Search Results
Photobiomodulation of lymphatic drainage and clearance: Perspective strategy for augmentation of meningeal lymphatic functions
2020, Semyachkina-Glushkovskaya, Oxana, Abdurashitov, Arkady, Dubrovsky, Alexander, Klimova, Maria, Agranovich, Ilana, Terskov, Andrey, Shirokov, Alexander, Vinnik, Valeria, Kuzmina, Anna, Lezhnev, Nikita, Blokhina, Inna, Shnitenkova, Anastassia, Tuchin, Valery, Rafailov, Edik, Kurths, Jurgen
There is a hypothesis that augmentation of the drainage and clearing function of the meningeal lymphatic vessels (MLVs) might be a promising therapeutic target for preventing neurological diseases. Here we investigate mechanisms of photobiomodulation (PBM, 1267 nm) of lymphatic drainage and clearance. Our results obtained at optical coherence tomography (OCT) give strong evidence that low PBM doses (5 and 10 J/cm2) stimulate drainage function of the lymphatic vessels via vasodilation (OCT data on the mesenteric lymphatics) and stimulation of lymphatic clearance (OCT data on clearance of gold nanorods from the brain) that was supported by confocal imaging of clearance of FITC-dextran from the cortex via MLVs. We assume that PBM-mediated relaxation of the lymphatic vessels can be possible mechanisms underlying increasing the permeability of the lymphatic endothelium that allows molecules transported by the lymphatic vessels and explain PBM stimulation of lymphatic drainage and clearance. These findings open new strategies for the stimulation of MLVs functions and non-pharmacological therapy of brain diseases.
Music improves the therapeutic effects of bevacizumab in rats with glioblastoma: Modulation of drug distribution to the brain
2022, Semyachkina-Glushkovskaya, Oxana, Diduk, Sergey, Anna, Eroshova, Elina, Dosadina, Artem, Kruglov, Khorovodov, Alexander, Shirokov, Alexander, Fedosov, Ivan, Dubrovsky, Alexander, Blokhina, Inna, Terskov, Andrey, Navolokin, Nikita, Evsukova, Arina, Elovenko, Daria, Adushkina, Viktoria, Kurths, Jürgen
Background: The development of new methods for modulation of drug distribution across to the brain is a crucial step in the effective therapies for glioblastoma (GBM). In our previous work, we discovered the phenomenon of music-induced opening of the blood-brain barrier (OBBB) in healthy rodents. In this pilot study on rats, we clearly demonstrate that music-induced BBB opening improves the therapeutic effects of bevacizumab (BZM) in rats with GBM via increasing BZM distribution to the brain along the cerebral vessels. Methods: The experiments were performed on Wistar male rats (200-250 g, n=161) using transfected C6-TagRFP cell line and the loud rock music for OBBB. The OBBB was assessed by spectrofluorometric assay of Evans Blue (EB) extravasation and confocal imaging of fluorescent BZM (fBZM) delivery into the brain. Additionally, distribution of fBZM and Omniscan in the brain was studied using fluorescent and magnetic resonance imaging (MRI), respectively. To analyze the therapeutic effects of BZM on the GBM growth in rats without and with OBBB, the GBM volume (MRI scans), as well as immunohistochemistry assay of proliferation (Ki67 marker) and apoptosis (Bax marker) in the GBM cells were studied. The Mann-Whitney-Wilcoxon test was used for all analysis, the significance level was p < 0.05, n=7 in each group. Results: Our finding clearly demonstrates that music-induced OBBB increases the delivery of EB into the brain tissues and the extravasation of BZM into the brain around the cerebral vessels of rats with GBM. Music significantly increases distribution of tracers (fBZM and Omniscan) in the rat brain through the pathways of brain drainage system (perivascular and lymphatic), which are an important route of drug delivery into the brain. The music-induced OBBB improves the suppressive effects of BZM on the GBM volume and the cellular mechanisms of tumor progression that was accompanied by higher survival among rats in the GBM+BZM+Music group vs. other groups. Conclusion: We hypothesized that music improves the therapeutic effects of BZM via OBBB in the normal cerebral vessels and lymphatic drainage of the brain tissues. This contributes better distribution of BZM in the brain fluids and among the normal cerebral vessels, which are used by GBM for invasion and co-opt existing vessels as a satellite tumor form. These results open the new perspectives for an improvement of therapeutic effects of BZM via the music-induced OBBB for BZM in the normal cerebral vessels, which are used by GBM for migration and progression.
Photodynamic Opening of the Blood–Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors
2022, Semyachkina-Glushkovskaya, Oxana, Terskov, Andrey, Khorovodov, Alexander, Telnova, Valeria, Blokhina, Inna, Saranceva, Elena, Kurths, Jürgen
Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood–brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM.
Intranasal Delivery of Liposomes to Glioblastoma by Photostimulation of the Lymphatic System
2022, Semyachkina-Glushkovskaya, Oxana, Shirokov, Alexander, Blokhina, Inna, Telnova, Valeria, Vodovozova, Elena, Alekseeva, Anna, Boldyrev, Ivan, Fedosov, Ivan, Dubrovsky, Alexander, Khorovodov, Alexandr, Terskov, Andrey, Evsukova, Arina, Elovenko, Daria, Adushkina, Viktoria, Tzoy, Maria, Agranovich, Ilana, Kurths, Jürgen, Rafailov, Edik
The blood–brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice.