MRI-guided focused ultrasound combined with microbubbles can open the blood-brain barrier (BBB) and allow therapeutic drugs to reach the diseased brain location under the guidance of MRI.
Researchers have recently shown that the magnetic field of the MRI scanner decreases the BBB opening volume in a mouse model by 3.3-fold to 11.7-fold, depending on the strength of the magnetic field.
Following focused-ultrasound sonication, the team also used Evans blue, a model drug, to test whether the static magnetic field affects trans-BBB drug delivery efficiency. They found that the fluorescence intensity of the Evans blue was lower in mice that received the treatment in one of the three strengths of magnetic fields compared with mice treated outside the magnetic field.
These findings suggest that the impact of the magnetic field needs to be considered in the clinical applications of focused ultrasound in brain drug delivery.
Yang Y, Pacia CP, Ye D, et al. Static Magnetic Fields Dampen Focused Ultrasound-mediated Blood-Brain Barrier Opening. Radiology, 2021; 204441 DOI: 10.1148/radiol.2021204441
Researchers from the University of Copenhagen have delivered nanoparticle liposome drug carriers past the blood-brain barrier, while tracking and monitoring them all the way through the system.
Working with colleagues at the Technical University of Denmark and Aalborg University, the researchers used two-photon imaging to deconstruct the blood-brain barrier in order to understand how the nanoparticle drug carriers travel past the blood-brain barrier in a living organism.
By tagging the particles with fluorescent molecules, they could see that nanoparticles enter the brain mainly via big vessels (venules) that are surrounded by perivascular space, and not, as previously believed, via small and numerous capillaries.
Kucharz K, Kristensen K, Johnsen KB, et al. Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles. Nat Commun. 2021;12(1):4121. doi: 10.1038/s41467-021-24323-1
Researchers at Uppsala University have discovered lymph node-like structures close to the tumour in brain cancer patients, where immune cells can be activated to attack the tumour.
'It was extremely exciting to discover for the first time the presence of lymph node-like structures in glioma patients. These structures are known as tertiary lymphoid structures (TLS) and they are not found in healthy individuals. They have all the components needed to support lymphocyte activation on-site which means that they could have a positive effect on the anti-tumour immune response,' says Alessandra Vaccaro, PhD student at the Department of Immunology, Genetics and Pathology and shared first author of the study.
The researchers also showed that the formation of TLS in the brain can be induced by a type of immunotherapy in glioma-bearing mice. Indeed, when they treated the mice with immunostimulatory antibodies called αCD40, the formation of TLS was enhanced and always occurred in proximity to tumours.
van Hooren, L., Vaccaro, A., Ramachandran, M. et al. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat Commun 12, 4127 (2021). https://doi.org/10.1038/s41467-021-24347-7
A major challenge in treating neurological diseases is getting drugs across the blood-brain barrier. Essential nutrients like omega-3s require the assistance of dedicated transporter proteins that specifically recognise them and get them across this barrier.
The transporter that lets in omega-3s is called MFSD2A. Researchers have used single-particle cryo-electron microscopy to obtain a three-dimensional structure of this transporter protein, providing insight into how omega-3s bind to the transporter. It is hoped that this information will allow for the design of drugs that mimic omega-3s, hijack the transporter system, and cross the blood-brain barrier into the brain.
Cater RJ, Chua GL, Erramilli SK, et al (2021) Structural basis of omega-3 fatty acid transport across the blood-brain barrier. Nature. 2021 Jun 16. doi: 10.1038/s41586-021-03650-9
The Wyss Institute for Biologically Inspired Engineering at Harvard University has announced that it is collaborating with multiple industry partners to discover more effective approaches to deliver drugs across the blood-brain barrier (BBB) for the treatment of brain diseases.
The collaboration aims to identify new shuttle target proteins that are highly enriched within brain microvascular endothelial cells that line BBB microvessels but that are relatively scarce or absent in microvessels in other organs. To do this, the researchers will employ comparative proteomic and transcriptomic approaches and a bioinformatic brain delivery target discovery platform.
