Photodynamic Opening of the Blood–Brain Barrier Using Different Photosensitizers in Mice

Abstract

In a series of previous studies, we demonstrated that the photodynamic therapy (PDT), as a widely used tool for treatment of glioblastoma multiforme (GBM), also site-specifically opens the blood–brain barrier (BBB) in PDT-dose and age-related manner via reversible disorganization of the tight junction machinery. To develop the effective protocol of PDT-opening of the BBB, here we answer the question of what kind of photosensitizer (PS) is the most effective for the BBB opening. We studied the PDT-opening of the BBB in healthy mice using commercial photosensitizers (PSs) such as 5-aminolevulenic acid (5-ALA), aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc) and new synthetized PSs such as galactose functionalized ZnPc (GalZnPc). The spectrofluorimetric assay of Evans Blue albumin complex (EBAC) leakage and 3-D confocal imaging of FITC-dextran 70 kDa (FITCD) extravasation clearly shows a revisable and dose depended PDT-opening of the BBB to EBAC and FITCD associated with a decrease in presence of tight junction (TJ) in the vascular endothelium. The PDT effects on the BBB permeability, TJ expression and the fluorescent signal from the brain tissues are more pronounced in PDT-GalZnPc vs. PDT-5-ALA/AlPcS/ZnPc. These pre-clinical data are the first important informative platform for an optimization of the PDT protocol in the light of new knowledge about PDT-opening of the BBB for drug brain delivery and for the therapy of brain diseases.

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma

“…The BBBO-mediated activation of the MLVs might be explained by the expression of similar proteins in the lymphatic and blood vessel endothelium, including CLND-5, ZO-1, JAM, VE-cadherin, CD31 [ 86 , 87 ]. In various series of our experimental studies, we show that PDT-BBBO causes temporal changes in the TJs expression in both the blood and lymphatic vessel endothelium [ 37 , 88 , 89 ].…”

A review of career devoted to Biophotonics – In memoriam to Ekaterina Borisova (1978–2021)

“…Another significant scientific scope of research was extensively studied by Assoc. Prof. Ekaterina Borisova and colleagues -the photodynamic opening of the blood-brain barrier [64] and evaluation of pathways for brain clearing [65], also including the use of different photosensitizers [66], optimizing laser technologies for targeted opening of the blood-brain barrier and targeted drug brain delivery [67,68].…”

“…Russian-Bulgarian collaboration was very productive, including organization of exchange of students, training courses and publication more than 30 articles in the peer review journals (see Refs. [64][65][66][67][68][87][88][89][90][91][92][93][94][95][96][97][98][99]) as well as preparation of several thesis of candidate of science. She kindly allowed us to publish for the first time the maps of autofluorescence emission of normal skin in vivo measured by her in the monograph (Fig.…”

Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events

“…In another study conducted by the same group, the more pronounced PDT‐induced BBB disruption was observed in juvenile mice compared with adult mice suggesting age differences in PDT‐related BBB opening (Zhang et al., 2019). Recently, Semyachkina‐Glushkovskay et al evaluated PDT‐opening of BBB using other PSs from the family of phthalocyanines, such as aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc), and a galactose functionalized ZnPc (GalZnPc) in preclinical assays with healthy mice (Semyachkina‐glushkovskaya et al., 2020). Regarding this last PSs, the galactose functionalization causes the more pronounced increase in the BBB permeability to EBAC induced by GalZnPc which is associated by enhancement of the transendothelial permeability via activation of protein kinase C (PKC), also with decrease in TJ protein levels (CLND, OCC, and JAM) (Semyachkina‐glushkovskaya et al., 2020).…”

“…Recently, Semyachkina‐Glushkovskay et al evaluated PDT‐opening of BBB using other PSs from the family of phthalocyanines, such as aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc), and a galactose functionalized ZnPc (GalZnPc) in preclinical assays with healthy mice (Semyachkina‐glushkovskaya et al., 2020). Regarding this last PSs, the galactose functionalization causes the more pronounced increase in the BBB permeability to EBAC induced by GalZnPc which is associated by enhancement of the transendothelial permeability via activation of protein kinase C (PKC), also with decrease in TJ protein levels (CLND, OCC, and JAM) (Semyachkina‐glushkovskaya et al., 2020). PKC is a family of serine/threonine protein kinases that regulate various cellular functions, including adhesion, proliferation, differentiation, etc., and specifically PKCa which as associated with EC contraction and disassembly of VE‐cadherin junctions (Abdala‐Valencia & Cook‐Mills, 2006; Konopatskaya & Poole, 2010).…”