The technology allows for the enhanced delivery of anti-cancer drugs to the specific locations of brain tumors while sparing normal brain regions. The result is improved effectiveness and reduced toxicities of anti-cancer drugs, according to their study, published March 2, 2023, in Nature Materials.

"We show that we can more successfully deliver lower doses of the drug in a more effective manner to the specific sites of tumor within the brain, while sparing the bone toxicity that is seen in younger patients," says Praveen Raju, MD, PhD, Co-Director of the Children's Brain and Spinal Tumor Center at Mount Sinai Kravis Children's Hospital, and senior author of the study.

Medulloblastoma is the most common malignant pediatric brain tumor, accounting for about 20 percent of all brain tumors in children. It is highly aggressive and difficult to treat, and is considered incurable in nearly 30 percent of patients. Even children who are "cured" experience severe long-term disabilities and health issues, primarily due to the adverse side effects of radiation and chemotherapy. Site-directed drug delivery to the affected brain tissue is hindered by a distinct and highly regulated blood-brain barrier, which normally protects the brain from infections or other harmful substances.

In this study, the researchers made use of a normal mechanism that the immune system uses to traffic white blood cells to sites of infection, inflammation, or tissue injury. Rather than randomly sending immune cells throughout the body, there is a homing mechanism on activated blood vessels that immune cells use to go where they are needed. The researchers used this unique homing feature, which is also found within brain tumor blood vessels, to target their drug-loaded nanoparticles to the site of the disease and not the normal brain regions.

Using the new drug delivery platform in a genetically relevant mouse model of medulloblastoma, the research team was able to enhance the efficacy of an anti-cancer drug that could potentially be useful for a subset of medulloblastoma patients, but which is currently limited by the bone toxicity it secondarily creates in children.

"In addition, we showed that this targeted drug delivery approach is further enhanced with very-low-dose radiation, which is a standard therapy already used for most children and adults with primary and metastatic brain tumors," says Dr. Raju, Associate Professor of Neurology, Neuroscience, and Pediatrics at Icahn School of Medicine at Mount Sinai. "Importantly, our blood-brain barrier drug delivery approach has the potential to improve the delivery of drugs for other pediatric brain tumors and localized diseases in the brain in both children and adults, including focal epilepsy, multiple sclerosis, stroke, and possibly neurodegenerative disorders."

"Certain proteins appear on blood vessels at sites of inflammation that help white blood cells exit the bloodstream. They work like police officers at the site of a car accident, who let in emergency personnel to help," says Daniel Heller, PhD, Head of the Cancer Nanomedicine Laboratory and Member in the Molecular Pharmacology Program at Memorial Sloan Kettering Cancer Center, and senior author on the study. "We sent in our own emergency personnel, in the form of drug-loaded nanoparticles, composed of certain sugar molecules that can target these same proteins."

The researchers anticipate that continued investigation and development of this method to harness and improve the transport of materials across the blood-brain barrier and other sites will be instrumental for improving the efficacy of several classes of approved and experimental therapeutics. This drug delivery platform can be used to treat cancers in the brain and other sites of the body, as well as other inflammation-related diseases in the central nervous system and elsewhere.

Dr. Raju and his colleagues were recently awarded $2.8 million from the National Institutes of Health to dissect the mechanism of medulloblastoma tumor cell maturation and to identify targets to induce differentiation therapeutically using high-resolution genomics and epigenetics techniques and this new blood-brain barrier penetrating drug delivery platform. Dr. Raju was also recently awarded a ChadTough Defeat DIPG Foundation Game Changer Grant of $600,000 that will support research into using this drug delivery approach for diffuse intrinsic pontine glioma (DIPG), a difficult-to-treat pediatric brain tumor localized to the pons, a part of the brain stem. Oren Becher, MD, Chief of the Jack Martin Fund Division of Pediatric Hematology-Oncology, the Steven Ravitch Chair in Pediatric Hematology-Oncology, and Professor of Pediatrics at Icahn Mount Sinai, is collaborating in that research.

Funding for the study was provided by National Institutes of Health grant R01NS116353; National Cancer Institute grant R01CA215719; the Cancer Center Support Grant P30CA008748; the American Cancer Society Research Scholar Grant GC230452; Unravel Pediatric Cancer; Emerson Collective; the Pershing Square Sohn Cancer Research Alliance; The Hartwell Foundation; the Expect Miracles Foundation -- Financial Services Against Cancer; MSK's Cycle for Survival's Equinox Innovation Award in Rare Cancers; the Alan and Sandra Gerry Metastasis Research Initiative; Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research; the Experimental Therapeutics Center; the Imaging & Radiation Sciences Program; and the Center for Molecular Imaging and Nanotechnology of Memorial Sloan Kettering Cancer Center.