Wyss Institute researchers will further investigate emerging target shuttle proteins for their potential to transport drug-like cargo molecules, using the Wyss Institute's antibody shuttle discovery platform that seeks to integrate both human in vitro and humanized in vivo models. The Wyss team is developing humanized mice in which the mouse shuttle target proteins in the BBB have been replaced by the analogous human proteins. In parallel, they are developing human in vitro BBB models that recapitulate drug delivery, some of which could be conducted under dynamic fluid flow, similar to the conditions found in the brain vasculature in vivo. By assessing correlation of the in vitro and in vivo models, the team will select the best assays to identify and rank shuttle proteins that can efficiently transport drugs into the human brain.
Novocure and GT Medical Technologies have entered into a clinical trial agreement to evaluate tumor treating fields together with GammaTile® therapy in recurrent glioblastoma.
Novocure’s TTFields are electric fields that disrupt cancer cell division. GammaTile is an FDA-cleared therapy for the treatment of all types of brain tumors.
Novocure and GT Medical Technologies plan to conduct a phase 2 pilot study to test the effectiveness and safety of neo-adjuvant TTFields followed by resection, GammaTile Therapy, and adjuvant TTFields for recurrent GBM. The study is designed to enroll approximately 55 patients in the United States.
The Ivy Brain Tumor Center at Barrow Neurological Institute has announced the dosing of its first patient in a first-in-human Phase 0 clinical trial of sonodynamic therapy (SDT), a non-invasive drug-device combination developed by SonALAsense in collaboration with Insightec. The study combines metabolic targeting of glioblastoma with inert drug activated using MRI-guided focused ultrasound. It aims to develop a new non-invasive treatment option for patients with recurrent glioblastoma (rGBM) and other high-grade gliomas.
The Ivy Brain Tumor Center is evaluating sonodynamic therapy using Insightec’s magnetic resonance-guided focused ultrasound technology in combination with SonALAsense’s proprietary formulation of 5-aminolevulinic acid (Sonala-001) in a Phase 0 clinical trial. Sonala-001 is administered intravenously and metabolized selectively by tumor cells. The drug’s non-toxic by-product is then activated using non-invasive MR-guided focused ultrasound, enabling selective targeting of tumour cells without impacting the matrix of surrounding normal brain cells.
Scientists from Nanjing University and the University of Macau are using nanoscale apoptotic bodies (ABs) as brain-targeting drug carriers, bringing promise for a range of brain diseases.
The researchers used small apoptotic bodies (sABs), which have a more uniform size, with few DNA fragments and abundant RNAs, compared with micron-sized apoptotic bodies. sABs are also stable in serum and have a long circulating time in vivo. The drug loading efficiency into sABs is high and the process is productive and controllable. Additionally, targeting ligands can be incorporated as the sABs are shed from the cell membrane as vesicles.
The researchers successfully loaded TNF-alpha antisense oligonucleotide (ASO) into sABs secreted by melanoma cells with high brain metastasis. The drug-loaded sABs penetrated the BBB, delivering the anti-inflammatory ASO to microglia and showing efficacy in alleviating the development of Parkinson's disease in mice.
Yulian Wang et al (2021) Delivering Antisense Oligonucleotides across the Blood‐Brain Barrier by Tumor Cell‐Derived Small Apoptotic Bodies, Advanced Science, DOI: 10.1002/advs.202004929
RNA-based therapies offer unique advantages for treating brain tumours. However, tumour penetrance and uptake are hampered by RNA therapeutic size and charge, and need to be ‘packaged’ in large carriers to improve bioavailability.
Here, researchers have examined delivery of siRNA, packaged in 50-nm cationic lipid-polymer hybrid nanoparticles (LPHs:siRNA), combined with microbubble-enhanced focused ultrasound (MB-FUS) in paediatric and adult preclinical brain tumour models.
