Increased nanoparticle‐loaded exogenous macrophage migration into the brain following PDT‐induced blood–brain barrier disruption

Abstract

Background and Objective Photodynamic therapy (PDT)-induced disruption of the blood–brain barrier (BBB) has been investigated as a technique for the delivery of therapeutic agents to selective regions of the brain. The purpose of this study was to determine the effects of PDT on the migration of systemically administered exogenous macrophages (Ma) loaded with iron oxide nanoparticles in non-tumor bearing rats. Materials and Methods A control group consisting of three Sprague–Dawley rats was injected with iron oxide-loaded rat alveolar Ma via jugular vein catheter while two animals were subjected to intracranial injection of iron oxide-loaded Ma. PDT-treated animals were injected with photosensitizer (AlPcS2a; 1 mg/kg i.p.) followed by light irradiation (wavelength = 670 nm; light dose = 2.5 J) 48 hours later. Light irradiation was performed through the skull. Prior to light irradiation, iron oxide-loaded Ma were administered to each animal. Animals in all groups were imaged in a 7 Tesla (T) magnetic resonance (MR) imager to determine the extent of PDT-induced edema and to evaluate for the presence of iron oxide nanoparticles. Animals were sacrificed 7 days post-Ma administration and their brains analyzed for the presence of iron oxide using Perls staining. Results Significant uptake of iron oxide nanoparticles by rat alveolar Ma was observed thus providing the rationale for their use as delivery vectors. Histopathological analyses failed to find evidence of iron oxide in normal rat brain. Accumulations of iron oxide-loaded Ma were observed in both MR images and histological sections of non-tumor bearing rat brain following PDT-induced disruption of the BBB. Conclusions MR imaging was shown to be useful for localizing iron-oxide loaded Ma in rat brains. Exogenous Ma are incapable of traversing the normal BBB and therefore, the use of Ma as delivery vehicles into the brain requires selective disruption of the BBB.

Increased sensitivity of glioma cells to 5-fluorocytosine following photo-chemical internalization enhanced nonviral transfection of the cytosine deaminase suicide gene

“…In addition to the PDT effect on the endosomal membrane (PCI effect), PDT also has a direct effect on the vasculature in the vicinity of the illuminated volume. PDT has been shown to open the blood brain barrier both to drugs and to cells carrying magnetic nano-particles [39, 40]. This effect can prove advantageous by increasing delivery of gene carrying nanoparticles that can protect the gene-carrying polyplex during circulation, allowing for systemic injection and cellular internalization.…”

Macrophages as nanoparticle delivery vectors for photothermal therapy of brain tumors

“…An additional complicating factor is the presence of the BBB which was circumvented in this study. Recent studies by our group have shown that exogenously loaded Ma are unable to traverse the BBB in normal rat brain suggesting that elimination of infiltrating glioma cells requires targeted opening of the BBB prior to Ma administration [52]. BBB infiltration could therefore be accomplished using a variety of targeted approaches including ultrasound or PDT as described previously in this review.…”

“…It may thus be possible to confine BBB opening to the surgical resection cavity via balloon catheter light applicators [51]. The effects of PDT on the migration of intravenous injected exogenous Ma loaded with iron oxide nanoparticles in nontumor bearing rats has been investigated [52]. The extent of loaded Ma infiltration was evaluated using MRI and histology.…”

Blood–brain barrier and laser technology for drug brain delivery

“…So, the traditional explanation of anti-cancer PDT e®ect is However, several studies show that PDF increases the BBB permeability temporally. [67][68][69][70] Hirschberg et al 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. 67 The disruption of BBB is greater using the higher°uence level of 26 J but the damages of surrounding tissues (necrosis, edema, hemorrhage) are observed for 17 days.…”

“…7). [68][69][70] The nanoparticles show great promise for PDT. 75 Madsen et al in experiment in vivo showed that PDT (the photosensitizer - Despite the promising e®ect of PDT on the transportation of macrophages through the BBB, there is an important question: \How the brain cleans from gold nanoparticles and is it possible to use this procedure for human?…”