Nanotherapeutic Penetrates Blood-Brain Barrier, Shows Promise in Glioblastoma

By Marilynn Larkin

March 16, 2021

NEW YORK (Reuters Health) - In a first-in-human trial, a nanotherapeutic, NU-0129, penetrated the blood-brain barrier after infusion into eight patients with recurrent glioblastoma, showing some efficacy and no severe side effects.

"This is the first time a nanotherapeutic has been shown to cross the blood-brain barrier when given through intravenous infusion," Dr. Priya Kumthekar of the Feinberg School of Medicine, Northwestern University in Chicago told Reuters Health by email. "Further, it was shown to alter the genetic machinery of a tumor to cause cell death through RNA interference."

"The novel spherical nucleic acid (SNA) platform on which it is based can be applied to other types of neurological diseases, including other tumor types, degenerative diseases such as Alzheimer's or even movement disorders such as Huntington's and Parkinson's," she added.

As reported in Science Translational Medicine, Dr. Kumthekar and colleagues developed the brain-penetrant RNA interference-based SNAs, which consist of gold nanoparticle cores covalently conjugated with densely packed small interfering RNA (siRNA) oligonucleotides.

Following previous preclinical assessments, they conducted toxicology and toxicokinetic studies in nonhuman primates and this in single-arm, open-label phase 0 proof-of-principle trial to determine safety, pharmacokinetics, intratumoral accumulation and the gene-suppressive activity of the treatment.

Eight patients with recurrent glioblastoma were treated with intravenous administration of SNAs carrying siRNA specific for the glioblastoma oncogene Bcl2Like12 (NU-0129), at a dose corresponding to 1/50th of the level at which they did not observe adverse events in previous experiments. Drug administration was followed by tumor resection.

The safety assessment revealed no grade 4 or 5 treatment-related toxicities. Various imaging technologies showed that the SNAs reached patient tumors in resected glioblastoma tissue; gold enrichment was seen in tumor-associated endothelium, macrophages, and tumor cells.

Further, NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison with a matched primary tumor.

The authors state, "Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of glioblastoma."

Dr. Kumthekar said next steps include using the technology "to create compounds that can be used to manipulate tumor growth in the future."

Dr. Vinay Puduvalli, Chair of Neuro-Oncology at The University of Texas MD Anderson Cancer Center in Houston told Reuters Health that the study "clearly breaks new ground" in the use of nanotherapeutics for brain tumors. "The proof-of-principle demonstration of the use of RNA-interference technology to block specific targets is both a necessary step and a significant advance in the field."

That said, he noted, "The authors showed that the nanoparticles were able to get into the resected part of the tumor, which often has disruptions in the blood-brain barrier... Whether the nanoparticles were able to achieve the same in the remaining infiltrative portion of the tumor, which may be protected by the blood-brain barrier, was not demonstrated."

"Further," he added, "the persistence of the nanoparticle in the tumor region close to six months after treatment raises questions about long-term effects of such treatment."

"The study demonstrates the feasibility of such nanotherapy approaches, which may help develop other such therapies, including combinations, once safety is well established," he said. "A phase I trial to assess safety of the treatment would be the next step. This should also include measures of long-term toxicity."

SOURCE: Science Translational Medicine, online March 10, 2021.