Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

Rodriguez, Analiz; Tatter, Stephen B.; Debinski, Waldemar

doi:10.3390/pharmaceutics7030175

Cited by 97 publications

(68 citation statements)

References 69 publications

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“…Mannitol-induced disruption of the BBBP has been reported in other animal models, which demonstrate increased permeability to Evans Blue, methotrexate, radiolabeled markers including [ 14 C]-sucrose and 86 Rb +19, 33 , and in clinical use for therapeutic delivery in humans 34, 35 . One study by Cosolo et al described methotrexate levels 4–5 times higher following intra-arterial mannitol-injection compared to non-injected hemisphere in rats, in keeping with our total brain PS comparison between mannitol and saline treated mice 33 .…”

Section: Discussionmentioning

confidence: 82%

Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model

Weidman

Foley

Kallas

et al. 2016

American Journal of Neuroradiology

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Background and Purpose Permeability surface area product has been suggested as a marker for BBB permeability with potential applications in clinical care and research. However, few studies have demonstrated its correlation with actual quantitative measurements of BBB permeability. Our aim was to demonstrate the correlation of quantitative permeability surface area product and BBB permeability in a murine model by histologic confirmation. Materials and Methods Coronal MRI was performed on mice treated with mannitol (n=6) for disruption of the BBB and controls treated with saline (n=5). Permeability surface area product was determined by ROI placement and compared between saline and mannitol treated mice. Correlation was made with contrast enhancement measurements and immunohistologic stained sections of tripeptidyl peptidase-1 distribution in mice treated with mannitol and saline followed by injection of a viral vector containing the CLN2 gene, which directs production of tripeptidyl peptidase-1. Results Significantly increased permeability surface area product was seen in mannitol compared to saline-treated mice in the whole brain (P = 0.008), MCA territory (P = 0.014) and mixed vascular territories (P = 0.008). These findings were compared to contrast enhancement measurements of BBB permeability and correlated with immunohistologic stained sections demonstrating BBB permeability to a large vector. Conclusion Permeability surface area product is increased in situations with known disruptions of the BBB, as evidenced by immunologic staining of large vector passage through the BBB and concordance with contrast enhancement measurements in a murine model. Quantitative permeability surface area product has potential as an imaging marker of BBB permeability.

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Section: Discussionmentioning

confidence: 82%

Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model

Weidman

Foley

Kallas

et al. 2016

American Journal of Neuroradiology

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“…Invasive tumor cells that lie beyond the enhancing tumor border in areas protected by the intact BBB limit the efficacy of systemically administered drugs [12,13,34,35], and locally administered therapeutics do not diffuse well beyond the resection cavity [36,37]. Standard polymeric nanoparticles can provide extended drug release; however, they are immobilized in the complex tumor parenchyma [38,39] and do not spread well within tumors.…”

Section: Discussionmentioning

confidence: 99%

MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound

Timbie

Afzal

Date

et al. 2017

Journal of Controlled Release

105

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Systemically administered chemotherapeutic drugs are often ineffective in the treatment of invasive brain tumors due to poor therapeutic index. Within gliomas, despite the presence of heterogeneously leaky microvessels, dense extracellular matrix and high interstitial pressure generate a “blood-tumor barrier” (BTB), which inhibits drug delivery and distribution. Meanwhile, beyond the contrast MRI-enhancing edge of the tumor, invasive cancer cells are protected by the intact blood-brain barrier (BBB). Here, we tested whether brain-penetrating nanoparticles (BPN) that possess dense surface coatings of polyethylene glycol (PEG) and are loaded with cisplatin (CDDP) could be delivered across both the blood-tumor and blood-brain barriers with MR image-guided focused ultrasound (MRgFUS), and whether this treatment could control glioma growth and invasiveness. To this end, we first established that MRgFUS is capable of significantly enhancing the delivery of ~60 nm fluorescent tracer BPN across the blood-tumor barrier in both the 9L (6-fold improvement) gliosarcoma and invasive F98 (28-fold improvement) glioma models. Importantly, BPN delivery across the intact BBB, just beyond the tumor edge, was also markedly increased in both tumor models. We then showed that a CDDP loaded BPN formulation (CDDP-BPN), composed of a blend of polyaspartic acid (PAA) and heavily PEGylated polyaspartic acid (PAA-PEG), was highly stable, provided extended drug release, and was effective against F98 cells in vitro. These CDDP-BPN were delivered from the systemic circulation into orthotopic F98 gliomas using MRgFUS, where they elicited a significant reduction in tumor invasiveness and growth, as well as improved animal survival. We conclude that this therapy may offer a powerful new approach for the treatment invasive gliomas, particularly for preventing and controlling recurrence.

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“…Also, recent advances could allow more efficient penetration of such drugs given systemically through an opening of the blood-brain barrier as reviewed in Rodriguez et al . [56] The drug conjugates of this type can be also administered to brain tumor patients loco-regionally, directly to tumor bed using convection-enhanced delivery [57] . Local administration can be repeated many times and drugs can be infused for prolonged periods of time, which would represent a desirable feature of the treatment plan.…”

Section: Discussionmentioning

confidence: 99%

Novel molecular multilevel targeted antitumor agents

et al. 2017

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A multifunctional fusion protein, IL-13.E13K-D2-NLS, effectively recognizes glioblastoma (GBM) cells and delivers its portion to the cell nucleus. IL-13.E13K-D2-NLS is composed of a cancer cell targeting ligand (IL-13.E13K), specialized cytosol translocation bacterial toxin domain 2 of Pseudomonas exotoxin A (D2) and SV40 T antigen nuclear localization signal (NLS). We have now tested whether we can produce proteins that would serve as a delivery vehicle to lysosomes and mitochondria as well. Moreover, we examined whether IL-13.E13K-D2-NLS can deliver anti-cancer drugs like doxorubicin to their nuclear site of action in cancer cells. We have thus constructed two novel proteins: IL-13.E13K-D2-LLS which incorporates lysosomal localization signal (LLS) of a human lysosomal associated membrane protein (LAMP-1) for targeting to lysosomes and IL-13-D2-KK2, which incorporates a pro-apoptotic peptide (KLAKLAK)2 (KK2) exerting its action in mitochondria. Furthermore, we have produced IL-13.E13K-D2-NLS and IL-13.E13K-D2-LLS versions containing a cysteine for site-specific conjugation with a modified doxorubicin, WP936. We found that single-chain recombinant proteins IL-13.E13K-D2-LLS and IL-13-D2-KK2 are internalized and localized mostly to the lysosomal and mitochondrial compartments, respectively, without major trafficking to cells’ nuclei. We also determined that IL-13.E13K-D2-NLS-cys[WP936], IL-13.E13K-D2-LAMP-cys[WP936] and IL-13-D2-KK2 were cytotoxic to GBM cells overexpressing IL-13RA2, while much less cytotoxic to GBM cell lines expressing low levels of the receptor. IL-13.E13K-D2-NLS-cys[WP936] was the most potent of the tested anti-tumor agents including free WP936. We believe that our receptor-directed intracellular organelle-targeted proteins can be employed for numerous specific and safer treatment applications when drugs have specific intracellular sites of their action.

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Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

Cited by 97 publications

References 69 publications

Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model

Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model

MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound

Novel molecular multilevel targeted antitumor agents

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