By Ricardo Borges

The blood-brain barrier (BBB) is crucial to maintaining central nervous system (CNS) homeostasis. Through a combination of physical and molecular barrier properties, and a number of highly specific transporters that exercise fine control over the movement of nutrients from blood vessels into the CNS or waste products back out into the bloodstream, the blood-brain barrier keeps tight regulation of everything going in and out of the CNS (Daneman & Prat, 2015). While this is useful for protecting the CNS from toxins and pathogens, this presents a unique challenge for non-invasive delivery of therapeutic agents in the treatment of brain cancers. Structural impediments like tight junctions between non-fenestrated endothelial cells leave no paracellular route for drug diffusion, and extremely low rates of transcytosis controlled by highly specific receptors heavily limit transcellular delivery. The resulting barrier is highly efficient in keeping neural tissue and tumors insulated from potentially therapeutic drugs intended to target cancerous cells.

Successful delivery of drugs across the BBB largely involves crossing two membranes: the luminal and abluminal membranes of the endothelial cells. Lipid soluble molecules smaller than 400 Da are able to diffuse across these membranes via lipid-mediated free diffusion (Pardridge, 2005). However, most anti-neoplastic low molecular weight drugs are substrates for the ATP-binding cassette transporters (ABC transporters) present on endothelial cells of the CNS, which clear these agents into the lumen of the blood vessel and away from parenchymal tissue (Arvanitis et al., 2019). The use of transporter inhibitors in conjunction with therapeutic agents has shown promise in preclinical studies in combating active efflux of pharmacological compounds from parenchymal tissue. By inhibiting the action of ABC transporters, anti-cancer drugs are able to maintain higher concentrations within brain tissue. As this strategy continues to develop, more potent inhibitors with higher specificity can eventually lead to increased penetration of therapeutic agents across the BBB and decreased clearance from tumor tissue.

Methods for hijacking the endothelial cells’ mechanisms for transport across the barrier are also being explored for improved penetration of the BBB. By identifying a ligand that binds to an endocytosis-triggering receptor on the surface of the endothelial cell and attaching a therapeutic agent to that ligand, the cell’s vesicular transporting machinery can be recruited to deliver drugs to their intended target (Arvanitis et al., 2019). As many such receptors are not specific to CNS endothelial cells, this approach does present potential risk for toxicity to other non-targeted tissues. The use of solute-linked carrier (SLC) proteins provides a similar alternative, particularly as overexpression of the glucose transporter GLUT1 in CNS endothelial cells is correlated with poor survival in most solid tumors (Arvanitis et al., 2019).

A 2015 study also showed promise for the use of exosomes derived from brain cells to deliver anti-cancer drugs across the BBB. In the study, four types of exosomes derived from brain tissue were used to deliver paclitaxel and doxorubicin across the BBB in zebrafish models (Yang et al., 2015). Each type of exosome was cultured from different types of brain cells, with the exosome derived from CNS endothelial cells showing marked enhancement of the delivery of the anti-cancer drugs across the BBB and overall improved cytotoxicity to the target tumor cells. As paclitaxel and doxorubicin are not typically used to treat brain cancer specifically due to their inability to cross the BBB, the results of this study underscore the potential of exosome-enhanced receptor mediated endocytosis in overcoming the BBB.

Inorganic nanoparticles provide an alternative avenue to biological carriers. Gold-based nanomaterials (GBNs) have a history of use in biomedicine, particularly in cancer treatment, due to their biocompatibility and versatility (Tu et al., 2021). As such, production of GBNs is well-established, allowing for precise control over size, shape, and other physicochemical properties. This makes them ideal for tailoring for both the attachment of a variety of therapeutic agents and optimal BBB penetration. As they are not derived from organic material, they also have the added benefit of not needing to be cultured prior to use. However, further study is required to refine the parameters for safe but effective treatment of brain tumors. Larger GBNs struggle to cross the BBB, while smaller GBNs are found to accumulate in other tissues, indicating toxicity. Surface chemical modification of GBNs also have the potential to trigger immune responses in in vitro and in vivo murine models (Moyano et al., 2016).

Stem cell-mediated delivery of anti-cancer drugs present another promising strategy for treatment of brain tumors. Neural stem cells (NSCs) are able to cross the BBB and demonstrate tumor-tropic properties (Mooney et al., 2018). Cancerous tissue produces numerous chemical factors that bind to receptors of the surface of NSCs, causing them to migrate toward the tumor. These NSCs can be engineered for an array of anti-cancer applications, such as the production of prodrug-converting enzymes, release oncolytic viruses, or use as a nanoparticle carrier for small-molecule anti-cancer drugs. Future application of NSCs will likely synchronize the use of multiple anti-cancer agents to bolster a more robust effect in the elimination of heterogeneous tumors.

Glioblastoma multiforme (GBM), the most common and aggressive form of brain tumor, results in 3-4% of all cancer related deaths, with a paltry median 12.6-month survival rate (Carlsson et al., 2014). While treatments for other types of cancer throughout the body have improved with the advancement of medical technology and knowledge, the treatment of malignant brain tumors such as GBM has lagged behind due to the difficulty of getting therapeutic agents across the BBB. As more is learned about the BBB, and technology for the development and production of inorganic and biological nanoparticles and stem cells continues to progress, these medical advancements can be brought to bear on the various types of brain cancers, improving the longevity and quality of life for those afflicted.

References 

Arvanitis, C. D., Ferraro, G. B., & Jain, R. K. (2019, October 10). The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nature reviews. Cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246629/. 

Carlsson, S. K., Brothers, S. P., & Wahlestedt, C. (2014, October 13). Emerging treatment strategies for glioblastoma multiforme. EMBO molecular medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237465/. 

Daneman, R., & Prat, A. (2015, January 5). The blood-brain barrier. Cold Spring Harbor perspectives in biology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/. 

Mooney, R., Hammad, M., Batalla-Covello, J., Abdul Majid, A., & Aboody, K. S. (2018, October 21). Concise review: Neural stem cell-mediated targeted cancer therapies. Stem cells translational medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186269/. 

Moyano, D. F., Liu, Y., Ayaz, F., Hou, S., Puangploy, P., Duncan, B., Osborne, B. A., & Rotello, V. M. (2016, August 11). Immunomodulatory effects of coated gold nanoparticles IN Lps-stimulated in Vitro AND in vivo murine model systems. Chem. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328597/. 

Pardridge, W. M. (2005, January). The blood-brain barrier: Bottleneck in brain drug development. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC539316/. 

Tu, L., Luo, Z., Wu, Y.-L., Huo, S., & Liang, X.-J. (2021, June 15). Gold-based nanomaterials for the treatment of brain cancer. Cancer biology & medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185869/. 

Yang, T., Martin, P., Fogarty, B., Brown, A., Schurman, K., Phipps, R., Yin, V. P., Lockman, P., & Bai, S. (2015, January 22). Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharmaceutical research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520542/.