Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption

Phillip W Janowicz; Zachary H Houston; Jens Bunt; Nicholas L Fletcher; Craig A Bell; Gary Cowin; Christopher B Howard; Dewan Taslima; Nicholas Westra van Holthe; Amber Prior; Vanessa Soh; Saikat Ghosh; James Humphries; Pie Huda; Stephen M Mahler; Linda J Richards; Kristofer J Thurecht

doi:10.1016/j.biomaterials.2022.121416

Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption

Biomaterials. 2022 Apr:283:121416. doi: 10.1016/j.biomaterials.2022.121416. Epub 2022 Feb 17.

Authors

Phillip W Janowicz¹, Zachary H Houston², Jens Bunt³, Nicholas L Fletcher², Craig A Bell², Gary Cowin⁴, Christopher B Howard⁵, Dewan Taslima⁶, Nicholas Westra van Holthe⁶, Amber Prior⁷, Vanessa Soh⁷, Saikat Ghosh⁷, James Humphries⁶, Pie Huda⁶, Stephen M Mahler⁸, Linda J Richards⁹, Kristofer J Thurecht¹⁰

Affiliations

¹ Centre for Advanced Imaging, The University of Queensland, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia; Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, Australia.
² Centre for Advanced Imaging, The University of Queensland, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia; Australian Research Council Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Australia.
³ Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, Australia; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
⁴ Centre for Advanced Imaging, The University of Queensland, Australia; National Imaging Facility, The University of Queensland, St Lucia, Queensland, 4072, Australia.
⁵ Centre for Advanced Imaging, The University of Queensland, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia; Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Australia.
⁶ Centre for Advanced Imaging, The University of Queensland, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia.
⁷ Centre for Advanced Imaging, The University of Queensland, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia; Australian Research Council Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Australia.
⁸ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia; Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Australia.
⁹ Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, Australia.
¹⁰ Centre for Advanced Imaging, The University of Queensland, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia; Australian Research Council Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Australia. Electronic address: k.thurecht@uq.edu.au.

PMID: 35217483
DOI: 10.1016/j.biomaterials.2022.121416

Abstract

Personalised nanomedicine is an advancing field which has developed significant improvements for targeting therapeutics to aggressive cancer and with fewer side effects. The treatment of gliomas such as glioblastoma (or other brain tumours), with nanomedicine is complicated by a commonly poor accumulation of drugs in tumour tissue owing to the partially intact blood-brain barrier (BBB). Nonetheless, the BBB becomes compromised following surgical intervention, and gradually with disease progression. Increased vasculature permeability generated by a tumour, combined with decreased BBB integrity, offers a mechanism to enhance therapeutic outcomes. We monitored a spontaneous glioma tumour model in immunocompetent mice with ongoing T2-weighted and contrast-enhanced T1-weighted magnetic resonance imaging gradient echo and spin echo sequences to predict an optimal "leakiness" stage for nanomedicine injections. To ascertain the effectiveness of targeted nanomedicines in treating brain tumours, subsequent systemic administration of targeted hyperbranched polymers was then utislised, to deliver the therapeutic payload when both the tumour and brain vascularity had become sufficiently susceptible to allow drug accumulation. Treatment with either doxorubicin-loaded hyperbranched polymer, or the same nanomedicine targeted to an ephrin receptor (EphA2) using a bispecific antibody, resulted in uptake of chemotherapeutic doxorubicin in the tumour and in reduced tumour growth. Compared to vehicle and doxorubicin only, nanoparticle delivered doxorubicin resulted in increased tumour apoptosis, while averting cardiotoxicity. This suggests that polyethylene based (PEGylated)-nanoparticle delivered doxorubicin could provide a more efficient treatment in tumours with a disrupted BBB, and that treatment should commence immediately following detection of gadolinium permeability, with early detection and ongoing 'leakiness' monitoring in susceptible patients being a key factor.

Keywords: Bispecific antibody; Blood brain barrier; Brain cancer; Brain tumour; Glioblastoma; Hyperbranched polymer; MRI; Nanomedicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier
Brain
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / drug therapy
Doxorubicin
Drug Delivery Systems / methods
Humans
Mice
Nanomedicine* / methods

Substances

Doxorubicin