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.