Nanomaterials come in a plethora of designs, shapes, chemical formulations, sizes, and ionic forms and can be readily tuned to surpass many of the biological barriers within the body, but have had limited success in surpassing the final frontier of barriers: the blood-brain barrier (BBB). While their size is a significant advantage of nanoparticles for their delivery to solid tumour masses, it is also their Achilles’ heel for crossing the BBB. This makes the application of nanomedicines in neuro-oncology often considered unfeasible, with efficacy limited to regions of significant disease progression and compromised BBB. However, little is understood about how the evolving tumour-brain physiology during disease progression affects the permeability and retention of designer nanomedicines.
Dr. Zachary H. Houston
Postdoctoral Fellow at The University of Queensland
Influence of targeting and size on nanomedicines permeability across the blood-brain barrier
A major area of interest for nanoparticle therapeutics is the delivery to glioblastoma (GBM), as it is the most aggressive form of brain cancer. In this project we studied the influence of size and taregting on the ability of nanomedicines to cross the BBB. We applied simultaneous PET-MRI to develop a toolkit for monitoring tumour progression and its effect on BBB integrity of a spontaneous transgenic glioma model, for the purpose of establishing when the BBB is compromised enough for nanoparticles to cross. We developed a modular nanomedicine platform that when used in conjunction with a unique model of how tumorogenesis affects BBB integrity, allows investigation of how nanomaterial properties affect uptake and retention in brain tissue. Our data shows accumulation of nanomedicines in brain tumour tissue is better correlated with the leakiness of the BBB than actual tumour volume, and was evaluated by establishing brain tumours using a spontaneous and endogenously-derived glioblastoma model providing a unique opportunity to assess these parameters individually and compare the results across multiple mice. We also quantitatively demonstrated that smaller nanomedicines (20 nm) can indeed cross the BBB and accumulate in tumours at earlier stages of the disease than larger analogues, therefore opening the possibility of developing patient-specific nanoparticle treatment interventions in earlier stages of the disease. Importantly, these results provide a more predictive approach for designing efficacious personalised nanomedicines based on a particular patient’s condition.
The initial project was a large collaborative effort between 4 major groups and 15 people in addition to myself. I lead the project, and performed all of the radioactive materials preparation, imaging, and post-mortem animal handling. The other people involved in this project and their roles are listed below (Affiliations denoted in superscripts).
- Jens Bunt3 ‐ Animal model development
- Kok-Siong Chen3,13 – Confocal microscopy
- Simon Puttick2,10 – Image analysis and project direction support
- Christopher B. Howard1,2,5,6,11 – Bispecific antibody production
- Nicholas L. Fletcher1,2,5 – Assistance in radiolabelling and animal injections
- Adrian V. Fuchs1,2,5 – Materials development
- Jiwei Cui4,5,12 Materials development
- Yi Ju4,5 – Materials development
- Gary Cowin1 – Imaging support
- Xin Song1 – Animal injections
- Andrew W. Boyd7,8 – Antibody development
- Stephen M. Mahler2,11 – Bispecific antibody development
- Linda J. Richards3,9 – Animal model and technical advisement
- Frank Caruso4,5 – Materials development and advisement
- Kristofer J. Thurecht1,2,5,6 – Materials development and imaging advisement
Affiliations
- Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia.
- Queensland Brain Institute, The University of Queensland, St Lucia, QLD 4072, Australia
- Department of Chemical Engineering, The University of Melbourne, Parkville, VIC 3010, Australia
- ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, St Lucia, QLD 4072, Australia
- ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, St Lucia, QLD 4072, Australia
- Leukaemia Foundation Laboratory, QIMR-Berghofer Medical Research Institute, Herston, QLD 4006, Australia
- Department of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia
- The School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia
- Commonwealth Scientific and Industrial Research Organisation, Probing Biosystems Future Science Platform
- ARC Training Centre for Biopharmaceutical Innovation The University of Queensland, St Lucia, QLD 4072, Australia
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Media
- Radio Interview: 2GB Sydney, 13-May-2020.
- Radio Interview: Mornings with Gareth Parker, 6PR Perth, 13-May-2020.
- “Brain cancer treatment breakthrough,” The West Australian, pg 18. 13-May-2020.
- “Missile targets cancer in the brain,” Courier Mail, Brisbane, pg 5. 13-May-2020.
- “Tiny missile cancer cure,” The Daily Telegraph, Brisbane, pg 21. 13-May-2020.
- “New Cancer drug works like a guided missile,” Hearald Sun, 13-May-2020.
- “New cancer drug works like a guided missile”, News Ltd. Australia, 13-May-2020.
- NT News
- Adelaide Advertiser
- Hobart Mercury
- Herald Sun
- “Nanomedicines for brain cancer.” Chemistry in Australia – The Magazine of the Royal Australian Chemical Institute, pg 16. July/August 2020.