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.
Highlights
The blood–brain barrier (BBB) is a major hindrance for the effective delivery of therapeutic compounds to the brain [1]
Here we study the BBB opening in healthy mice using the Photodynamic therapy (PDT) protocol with different PS, including commercial PS such as 5-aminolevulenic acid (5-ALA) and aluminum phthalocyanine disulfonate (AlPcS) as well as new synthesized PS such as zinc phthalocyanine (ZnPc) and functionalized by galactose ZnPc (GalZnPc)
Photodynamic Opening of the BBB Using Different PSs. In this session of experiments, we studied the PDT-opening of the BBB using different PSs, including two commercial PSs such as 5-ALA and AlPcS as well as new synthetized ones, such as ZnPc and its functionalized form galactose functionalized ZnPc (GalZnPc)
Summary
The blood–brain barrier (BBB) is a major hindrance for the effective delivery of therapeutic compounds to the brain [1]. Nowadays the photodynamic effect on the BBB is actively discussed as a new strategy for drug brain delivery, especially for post-surgery therapy of glioblastoma multiforme (GBM) [6]. For the first time a targeted disruption of the BBB following a 5-aminolevulenic acid (5-ALA) mediated PDT via the opened skull was shown by Hirschberg et al in 2008 [9]. In this work we attempt to answer the question of what kind of photosensitizer might be most effective for PDT-opening of the BBB. We analyzed the BBB permeability to high molecular weight molecules using two types of photosensitizers (PS) such as 5-ALA and phthalocyanines (PCs) since their application for drug delivery systems has been shown in other studies [16,17]
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