gms | German Medical Science

German Congress of Orthopaedics and Traumatology (DKOU 2022)

25. - 28.10.2022, Berlin

DOX-Loaded mPEG Nanoparticles as a Promising Treatment in a Humanized Mouse Model for Breast Cancer Bone Metastasis

Meeting Abstract

  • presenting/speaker Tina Frankenbach - Klinikum der Universität München, Muskuloskelettales Universitätszentrum München (MUM), München, Germany
  • Marietta Landgraf - Centre in Regenerative Medicine, QUT, Brisbane, Australia; School of Biomedical Sciences at TRI, QUT, Brisbane, Australia
  • Nicholas Fletcher - Centre of Advanced Imaging, UQ, Brisbane, Australia; Australian Inst. for Bioengineering and Nanotechnology, UQ, Brisbane, Australia
  • Christopher Howard - Australian Inst. for Bioengineering and Nanotechnology, UQ, Brisbane, Australia
  • Akhilandeshwari Ravichandran - School of Mechanical, Medical and Process Engineering, QUT, Brisbane, Australia; ARC Training Centre in Cell and TE Technologies QUT, Brisbane, Australia
  • Abbas Shafiee - Centre in Regenerative Medicine, QUT, Brisbane, Australia; UQ Diamantina Institute, TRI, Brisbane, Australia; Herston Biofabrication Institute, Brisbane, Australia
  • Boris Holzapfel - Klinikum der Universität München, LMU München, Muskuloskelettales Universitätszentrum München (MUM), München, Germany
  • Kristofer Thurecht - Centre of Advanced Imaging, UQ, Brisbane, Australia; Australian Inst. for Bioengineering and Nanotechnology, UQ, Brisbane, Australia
  • Jacqui McGovern - Centre in Regenerative Medicine, QUT, Brisbane, Australia; School of Mechanical, Medical and Process Engineering, QUT, Brisbane, Australia; School of Biomedical Sciences at TRI, QUT, Brisbane, Australia
  • Dietmar W. Hutmacher - Centre in Regenerative Medicine, QUT, Brisbane, Australia; School of Mechanical, Medical and Process Engineering, QUT, Brisbane, Australia; School of Biomedical Sciences at TRI, QUT, Brisbane, Australia

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2022). Berlin, 25.-28.10.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocAB14-738

doi: 10.3205/22dkou028, urn:nbn:de:0183-22dkou0280

Published: October 25, 2022

© 2022 Frankenbach et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objectives: Breast cancer (BCa) is the most common cancer amongst women worldwide and the leading cause of cancer related death. The triple negative BCa (TNBCa) subtype is associated with a particularly aggressive clinical behavior including an early peak of fatal distant metastasis, predominantly to bone. Routine systemic chemotherapeutic treatment with doxorubicin (DOX) is limited due to its severe side effects, especially cardiotoxicity. Novel (targeted) nanotherapies are a promising breakthrough to enhance treatment efficacy and specificity of known chemotherapeutics while at the same time decreasing their systemic toxicity. Therefore, we studied the therapeutic effect of non-targeted and targeted DOX-containing nanoparticles as a novel treatment approach against TNBCa bone metastases using a humanized tissue-engineered mouse model.

Methods: A humanized bone microenvironment was created in NSG mice by subcutaneous implantation of humanized tissue-engineered bone constructs (hTEBCs) consisting of tubular biodegradable medical grade polycaprolactone scaffolds seeded with human osteoblasts and an inner vascular bone marrow niche. After 13 weeks of in vivo bone formation, TNBCa primary tumor was induced by injecting MDA-MB-231BO-Luc cells into the mammary fat pad and the tumor was allowed to grow and metastasize to humanized bone. Subsequently, treatment with DOX-loaded hyper branched methoxy polyethylene glycol (mPEG) (HBP) nanoparticles was performed. The DOX-HBP nanoparticles were either non-targeted or targeted with a Thomsen-Friedenreich (TF)-mPEG bispecific antibody (BsAb) and administered once per week over a duration of 3 weeks.

Results and conclusion: Implantation of the hTEBCs resulted in the formation of a chimeric bone organ in vivo containing human-derived extracellular matrix, bone marrow and showing evidence of ongoing complex bone formation through endochondral ossification. HBP nanoparticles predominantly accumulated at the primary tumor and hTEBCs. The non-targeted HBP-DOX nanoparticles were able to slow primary tumor growth and reduce metastasis compared to the targeted HBP-DOX nanoparticles and non-DOX containing control groups. Additionally, the non-targeted nanoparticles reduced systemic toxicity effects (cardiotoxicity, hepatotoxicity, hematological toxicity) and prolonged survival compared to free DOX treatment. Further targeting with the BsAb did not improve treatment outcome, most likely because of enhanced clearance (accumulation in liver and spleen). However, the targeted HBP-DOX nanoparticles lead to increased lung metastases and tended to increase metastasis to the liver and hTEBCs compared to the saline control.

In conclusion, this study is an exciting example of complex pre-clinical disease modelling including a humanized bone niche in the mouse. Furthermore, it highlights the great potential of nanomedicines in cancer therapy, but also demonstrates how changed nanoparticle properties can alter their treatment efficacy in vivo.