Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo

Fellner, Stephan; Bauer, Björn; Miller, David S.; Schaffrik, Martina; Fankhänel, Martina; Spruß, Thilo; Bernhardt, Günther; Graeff, Claudia; Färber, L; Buschauer, Armin; Fricker, Gert

doi:10.1172/jci200215451

Cited by 85 publications

(99 citation statements)

References 43 publications

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“…In addition, the distribution of BODIPY-taxol in nicardipine pretreated TS Adr was relatively homogeneous at all tissue depths examined, indicating that effective inhibition of P-gp is possible within a solid tissue mass. The pivotal role for P-gp in determining drug pharmacokinetic profiles has also been demonstrated in normal noncancerous tissue through prevention of paclitaxel and BODIPY-taxol passage across the blood -brain barrier (Fellner et al, 2002). In summary, the results presented in this paper show that the expression of P-gp in 3-D organisation of cells does affect the overall accumulation of a variety of compounds.…”

Section: Discussionsupporting

confidence: 52%

“…For example, calcein-AM and rhodamine 123 were included, since they are well-characterised allocrites for P-gp and display high fluorescence intensity (Homolya et al, 1993;Shapiro and Ling, 1998). BODIPY-taxol, a novel fluorescent derivative of the anticancer drug paclitaxel has been suggested, but not proven, to interact with P-gp (Fellner et al, 2002). Taken together, the data presented in Figure 1 obtained using purified and reconstituted Pgp demonstrate that BODIPY-taxol is indeed capable of direct interaction with this transporter.…”

Section: Verification Of Bodipy-taxol As a Substrate For P-gpmentioning

confidence: 99%

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The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

et al. 2003

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Solid tumours display a complex drug resistance phenotype that involves inherent and acquired mechanisms. Multicellular resistance is an inherent feature of solid tumours and is known to present significant barriers to drug permeation in tumours. Given this barrier, do acquired resistance mechanisms such as P-glycoprotein (P-gp) contribute significantly to resistance? To address this question, the multicellular tumour spheroid (MCTS) model was used to examine the influence of P-gp on drug distribution in solid tissue. Tumour spheroids (TS) were generated from either drug-sensitive MCF7 WT cells or a drug-resistant, P-gp-expressing derivative MCF7 Adr . Confocal microscopy was used to measure time courses and distribution patterns of three fluorescent compounds; calcein-AM, rhodamine123 and BODIPY-taxol. These compounds were chosen because they are all substrates for P-gp-mediated transport, exhibit high fluorescence and are chemically dissimilar. For example, BODIPY-taxol and rhodamine 123 showed high accumulation and distributed extensively throughout the TS WT , whereas calcein-AM accumulation was restricted to the outermost layers. The presence of P-gp in TS Adr resulted in negligible accumulation, regardless of the compound. Moreover, the inhibition of P-gp by nicardipine restored intracellular accumulation and distribution patterns to levels observed in TS WT . The results demonstrate the effectiveness of P-gp in modulating drug distribution in solid tumour models. However, the penetration of agents throughout the tissue is strongly determined by the physico-chemical properties of the individual compounds.

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Section: Discussionsupporting

confidence: 52%

Section: Verification Of Bodipy-taxol As a Substrate For P-gpmentioning

confidence: 99%

The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

et al. 2003

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“…The taxanes, including paclitaxel and docetaxel, have poor BBB permeability that is thought to result, at least in part, from these molecules being substrates for the P-glycoprotein (Pgp) transporter that prevents xenobiotics from accumulating in the brain (Sparreboom et al 1997;Fellner et al 2002). Improved taxanes have been synthesized that are not Pgp substrates (Cisternino et al 2003;Ballatore et al 2007a;Ojima et al 2008;Metzger-Filho et al 2009), but recent data from our laboratory suggest that such compounds still have poor brain penetration (Brunden et al 2011).…”

Section: Compensation For Tau Loss-of-functionmentioning

confidence: 99%

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

Lee¹,

Brunden²,

Hutton³

et al. 2011

Cold Spring Harbor Perspectives in Medicine

107

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“…To date, some glycoproteins in brain have been reported to be closely related to various diseases, such as P-glycoprotein with AIDS and brain tumor [24,25]; synaptophysin with epilepsy and Alzheimer's disease [26,27]. Therefore, a comprehensive glycoproteome analysis is of great significance for the in-depth understanding of brain functions.…”

mentioning

confidence: 99%

Large‐scale N‐glycoproteome map of rat brain tissue: Simultaneous characterization of insoluble and soluble protein fractions

Qiao

Tao

et al. 2011

Proteomics

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The large-scale N-glycosylation analysis is critical for biomedical research, since a variety of diseases are found to be associated with glycoproteins. By a combination of glycoprotein analysis in insoluble protein fraction solubilized with 1% v/v 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF 4 ) and those in soluble fraction, a total number of 462 nonredundant N-glycoprotein groups, including 316 transmembrane glycoproteins, were successfully identified. Correspondingly, 849 unique N-glycosites were confidently recognized. The data set could provide a support for the further in-depth research of brain N-glycosylation, such as for the discovery of candidate drug targets and biomarkers.

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Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo

Cited by 85 publications

References 43 publications

The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

Large‐scale N‐glycoproteome map of rat brain tissue: Simultaneous characterization of insoluble and soluble protein fractions

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