As such, the integrity of the BBB can considerably impact treatment efficacy. Hydrophilic small-molecule drugs are routinely excluded from the brain by tight junctions and, while many lipophilic drugs are capable of entry via passive diffusion, penetration into diseased brain tissue is inefficient and typically requires high drug doses, often resulting in dose-limiting systemic toxicity 3. These restrictive physical and functional barriers inhibit drug exposure to intracranial tissues 2. Characteristic tight junctions between adjacent brain endothelial cells block paracellular transport, and the passive entry of molecules is constrained to a narrow window of size and lipophilicity. The BBB is comprised of a network of specialized endothelial cells, pericytes and astrocytes that prevent material extravasation 1.

Site-directed drug delivery to brain parenchymal tissue is a desirable but elusive goal due to the distinct and highly regulated blood–brain barrier (BBB). Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood–brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue.

We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood–brain barrier crossing. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling.

Parallels 14 activation key