Medulloblastoma
Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for approximately 20% of all childhood brain tumors. It is highly invasive and difficult to treat, with approximately 30% of patients considered untreatable. Even children who experience successful treatment may face serious long-term disabilities and health problems, mainly due to the adverse effects of radiation therapy and chemotherapy.
A Challenge in Drug Delivery
The blood-brain barrier (BBB) refers to the barrier between the brain capillary walls and the glial cells, as well as the barrier between the choroid plexus and the cerebrospinal fluid. It only allows specific types of molecules to pass from the bloodstream into the neurons of the brain and other surrounding cells. The presence of the blood-brain barrier is significant in preventing harmful substances from entering the brain through the bloodstream. However, it also hinders the transfer of most small and large molecule drugs (such as peptides, proteins, and nucleic acids), severely limiting the treatment options for central nervous system diseases such as neurodegenerative diseases, brain tumors, brain infections, and strokes.
The challenge persists in delivering drugs to affected brain tissues due to the protective role of the blood-brain barrier. This has been well-validated in the treatment of medulloblastoma, where approximately one-third of cases are mediated by the Sonic Hedgehog (SHH) signaling pathway (SHH-MB). These patients have poorer clinical outcomes, partially due to the limited entry of drugs caused by the blood-brain barrier, preventing drugs from reaching therapeutic concentrations.
A Novel Nanoparticle Drug Delivery System
Considering the difficulty of small molecule drugs in crossing the blood-brain barrier, researchers have turned to studying nanoparticles as a potential method to improve drug delivery to brain tissues. However, the existing nanoparticles carrying drugs have had limited success in breaking through intact or damaged blood-brain barriers. The research team of the Memorial Sloan Kettering Cancer Center has attempted to solve this problem by using active transportation. Their latest research findings were recently published in the Nature Materials sub-journal of Nature.
Study shows that endothelial cells in brain tumors express P-selectin and promote transcytosis of substances across the intact blood-brain barrier through caveolin-1-mediated endocytosis. Using this mechanism, Daniel E. Tylawsky et al. have developed targeted algae polysaccharide nanoparticles that bind to P-selectin. These nanoparticles carry the anticancer drug Vismodegib, which can efficiently penetrate the blood-brain barrier and actively transport it to brain tumor tissues without affecting normal brain tissues.
The effectiveness of this alginate nanoparticle drug delivery platform was validated in the SHH-MB mouse model with an intact blood-brain barrier. The experimental results showed that the alginate nanoparticles loaded with Vismodegib referred to as FiVi, demonstrated powerful anti-tumor effects at low doses and significantly reduced bone toxicity. Furthermore, additional ultra-low dose radiation therapy (XRT) further enhanced the treatment effectiveness.
Reference
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Tylawsky, D. E.; et al. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis. Nature Materials. 2023, 22(3): 391-399.
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