Researchers from Mount Sinai Health System and Memorial Sloan Kettering Cancer Center have developed a novel drug delivery approach that uses nanoparticles to enable more efficient and targeted delivery of cancer drugs to treat brain tumors in children.
The technology allows for improved delivery of anti-cancer drugs to specific brain tumor locations while sparing normal brain regions. The result is improved efficacy and reduced toxicity of cancer drugs, according to their study, published March 2, 2023, in Natural materials.
“We show that we can more effectively deliver lower doses of the drug more effectively to specific tumor sites in the brain, while sparing the bone toxicity 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 lead author of the study.
Medulloblastoma is the most common malignant pediatric brain tumor, accounting for approximately 20% of all brain tumors in children. It is very aggressive and difficult to treat, and is considered incurable in nearly 30% of patients. Even children who are “cured” experience serious long-term disabilities and health problems, primarily due to the adverse side effects of radiation therapy and chemotherapy. Directed drug delivery to affected brain tissue is impeded 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 used a normal mechanism that the immune system uses to transport white blood cells to sites of infection, inflammation or tissue damage. Rather than sending immune cells randomly all over 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 function, which is also found in the blood vessels of brain tumors, to target their drug-loaded nanoparticles to the site of disease and not to normal brain regions.
By using the novel drug delivery platform in a genetically relevant mouse model of medulloblastoma, the research team was able to improve the efficacy of an anti-cancer drug that might potentially benefit a subset of medulloblastoma patients. , but which is currently limited by bone. toxicity that it creates secondarily in children.
“Furthermore, we have shown that this targeted drug delivery approach is further enhanced by very low dose radiotherapy, which is a standard therapy already used for most children and adults with primary and metastatic brain tumours” , says Dr. Raju, associate professor. of Neurology, Neuroscience, and Pediatrics at the Icahn School of Medicine at Mount Sinai. “Importantly, our blood-brain barrier drug delivery approach has the potential to improve drug delivery for other pediatric brain tumors and localized brain diseases in 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 move out of the bloodstream. They function like police officers at the site of a car accident, who let emergency personnel in to help,” says Daniel Heller, PhD, head of the Cancer Nanomedicine Laboratory and member of the Molecular Pharmacology Program at Memorial. Sloan Kettering Cancer Center, and lead author of the study. “We sent in our own emergency personnel, in the form of drug-laden nanoparticles made up of certain sugar molecules that can target those same proteins.”
The researchers anticipate that continued research and development of this method to harness and enhance the transport of materials across the blood-brain barrier and other sites will help improve 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 recently received $2.8 million from the National Institutes of Health to dissect the mechanism of medulloblastoma tumor cell maturation and identify targets to induce therapeutic differentiation using genomics and diagnostic techniques. high-resolution epigenetics and this novel blood-brain barrier penetrating drug delivery platform. Dr. Raju was also recently awarded a ChadTough Defeat DIPG Foundation Game Changer grant of $600,000 which will support research into the use of this drug delivery approach for diffuse intrinsic pontine glioma (DIPG), a difficult pediatric brain tumor. to be treated localized to the pons, part of the brainstem. Oren Becher, MD, Chief of the Pediatric Hematology-Oncology Division of the Jack Martin Fund, Steven Ravitch Chair in Pediatric Hematology-Oncology, and Professor of Pediatrics at Icahn Mount Sinai, is collaborating in this research.
Funding for the study was provided by National Institutes of Health grant R01NS116353; grant R01CA215719 from the National Cancer Institute; Cancer Center Support Grant P30CA008748; the American Cancer Society Research Scholar Grant GC230452; Unraveling pediatric cancer; Emerson Collective; the Pershing Square Sohn Cancer Research Alliance; The Hartwell Foundation; the Expect Miracles Foundation – Cancer Financial Services; MSK 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 Cancer Research Foundation; the Center for Experimental Therapeutics; the Imaging and Radiation Sciences program; and the Center for Molecular Imaging and Nanotechnology at Memorial Sloan Kettering Cancer Center.
