Site‐specific opening of the blood‐brain barrier

Abstract

The blood-brain barrier (BBB) poses a significant impediment for the delivery of therapeutic drugs into the brain. This is particularly problematic for the treatment of malignant gliomas which are characterized by diffuse infiltration of tumor cells into normal brain where they are protected by a patent BBB. Selective disruption of the BBB, followed by administration of anti-cancer agents, represents a promising approach for the elimination of infiltrating glioma cells. A summary of the techniques (focused ultrasound, photodynamic therapy and photochemical internalization) for site-specific opening of the BBB will be discussed in this review. Each approach is capable of causing localized and transient opening of the BBB with minimal damage to surrounding normal brain as evidenced from magnetic resonance images and histology. T1-weighted MRI contrast enhanced images (a, b) showing focal enhancement in the area of light treatment. Fluence levels of 9 (a) and 17 J (b) at a fluence rate of 10 mW were performed 4 h following ALA administration (125 mg kg−1 i.p.). Scans were acquired 3–4 h post-PDT and 15 min following i.p. Gd contrast administration. Coronal H&E sections (c, d) taken from the brains of Fischer rats 14 days post-treatment. No significant pathology was observed following delivery of 9 J (c). At the high fluence (17 J), extensive infiltration of lymphocytes and macrophages was apparent as shown by the arrow in (d) [19]. Reprinted with permission.

Brainpeps: the blood–brain barrier peptide database

“…Because selective and sufficient entry of drugs and their modification tools is important in CNS drug design, while still limiting the access of toxic compounds, knowledge about the BBB behaviour of drugs is highly researched (Chu et al 2006;Engelhardt 2006). Moreover, the addition of physical techniques to temporarily and spatial-selectively open the BBB, can even further extend the clinical possibilities (Campbell et al 2011;Liu et al 2010;Madsen and Hirschberg 2010;Rossi 2011).…”

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?…”

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors

“…[19] In low-grade gliomas, BBTB resembles BBB, while in high-grade gliomas, BBTB becomes disrupted and "leaky," characterized by major alterations of the normal vascular function manifested by contrast-enhanced MRI by Dhermain et al [19,26] However, the magnitude of this disruption is unlikely sufficient to allow drug penetration in therapeutically meaningful quantities, and thus BBTB remains a major obstacle for brain drug delivery. [27,28] …”