Targeted opening of the blood-brain barrier using VCAM-1 functionalised microbubbles and "whole brain" ultrasound
Vanessa A Johanssen1, Jia-Ling Ruan1, Oliver Vince2
1Department of Oncology, University of Oxford, Oxford, UK.
Abstract:
Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically. The aim of this study was to exploit this targeting approach to enable localised and temporary BBB opening at the site of early-stage metastases using functionalised microbubbles and ultrasound. Methods: Microbubbles functionalised with anti-VCAM1 were synthesised and shown to bind to VCAM-1-expressing cells in vitro. Experiments were then conducted in vivo in a unilateral breast cancer brain metastasis mouse model using Gadolinium-DTPA (Gd-DTPA) enhanced MRI to detect BBB opening. Following injection of Gd-DTPA and targeted microbubbles, the whole brain volume was simultaneously exposed to ultrasound (0.5 MHz, 10% duty cycle, 0.7 MPa peak negative pressure, 2 min treatment time). T1-weighted MRI was then performed to identify BBB opening, followed by histological confirmation via immunoglobulin G (IgG) immunohistochemistry. Results: In mice treated with targeted microbubbles and ultrasound, statistically significantly greater extravasation of Gd-DTPA and IgG was observed in the left tumour-bearing hemisphere compared to the right hemisphere 5 min after treatment. No acute adverse effects were observed. There was no investigation of longer term bioeffects owing to the nature of the study. Conclusion: The results demonstrate the feasibility of using targeted microbubbles in combination with low intensity ultrasound to localise opening of the BBB to metastatic sites in the brain. This approach has potential application in the treatment of metastatic tumours whose location cannot be established a priori with conventional imaging methods.
Insights
Researchers developed a novel method to temporarily open the blood-brain barrier (BBB) at brain metastasis sites using targeted microbubbles and ultrasound. This technique enhances drug delivery for treating brain cancers, improving early detection and treatment efficacy.
Area of Science:
- Oncology
- Nanotechnology
- Medical Imaging
Background:
- Brain metastases are a leading cause of cancer mortality, with current treatments limited by late diagnosis and poor drug delivery across the blood-brain barrier (BBB).
- Magnetic resonance imaging (MRI) contrast agents conjugated with anti-VCAM1 antibodies can detect micrometastases, significantly smaller than clinically detectable tumors.
Purpose of the Study:
- To investigate the use of functionalized microbubbles and ultrasound to achieve localized and temporary opening of the BBB at metastatic sites.
- To enable targeted delivery of therapies to early-stage brain metastases.
Main Methods:
- Synthesis of microbubbles functionalized with anti-VCAM1, confirmed for binding to VCAM-1-expressing cells in vitro.
- In vivo studies in a mouse model of unilateral breast cancer brain metastasis.
- Gadolinium-DTPA (Gd-DTPA) enhanced MRI to detect BBB opening after ultrasound exposure (0.5 MHz, 10% duty cycle, 0.7 MPa) in conjunction with targeted microbubbles and Gd-DTPA injection.
- Histological confirmation using immunoglobulin G (IgG) immunohistochemistry.
Main Results:
- Statistically significant greater extravasation of Gd-DTPA and IgG was observed in the tumor-bearing hemisphere compared to the contralateral hemisphere post-treatment.
- The targeted microbubble and ultrasound approach demonstrated localized BBB opening at metastatic sites.
- No acute adverse effects were observed during the study.
Conclusions:
- The study demonstrates the feasibility of using targeted microbubbles and low-intensity ultrasound to selectively open the BBB at brain metastatic sites.
- This approach holds potential for treating metastatic brain tumors, especially when precise localization is challenging with conventional imaging.
- Further research could explore the therapeutic applications and long-term bioeffects of this technique.
