Review of microdialysis in brain tumors, from concept to application:
First Annual Carolyn Frye-Halloran Symposium

Benjamin, Ramsis; Hochberg, Fred H.; Fox, Elizabeth; Bungay, Peter M.; Elmquist, William F.; Stewart, Clinton F.; Gallo, James M.; Collins, Jerry M.; Pelletier, Robert P.; Groot, John F. de; Hickner, Robert C.; Çavuş, Idil; Grossman, Stuart A.; Colvin, O. Michael

doi:10.1215/s1152851703000103

Cited by 45 publications

(18 citation statements)

References 55 publications

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“…From the point of view of tissue damage, problems associated with tissue reactions after the implantation of microdialysis probes have been raised explicitly (Benjamin et al, 2004). According to Clapp-Lilly et al (1999), microdialysis-induced tissue damage could result in synaptic and neuronal disruption; furthermore, the neurotransmitter efflux or concentrations of metabolites in the extracellular space might be affected as a result of axonal damage and neuronal degeneration.…”

Section: Microdialysismentioning

confidence: 99%

In vivomonitoring of the transfer kinetics of trace elements in animal brains with hyphenated inductively coupled plasma mass spectrometry techniques

Su¹,

Sun²,

Tzeng³

et al. 2009

Mass Spectrom. Rev.

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The roles of metal ions to sustain normal function and to cause dysfunction of neurological systems have been confirmed by various studies. However, because of the lack of adequate analytical method to monitor the transfer kinetics of metal ions in the brain of a living animal, research on the physiopathological roles of metal ions in the CNS remains in its early stages and more analytical efforts are still needed. To explicitly model the possible links between metal ions and physiopathological alterations, it is essential to develop in vivo monitoring techniques that can bridge the gap between metalloneurochemistry and neurophysiopathology. Although inductively coupled plasma mass spectrometry (ICP-MS) is a very powerful technique for multiple trace element analyses, when dealing with chemically complex microdialysis samples, the detection capability is largely limited by instrumental sensitivity, selectivity, and contamination that arise from the experimental procedure. As a result, in recent years several high efficient and clean on-line sample pretreatment systems have been developed and combined with microdialysis and ICP-MS for the continuous and in vivo determination of the concentration-time profiles of metal ions in the extracellular space of rat brain. This article reviews the research relevant to the development of analytical techniques for the in vivo determination of dynamic variation in the concentration levels of metal ions in a living animal.

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Section: Microdialysismentioning

confidence: 99%

In vivomonitoring of the transfer kinetics of trace elements in animal brains with hyphenated inductively coupled plasma mass spectrometry techniques

Su¹,

Sun²,

Tzeng³

et al. 2009

Mass Spectrom. Rev.

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“…For many therapeutic agents, however, slow diffusion within the brain tumor and brain around the tumor severely limits drug distribution after direct intratumoral injection. This could be circumvented using convection-enhanced delivery (71)(72)(73)(74)(75) or (as it has been alternatively referred to "microdialysis") (76), by which agents are directly infused into the brain to increase their uptake and distribution. Under normal physiological conditions, interstitial fluids move through the brain by both convection and diffusion.…”

Section: Boron Containing Nucleosides As Delivery Agents For Nctmentioning

confidence: 99%

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Barth¹,

Yang²,

Madhoun³

et al. 2004

Cancer Research

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The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4 -2OH, N5-2OH, and N7-2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5-2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(؉), and a mutant L929 cell line that is thymidine kinase-1(؊). N5-2OH was the least toxic (IC 50 , 43-70 M), and N7 and N7-2OH were the most toxic (IC 50 , 18 -49 M). The highest boron uptake was seen with N7-2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5-2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5-2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 ؎ 2.3 and 2.2 g/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5-2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(؊) tumors were 39.8 ؎ 10.8 and 12.4 ؎ 1.6 g/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 g/g, thereby indicating that there was selective retention by the thymidine kinase-1(؉) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5-2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.

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“…In addition, many compounds in the discovery stage are often very lipophilic, and it is difficult to apply microdialysis technique to study these compounds because of high nonspecific binding. Importantly for ethical reasons, this method cannot be used routinely to measure the interstitial fluid concentration in clinical trials, although it has been used to monitor glucose metabolism such as lactate and pyruvate ratio as a marker for ischemia in brain trauma patients in a few lifethreatening situations (Benjamin et al, 2004;Hillered et al, 2006;Chaurasia et al, 2007;Helmy et al, 2007). Because of these limitations, several alternative methods, such as brain homogenate, brain slice, and cerebral spinal fluid (CSF), have been proposed and used to estimate brain unbound drug concentrations (Liu et al, 2008).…”

mentioning

confidence: 99%

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

Liu

Natta²,

Yeo³

et al. 2008

Drug Metab Dispos

167

141

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ABSTRACT:The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C ub ), cerebral spinal fluid concentration (C CSF ), and unbound plasma concentration (C up ) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C m ). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C ub s were within 3-fold of their C m ; thiopental had a C m 4-fold of its C ub . The C CSF s of eight of the nine compounds were within 3-fold of their corresponding C m ; 9-hydroxyrisperidone showed a C CSF 5-fold of its C m . The C up s of five of the nine compounds were within 3-fold of their C m ; four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C up s 6-to 14-fold of their C m . In conclusion, the C ub and C CSF were within 3-fold of the C m for the majority of the compounds tested. The C up s were within 3-fold of C m for lipophilic non-P-glycoprotein (؊P-gp) substrates and greater than 3-fold of C m for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.For drugs with an intended action in the central nervous system it is assumed that unbound drug in brain interstitial fluid is in direct contact or in equilibrium with the site of action (de Lange and Danhof, 2002). Therefore, in preclinical and clinical pharmacokinetic/pharmacodynamic studies, it is critical to determine the concentration in the interstitial fluid for brain-targeted compounds. Unbound plasma concentration (C up ) has been used to represent the unbound concentration in tissue (Wilkinson, 2001). Because the brain is separated from the plasma by the blood-brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB), C up may not represent the interstitial fluid concentration (Davson and Segal, 1995;Hammarlund-Udenaes et al., 2008;Liu et al., 2008).Microdialysis has been considered as a standard approach to measure interstitial fluid concentration (C m ) (Joukhadar and Müller, 2005;Chaurasia et al., 2007). Although this technique has been developed for more than 2 decades, it is primarily used for determination of neurotransmitters and not drug concentrations in the brain. The main limitations of this technique include high resource requirements, low throughput, and special surgical skills to set up the experiment. In addition, many compounds in the discovery stage are often very lipophilic, and it is difficult to apply microdialysis technique to study these compounds because of high nonspecific bindi...

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Review of microdialysis in brain tumors, from concept to application: First Annual Carolyn Frye-Halloran Symposium

Cited by 45 publications

References 55 publications

In vivomonitoring of the transfer kinetics of trace elements in animal brains with hyphenated inductively coupled plasma mass spectrometry techniques

In vivomonitoring of the transfer kinetics of trace elements in animal brains with hyphenated inductively coupled plasma mass spectrometry techniques

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

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