BBB-crossing nanoparticles promise exciting future for drug delivery

Researchers have discovered a ‘potent’ new way to carry cancer drugs in nanoparticles across the blood-brain barrier (BBB) – with exciting implications for treating brain diseases.

The new method not only delivered vismodegib-laden nanocarriers to treat medulloblastoma tumours in mice successfully, but did so without the side-effects associated with current treatments.

In future, it could also be used to transport drugs to treat other brain cancers, brain metastases, and brain diseases - including epilepsy, multiple sclerosis, stroke, and neurodegenerative disorders.

“From our studies so far, it seems that it doesn’t matter what drug you put inside the particle; we can get it across the barrier,” said the research’s co-leader, Dr Daniel A. Heller, from the Memorial Sloan Kettering Institute (SKI).

“Currently, the few drugs used to treat brain tumors are those that get through the blood-brain barrier.

“But now, we may have a much wider range of drugs that can reach brain tumors effectively.”

In the new study, the SKI group built on its previous work using nanoparticles made from fucoidan - a polysaccharide extracted from seaweed, with an affinity for the abundant P-selectin proteins found within tumour-feeding blood vessels and the BBB. It found that the vismodegib-filled particles (FiVis) bound to P-selectin and were transported across the intact blood-brain barrier via caveolae-mediated endocytosis and transcytosis.

By combining the FiVis nanoparticles with a low dose of X-ray irradiation (XRT) to boost levels of P-selectin within the tumour, they were able to prolong the lives of mice with advanced-stage Sonic hedgehog medulloblastoma (SHH-MB), a highly aggressive form of paediatric brain cancer. “Although treatment with 10 mg kg^–1 FiVis considerably prolonged survival on its own,” the group noted, “when combined with 0.25 Gy XRT, FiVis treatment at 10 mg kg^–1 further extended survival by more than twofold.”

As well as proving successful in treating SHH-MB in mice, the FiVis delivery mechanism also managed to avoid the serious vismodegib side-effects that children experience with current delivery methods – notably premature bone growth plate fusion due to the high drug doses required. “We could see the particles accumulating at the site of the medulloblastoma tumors, where P-selectin is prominent, and not in normal brain regions or other parts of the body,” Dr Heller noted. “We found that even short-term treatment of mice aged 10 days with high doses of vismodegib caused obvious growth stunting,” the report added. “Notably, these growth defects did not occur in young mice treated with FiVis at 10 mg kg^–1.”

The implications of the SKI group’s findings are many, including the potential for fucoidan therapy to improve the efficiency of many classes of cancer drugs - in particular by allowing clinicians to treat patients with both radiation and drug combinations in more tolerable doses. The method could also be tried to treat other forms of brain cancer - such as glioma - as well as a range of non-cancerous brain diseases. 

“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,” said Dr Praveen Raju, co-senior author of the report.

“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.”