For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumours as well as brain metastases. In this Review, we highlight the cellular and molecular components of the blood–brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumours are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood–tumour barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of molecules. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging molecular, cellular and physical strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biology approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.
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The authors would like to thank C. Betsholtz, S. Chatterjee, M. Datta, Z. Amoozgar and S. Krishnan for their helpful input. C.D.A.’s research in this area is supported by NIH (National Institutes of Health) Grant R00EB016971 (National Institute of Biomedical Imaging and Bioengineering), NSF (National Science Foundation) Grants 1933158 and 1830577 (Leading Engineering for America’s Prosperity, Health, and Infrastructure) and CURE Childhood Cancer. G.B.F. received a fellowship from Susan G. Komen for the Cure. R.K.J.’s research in this general area is supported by an Outstanding Investigator Award from the National Cancer Institute (R35CA197743) and grants from the National Foundation for Cancer Research, the Ludwig Center at Harvard, the Advanced Medical Research Foundation, the Ellison Foundation, the Jane’s Trust Foundation and the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project Award.
R.K.J. received honorarium from Amgen; consultant fees from Chugai, Enlight, Ophthotech, SPARC and SynDevRx; owns equity in Enlight, Ophthotech and SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. The other authors declare no competing interests.
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- Convective transport
Mass transport mediated by bulk fluid flow that is driven by a pressure gradient.
- Fast electronic beam steering
Changing the direction of the ultrasound focus or pattern by changing the relative phases of the radiofrequency signals driving the transducer elements. Multiphase array transducers that are composed of hundreds of elements are able to perform electronic beam steering within a few microseconds.
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Arvanitis, C.D., Ferraro, G.B. & Jain, R.K. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat Rev Cancer 20, 26–41 (2020). https://doi.org/10.1038/s41568-019-0205-x
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