co-poly(2-((tert-butoxycarbonyl)amino)-3-propyl carbonate) (PEG-pLA-pTBPC) are synthesized in monomer ratios and arrangements to enable assembly into nanoparticles with different sizes and architectures. These materials are based on components in clinical use, or known to be biodegradable, and retain the same fundamental chemistry across 'AB' and 'BAB' block architectures. In MCF7 and MDA-MB-231 breast cancer cells, nanoparticles of < 100 nm are internalized most rapidly, by both clathrin-and caveolin-mediated pathways. In THP-1 cells, polymer architecture and length of the hydrophilic block is the most important factor in the rate of internalization. The organ distributions of systemically injected nanoparticles in healthy mice indicate highest accumulation of the BAB-blocks in lungs and liver and the lowest accumulation in these organs of a methoxyPEG5000-pLA-pTBPC polymer. Conjugation of doxorubicin via a serum-stable urea linker to the carbonate regions of PEG5000-pLA-pTBPC generates self-assembling nanoparticles which are more cytotoxic in 2D, and penetrate further in 3D spheroids of triple negative breast cancer cells, than the free drug. In an aggressive orthotopic triple negative breast cancer mouse model, the methoxyPEG5000-pLA-pTBPC is of similar potency to free doxorubicin but with no evidence of adverse effects in terms of body weight.

Citation

Taresco, V., Abelha, T. F., Cavanagh, R. J., Vasey, C. E., Anane-Adjei, A. B., Pearce, A. K., Monteiro, P. F., Spriggs, K. A., Clarke, P., Ritchie, A., Martin, S., Rahman, R., Grabowska, A. M., Ashford, M. B., & Alexander, C. (2021). Functionalized block co-polymer pro-drug nanoparticles with anti-cancer efficacy in 3D spheroids and in an orthotopic triple negative breast cancer model. Advanced Therapeutics, 4(1), Article 2000103. https://doi.org/10.1002/adtp.202000103

• Journal Article Type: Article
• Acceptance Date: Jul 16, 2020
• Online Publication Date: Aug 2, 2020
• Publication Date: 2021-01
• Deposit Date: Jul 16, 2020
• Publicly Available Date: Aug 3, 2021
• Journal: Advanced Therapeutics
• Electronic ISSN: 2366-3987
• Publisher: Wiley-VCH Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 1
• Article Number: 2000103
• DOI: https://doi.org/10.1002/adtp.202000103
• Keywords: polymer therapeutics; triple negative breast cancer; polymer pro-drugs; self- assembled nanoparticles; drug delivery
• Public URL: https://nottingham-repository.worktribe.com/output/4770523
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1002/adtp.202000103