Systemic delivery of bioactive molecules in the CNS is hampered by the blood-brain barrier, which has bottlenecked noninvasive physiological study of the brain and the development of CNS drugs. Here we report that irradiation with an ultrashort pulsed laser to the blood vessel wall induces transient leakage of blood plasma without compromising vascular integrity. By combining this method with a systemic injection, we delivered target molecules in various tissues, including the brain cortex. This tool allows minimally invasive local delivery of chemical probes, nanoparticles, and viral vectors into the brain cortex. Furthermore, we demonstrated astrocyte-mediated vasodilation in vivo without opening the skull, using this method to load a calcium indicator in conjunction with label-free photoactivation of astrocytes.femtosecond pulsed laser | laser tissue interaction | molecular delivery | permeability M icrovascular endothelial cells in the brain are interconnected through complex tight junctions, forming a physiological barrier against endogenous and exogenous molecules (1). Becauee of this blood-brain barrier (BBB), nearly 100% of macromolecules and more than 98% of small molecules do not cross the blood vessel wall. Thus, exogenously introduced molecular probes are widely used in vivo to study the molecular physiology of the brain. Systemic delivery through the blood circulation would be a safe, effective, and desirable method of distributing molecular probes or drugs into the brain.Various strategies have been proposed to circumvent the BBB. A transcranial approach invasively bypasses the BBB by drilling a hole in the head and injecting probes or drugs intracerebrally or intracerebroventricularly (2). At present, intracerebral injection is the gold standard for in vivo brain experiments; however, the invasiveness of opening the skull and inserting a pipette remains controversial (3, 4). A transnasal approach can noninvasively deliver molecular probes or drugs across the nasal mucosal barrier, but is limited to lipid-soluble small molecules (5). Another approach is to chemically modify therapeutic agents so that they can traverse the BBB effectively by enhancing lipid solubility, lowering molecular weight, or taking advantage of an endogenous transporter-mediated process. Various BBB disruption methods also have been proposed, including intracarotid arterial infusion of vasoactive agents and local ultrasonic irradiation with i.v. microbubble injection (6). However, no method allows the noninvasive and spatially specific delivery of large molecules into the brain.Near-infrared femtosecond pulsed lasers have been widely used for in vivo imaging because of their deep tissue penetration, reduced scattering, and localized nonlinear absorption. These properties also have enabled noninvasive optical modulation of live cells and tissues with subcellular resolution, including the generation of intracellular calcium, dissection of intracellular organelles, transient plasma membrane permeabilization, induction of arteria...
Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ.
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