Using single-cell image analysis, they show that MB-FUS in combination with LPHs:siRNA leads to more than 10-fold improvement in siRNA delivery into brain tumour microenvironments of the two models.
Guo BY, Lee H, Fang Z et al (2021) Single-cell analysis reveals effective siRNA delivery in brain tumors with microbubble-enhanced ultrasound and cationic nanoparticles. Science Advances, Vol. 7, no. 18, eabf7390, DOI: 10.1126/sciadv.abf7390
A modified herpes virus, alone and in combination with radiation, was well tolerated with early signs of clinical effectiveness in paediatric patients with high-grade brain tumours.
In the Phase 1 trial of 12 patients between 7 and 18 years of age, the researchers injected G207, a derivative of the herpes virus, into malignant brain tumours. The virus then infected, and killed, only the tumour cells. It also induced a strong immune response against the tumour.
In the trial, 11 of the 12 patients demonstrated a treatment response. The overall survival rate was more than double the typical survival rate for children with high-grade glioma. Following these encouraging results, the researchers are now working with the Pediatric Brain Tumor Consortium to develop a multi-institutional Phase 2 trial of G207, which they hope to initiate later in 2021.
Friedman GK, Johnston JM, Bag AK, et al. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas. N Engl J Med. 2021 Apr 10. doi: 10.1056/NEJMoa2024947. https://www.nejm.org/doi/full/10.1056/NEJMoa2024947
Researchers at the Harbin Institute of Technology in China have created controllable microrobots that can breach the blood-brain barrier (BBB) and deliver cancer drugs to tumours in the brains of mice.
The researchers created magnetic nanogels, loaded them with a cancer drug, and enveloped them with E.coli membrane. Neutrophils (a type of white blood cell) then consumed the coated nanogels via phagocytosis. Once the magnetic nanogels were inside the neutrophils, the researchers could control these 'neutrobots' by applying magnetic fields.
After injecting the neutrobots into mice with brain tumours, the researchers used magnetic fields to get them to move toward the brain. Once there, the neutrobots were able to cross the BBB and deliver the cancer drug to the tumours.
Zhang H, Li Z, Gao C et al (2021) Dual-responsive biohybrid neutrobots for active target delivery, Science Robotics 24 Mar 2021: Vol. 6, Issue 52, DOI: 10.1126/scirobotics.aaz9519
An early clinical trial in individuals with glioblastoma showed an experimental spherical nucleic acid (SNA) drug was able to penetrate the blood-brain barrier (BBB) and trigger the death of tumour cells.
This is the first time a nanotherapeutic has been shown to cross the BBB when given through intravenous infusion, and alter the genetic machinery of a tumour to cause cell death.
The phase 0 study was conducted with eight individuals who had recurrent glioblastoma at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Kumthekar P, Ko CH, Paunesku T, et al. A first-in-human phase 0 clinical study of RNA interference–based spherical nucleic acids in patients with recurrent glioblastoma. Sci. Transl. Med. 2021;13(584). doi:10.1126/scitranslmed.abb3945
Bionaut Labs, a company focused on revolutionizing the treatment of central nervous system disorders (CNS) with its Bionaut™ precision medicine treatment modality, today announced its launch backed by $20 million financing led by Khosla Ventures.
A Bionaut™ is a novel treatment modality that uses remote-controlled microscale robots to deliver biologics, nucleic acids, or small molecule therapies locally to targeted CNS disease areas. Through precision localized brain targeting, Bionaut™ therapeutics could offer better efficacy and safety that cannot be achieved by other traditional treatment modalities.
Researchers at Washington University have used focused ultrasound-mediated intranasal brain drug delivery (FUSIN) to deliver a therapeutic agent to brainstem gliomas in mouse models.
Immune checkpoint inhibitors have great potential for the treatment of gliomas; however, their therapeutic efficacy has been partially limited by their inability to efficiently cross the blood–brain barrier. The objective of this study was to evaluate the capability of FUSIN in achieving the locally enhanced delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain.
