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Updated: May 7, 2026
Rat Model of Blood-brain Barrier Disruption to Allow Targeted Neurovascular Therapeutics
Published on: November 30, 2012
Selective permeabilization of the blood-brain barrier at sites of metastasis
John J Connell1, Grégoire Chatain, Bart Cornelissen
1Affiliations of authors: CRUK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital, Oxford, UK (JJC, GC, BC, KAV, AH, NRS); Department of Pharmacology (JJC, AH, DCA) and Department of Oncology (JJC, GC, BC, KAV, AH, LS, NRS), University of Oxford, Oxford, UK.
Background:
Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases.
Methods:
BALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadolinium- diethylenetriaminepentaacetic acid, horseradish peroxidase, or radiolabeled trastuzumab ((111)In-BnDTPA-Tz) was injected intravenously. BBB permeability was assessed in vivo using gadolinium-enhanced T1-weighted magnetic resonance imaging and confirmed histochemically. Brain uptake of (111)In-BnDTPA-Tz was determined using in vivo single photon emission computed tomography/computed tomography. Endothelial expression of TNF receptors was determined immunohistochemically in both mouse and human brain tissue containing metastases. Group differences were analyzed with one-way analysis of variance followed by post hoc tests, Wilcoxon signed rank test, and Kruskal-Wallis with Dunn's multiple comparison test. All statistical tests were two-sided.
Results:
Localized expression of TNF receptor 1 (TNFR1) was evident on the vascular endothelium associated with brain metastases. Administration of TNF or LT permeabilized the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect at 6 hours. Metastasis-specific uptake ratio of (111)In-BnDTPA-Tz was also demonstrated after systemic TNF administration vs control (0.147±0.066 vs 0.001±0.001). Human brain metastases displayed a similar TNF receptor profile compared with the mouse model, with predominantly vascular TNFR1 expression.
Conclusions:
These findings describe a new approach to selectively permeabilize the BBB at sites of brain metastases to aid in detection of micrometastases and facilitate tumor-specific access of chemotherapeutic agents. We hypothesize that this permeabilization works primarily though TNFR1 activation and has the potential for clinical translation.
Insights
Researchers developed a method to open the blood-brain barrier (BBB) specifically at brain metastases using tumor necrosis factor (TNF). This approach enhances detection of micrometastases and improves drug delivery to brain tumors.
Area of Science:
- Neuro-oncology
- Vascular Biology
- Pharmacology
Background:
- The blood-brain barrier (BBB) restricts access of systemic chemotherapeutics to brain metastases.
- Developing strategies to selectively permeabilize the BBB at metastatic sites is crucial for effective treatment.
Purpose of the Study:
- To develop a method for specifically permeabilizing the BBB at the sites of cerebral metastases.
- To investigate the potential of tumor necrosis factor (TNF) and lymphotoxin (LT) in BBB permeabilization.
Main Methods:
- Brain metastases were induced in BALB/c mice.
- Systemic administration of TNF or LT was followed by injection of tracers (gadolinium, horseradish peroxidase, or radiolabeled trastuzumab).
- BBB permeability was assessed using MRI and histochemistry; tracer uptake was quantified using SPECT/CT.
Main Results:
- Localized expression of TNF receptor 1 (TNFR1) was observed on the vascular endothelium of brain metastases.
- TNF or LT administration selectively permeabilized the BBB at metastatic sites, with peak effect at 6 hours.
- Systemic TNF administration significantly increased metastasis-specific uptake of radiolabeled trastuzumab compared to controls.
Conclusions:
- A novel approach enables selective BBB permeabilization at brain metastases, aiding micrometastasis detection.
- This strategy facilitates tumor-specific delivery of chemotherapeutic agents.
- The permeabilization mechanism is hypothesized to involve TNFR1 activation, suggesting potential for clinical translation.
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