Age differences in photodynamic therapy‐mediated opening of the blood‐brain barrier through the optical clearing skull window in mice

Abstract

Background Photodynamic therapy (PDT), a minimally invasive therapeutic tool, has been an important option for post‐surgical treatment of malignant gliomas (MGs) in both adult and young patients. Recent studies have shown that PDT can also open the blood‐brain barrier (BBB). However, there are no optimized parameters of PDT for patients at different ages. To determine whether there are age differences in PDT effects on the BBB, we studied PDT‐related BBB opening through the optical clearing skull window in healthy 4‐ and 8‐week‐old mice. Methods In this work, we realized BBB opening by combining PDT with the optical clearing skull window by using different radiant exposures (635 nm, 10–20–30–40 J/cm2) and 5‐aminole‐vulinic acid (5‐ALA, 20 mg/kg). Then, we evaluated BBB permeability by: (i) spectrofluorimetric measuring of Evans Blue dye (EBd) leakage; (ii) confocal imaging of 70 kDa FITC‐dextran extravasation and the BBB integrity; and (iii) histological analysis of brain tissues. Results Using the skull optical clearing method, we demonstrated PDT‐induced BBB opening to EBd and FITC‐dextran in a radiant exposure manner. The histological analysis revealed the different severities of vasogenic edema corresponding to radiant exposures. Besides, the PDT‐related increase in the BBB permeability to high weight molecules (EBd and FITC‐dextran) and solutes (vasogenic edema) was more pronounced in 4‐week‐old mice than in 8‐week‐old mice. Conclusions The more pronounced PDT‐induced BBB disruption in juvenile mice compared with adult mice suggests age differences in PDT‐related BBB opening. This might be an important informative platform for a new application of PDT as a method for brain drug delivery, especially for post‐surgical treatment of MGs. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Photodynamic therapy of brain tumors and novel optical coherence tomography strategies for in vivo monitoring of cerebral fluid dynamics

“…Thus, the vascular resistance to photo-induced oxidative stress decreases, resulting in the redistribution of calcium, reduction of in°ux and calcium release from intracellular storage. [68][69][70][71] In our study, 48,49 using markers of neurovascular units such as SMI (the vascular endothelial cells), laminin (the basal membrane), and GFAP (the astrocytes), we show their disorders resulting in an increase of the BBB permeability, therefore, the tested tracer (dextran, 70 kDa or liposomes) passed through the vascular endothelium and the basal membrane with further distribution between astrocytes ( Fig. 3).…”

“…The traditional explanation of the anti-cancer PDT e®ect is 1 O 2 -induced damage of the endothelial cells resulting in tumor microvasculature collapse. 42,43 However, in recent several studies have been shown completely new vascular mechanisms of PDF such as an increase in the blood-brain barrier (BBB) permeability [44][45][46][47][48][49][50] (Fig. 3).…”

“…[59][60][61][62] Recently, it has been revealed that PDT, as a widely used tool for therapy of GBM, 14,[30][31][32][33][34][35][36][37][38][39][40][41] can also e®ectively and site-speci¯cally open BBB. [44][45][46][47][48][49][50] Hirschberg 44 using 400 m bare°at-end quartz¯ber (635 nm) and stereotaxic procedure clearly show that the ALA-PDT causes the opening of BBB. At the low°uence levels of 9L, the ALA-PDT opens the BBB rapidly without any damages of brain tissues, the disrupted BBB is observed during 2 h following PDT and restored during the next 72 h. 44 The disruption of BBB is greater using the higher°u ence level of 26 J but the damages of surrounding tissues (necrosis, edema, hemorrhage) are observed 17 days.…”

“…43 We con¯rmed these results in our work. [48][49][50] Using laser 635 nm (10-40 J/cm 2 , 40-100 mV, 250-400 s) and 5-ALA (NIOPIK, Russia, 20 mg/kg, i.v.) we showed opening of the BBB to°uorescent liposomes and for high weight molecular molecules in the middle dose of laser in°uences on the brain tissues (15-20 J/cm 2 , 40-60 mV, 375-333 s) ( Fig.…”

“…Ctrthe control group, no solute leakage; laser (10-20-30-40 J/cm 2 Þ causes the perivascular edema (black arrows), which looks as empty spaces around cerebral vessels. 48 tissues gave a new impulse in the reassessment of classical explanation of the role of the lymphatics in the brain drainage. 98,104,105 In these studies, which were performed on rodents and human brain, it was clearly demonstrated that the meningeal lymphatic vessels are localized along the main cerebral venous sinus and express all of the molecular hallmarks of lymphatic endothelium.…”