Brain diseases are notoriously difficult to treat. The human brain consists of a staggering 400 miles (650 km) of blood vessels. This intricate network of vessels acts as a physiological barrier, known as the blood-brain barrier (BBB), that guards against potential toxins and controls entry into the brain. Endothelial cells lining these blood vessels coordinate a series of physical, transport, and metabolic processes that make drug delivery to the brain particularly difficult. The BBB blocks 100% of largemolecule therapies and more than 98% of all small-molecule drugs (1). In the inaugural episode of the Drug Discovery News seminar series, researchers and clinicians discussed unique approaches for overcoming the BBB and delivering therapeutics to the brain. 

Zhenpeng Qin, a bioengineer at the Center for Advanced Pain studies, kicked off the presentations by discussing his work using gold nanoparticles to traverse the BBB in mice. “Nanoparticles allow targeting,” said Qin. “You can functionalize nanoparticles with agents such as antibodies and other molecules that allow you to target specific components in the vasculature.” 

Qin’s research group modified their gold nanoparticles to target the tight junctions between endothelial cells. To push the nanoparticle across the tight junction and into the brain, they excited the nanoparticles with a laser beam. The excited nanoparticle caused a mechanical force that stimulated calcium influx, resulting in cytoskeletal contraction and the opening of the nearby tight junctions. 

In a proof of principle experiment, Qin demonstrated the ability of the nanoparticle-laser technique to deliver drugs across the BBB. The team used the technique to transfer bombesin, a drug that causes itch behavior in mice across the blood-spinal cord barrier, which is similar in composition to the BBB. Qin proposed that this technique could be used in the future to deliver various therapeutics, including antibodies and genes, to treat an assortment of brain conditions. 

Inhibiting transporters

 Arguably, the most difficult brain condition to treat is cancer. Olaf van Tellingen, pharmacologist and group leader at the Netherlands Cancer Institute, described his team’s efforts to combat glioblastoma, a rare but deadly form of brain cancer. “Although it is a very heterogeneous disease, there is just one type of treatment and that is maximum surgical resectioning of the tumor,” said Tellingen. “This resectioning is never complete. There will always be cells left behind in the brain.” 

Physicians treat these remaining cells with various radiotherapy drugs that only marginally increase the lifespan of patients. Tellingen’s research team investigates ABC-transporters, a set of efflux transporters that sit along the BBB that limit drug efficacy. In his presentation, Tellingen described various brain tumor models and his team’s work identifying differences in BBB integrity that cause some tumors to be leakier than others. Surprisingly, they found that BBB leakiness did not improve drug potency because active efflux transporters shuttled the drug out of the tumor, limiting drug concentrations. Tellingen and his team observed higher drug efficacy when they inhibited the ABC-transporters. 

Tellingen’s group is now repurposing elacridar, a drug that was previously developed to modulate ABCB1-mediated drug resistance in tumor cells, as a pharmaco-enhancer for drug delivery to the central nervous system. 

“It may also be worthwhile to think about using this in combination with other strategies such as focused ultrasound in order to breach the blood-brain barrier,” said Tellingen. 

Focused ultrasound 

Scientists often combine focused ultrasound (FUS) with other techniques to disrupt the BBB. In his presentation, Costa Arvanitis, a biomedical engineer at the Georgia Institute of Technology and Emory University, described his team’s work combining FUS with microbubble technology. 

Arvanitis and his team used FUS to excite intravenously injected gas-filled microbubbles in mice. The excited microbubbles vibrate, causing a mechanical force that opens the BBB and increases inertial fluid in the brain. 

“High inertial fluid flow highlights the potential of this technology to deliver drugs with larger molecular weight where the transport can be driven by convective flow,” said Arvanitis. His team demonstrated the practicality of using FUS and microbubble vibration to open the BBB to deliver a nanoparticle carrying an siRNA that successfully silenced targeted gene activity in the brain. 

Arvanitis and his team perfected their approach further by characterizing the optimal nanoparticle size and microbubble characteristics for delivery. They even created a closed-loop system to monitor subtle changes in microbubble vibration in response to ultrasound pulsation. “The operation of our controller is analogous to listening to the sounds generated by the vibration of a cannon,” said Arvanitis. By using this system, scientists can fine-tune microbubble dynamics. 

Lastly, Arvanitis discussed his team’s work combining FUS with thermal stress to open the BBB. “This is really exciting news as we now have additional and many diverse strategies to deliver drugs to brain tumors with ultrasound,” said Arvanitis. 

Clinical applications 

Extending these strategies to treat humans is a challenge. In the last presentation of the seminar, Graeme Woodworth, a neurosurgeon at the University of Maryland School of Medicine demonstrated the reality of applying some of these technologies in the clinic. 

Woodworth described his team’s efforts combining magnetic resonance imaging (MRI) with ultrasound technology. Using MRI, Woodworth’s team captures the unique difference in each patient’s head shape, geometry, thickness, and density. He then uses this information to attach a hemispheric array of ultrasound transducers that can be individually controlled and adjusted to accommodate differences in each person’s skull. 

“It’s this hemispheric array that has really enabled us to think about employing some of the biophysical principles that Arvanitis and others spoke about related to using ultrasound in the human brain,” said Woodworth. This hemispheric array allows clinicians to target specific regions in the brain, essentially turning broad ultrasound technology into a targeted focusing element. The human head acts as a lens to generate heat that perturbs the BBB through the intact human skull. 

Woodworth demonstrated the effectiveness of MRI-guided FUS technology to permeabilize the BBB and allow a fluorescent dye to enter tumors, helping clinicians to more easily spot tumor cells during surgery. Using modifications to MRI technology, Woodworth and his team can also image and monitor ultrasound effects in real time and adjust ultrasound modes, frequencies, cycles, and durations to achieve the best results. 

Woodworth and his colleagues are now exploring the utility of FUS technology to facilitate better drug penetration after brain surgery. FUS would weaken the BBB to allow more drugs into the brain, effectively eliminating residual tumor cells. They are also exploring FUS technology to stimulate the release of crucial biomarkers into the bloodstream that could help clinicians detect brain tumors sooner. 

Research scientists and clinicians alike are working hard to break the barrier to delivering therapeutics to the brain. The technologies discussed during this seminar are not solely applicable to cancer. Qin, Tellingen, Arvanitis, and Woodworth each discussed the practicality of using their respective approaches to treat other brain conditions. 

“Thanks for putting this together,” said Woodworth. “It is really an exciting time when we consider such a huge barrier to therapeutics in the brain that’s been a decades-long challenge for scientists and clinicians trying to take care of patients with diseases that hide behind the blood brain barrier.” 

To learn more about Qin’s, Tellingen’s, Arvanitis’s, and Woodworth’s work on overcoming the BBB and delivering therapeutics to the brain, view the on-demand seminar on the Drug Discovery News website.