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

Research output: Contribution to journalArticlepeer-review

Authors

  • Vincenzo Taresco
  • Thais F. Abelha
  • Robert J. Cavanagh
  • Catherine E. Vasey
  • Akosua B. Anane-Adjei
  • Patrícia F. Monteiro
  • Keith A. Spriggs
  • Philip Clarke
  • Alison Ritchie
  • Stewart Martin
  • Ruman Rahman
  • Anna M. Grabowska
  • Marianne B. Ashford
  • Cameron Alexander

Colleges, School and Institutes

External organisations

  • University of Nottingham
  • AstraZeneca
  • University of Nottingham, Faculty of Medicine and Health Sciences

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.

Bibliographic note

Funding Information: V.T., T.F.A., and R.J.C. contributed equally to this work. This work was supported by the Engineering and Physical Sciences Research Council [grant numbers EP/N006615/1; EP/N03371X/1; EP/H005625/1; EP/L013835/1; EP/R035563/1]. This work was also funded by the Royal Society [Wolfson Research Merit Award WM150086] to CA. The authors would also like to thank Douglas Crackett and Paul Cooling for expert technical assistance and Carol Turrill for outstanding administrative support. Histological analysis was performed by the Translational Research team, Cellular Pathology, Nottingham University Hospitals (NUH) Trust and with the assistance of Mr. Dorman Osei. Publisher Copyright: © 2020 The Authors. Published by Wiley-VCH GmbH

Details

Original languageEnglish
Article number2000103
Number of pages15
JournalAdvanced Therapeutics
Volume4
Issue number1
Early online date2 Aug 2020
Publication statusPublished - Jan 2021

Keywords

  • drug delivery, polymer pro-drugs, polymer therapeutics, self-assembled nanoparticles, triple negative breast cancer