FUSIN enhanced the accumulation of aPD-L1 at the FUS-targeted brainstem by an average of 4.03- and 3.74-fold compared with intranasal (IN) administration alone in non-tumor mice and glioma mice, respectively.
An international and multidisciplinary team of researchers, clinicians and data scientists have been awarded a Sinergia grant from the Swiss National Science Foundation (SNSF) to improve treatment for children with aggressive brain tumours.
The new Sinergia consortium involves principal investigators from the DMG/DIPG Center Zurich, at University Children's Hospital, the ETH Zurich, and the Centre for Molecular Medicine Norway (NCMM). It aims to harness novel technologies for precision medicine in paediatric diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG).
The Sinergia consortium received CHF 3.1 million for a research project to discover therapeutic vulnerabilities in patient-derived preclinical DMG models, and to utilize a drug repurposing strategy whereby thousands of approved and investigational drugs are tested for anticancer activity.
Researchers have tested the effectiveness of targeted chemotherapy paired with MRI-guided focused ultrasound (MRgFUS) in murine models of DIPG.
Following IV administration of doxorubicin, MRgFUS-treated animals exhibited a 4-fold higher concentration of drug within the SU-DIPG-17 brainstem tumours compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals whose tumours also exhibited decreased Ki-67 expression.
These data provide critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may ameliorate DIPG chemotherapeutic approaches in children.
Ishida J, Alli S, Bondoc A, et al. MRI-guided focused ultrasound enhances drug delivery in experimental diffuse intrinsic pontine glioma. J. Control. Release (2020) https://doi.org/10.1016/j.jconrel.2020.11.010
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.
The study is the first to demonstrate an intravenous medication that can cross the blood-brain barrier.
Gregory, J.V., Kadiyala, P., Doherty, R. et al. Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy. Nat Commun 11, 5687 (2020). https://doi.org/10.1038/s41467-020-19225-7
Midatech Pharma PLC announces encouraging results from a Phase I study at UCSF University in patients with DIPG. Sabine Mueller MD PhD, Principal Investigator of the study, said: "The study has determined a proposed dose range for MTX110 for Phase II and has shown that repeated delivery of MTX110 via CED is feasible and safe. In an upcoming Phase II study efficacy in this patient population will be assessed." MTX110 was administered directly into the tumour via a micro-catheter using convection enhanced delivery ("CED") with gadolinium-enhanced intra-operative MRI to guide and track drug distribution to the tumour.
A combination of lipid vesicles and ultrasound waves can provide highly specific drug delivery to target sites in rat brains. A recent research project from ETH Zurich (Switzerland) has demonstrated an application of sound waves in combination with newly developed lipid vesicles for drug delivery, which can target drugs to precise locations within the brain. The team need to continue testing the method in animals and are currently looking at its applications in the treatment of brain tumors and some mental illnesses, such as anxiety.
Chiesi validates the power of Bioasis technology to propel drugs across the blood-brain barrier (BBB). Scientists at Bioasis Technologies Inc have worked for over a decade to develop a technology – the patented xB3 platform – which helps small molecules shuttle across the BBB safely. The xB3 platform is a very versatile, high capacity delivery system able to deliver antibodies, enzymes, siRNA as well as small molecules across the BBB.
CarThera, a French company that designs and develops innovative ultrasound-based medical devices to treat brain disorders, today announces that it has been selected by the EIC Accelerator Pilot to receive a €2 million ($2.3M) grant and €10.5M ($12M) in equity for the development of its DOMEUS project for the treatment of glioblastoma (GBM) patients.
A novel drug delivery system by the global engineering technologies company, Renishaw, was successfully used as part of an extension study to a first-in-human clinical trial for the treatment of Parkinson’s disease. As one of the novel infusion regimes, neuroinfuse is currently only used in approved clinical trial settings. In order to eventually make the device generally available to patients, Renishaw is seeking academic, clinical, and industrial partners across a wide range of indications, from oncology to neurodegenerative diseases.