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Lockman, Paul R.; Koziara, Joanna M.; Roder, Karen E.; Paulson, Jennifer; Abbruscato, Thomas J.; Mumper, Russell J.; Allen, David

doi:10.1023/a:1023492015851

Cited by 80 publications

(9 citation statements)

References 20 publications

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“…This method has similar advantages to the in situ brain perfusion method in that we may control aspects of the perfusion to determine both influx and efflux kinetics, transporter inhibition coefficients, and BTB or BBB permeability (Smith and Allen, 2003). This control helps determine accurate apparent permeability coefficients (Lockman et al, 2005a), the degree to what a substrate is efflux back into blood (Lockman et al, 2003b), inhibition constants for transporters (Lockman et al, 2001) and a direct measurement of BBB and BTB integrity (Lockman et al, 2003a, 2004, 2005b)…”

Section: Discussionmentioning

confidence: 99%

“…The in situ mouse heart perfusion technique was utilized to evaluate brain uptake of R123 (Takasato et al, 1984; Lockman et al, 2003a) Mice were anesthetized with ketamine/xylazine (100 and 8 mg/kg, respectively) and the heart exposed. Body temperature was monitored and maintained at 37°C using a heating pad attached to a feedback device (YSI Indicating Controller, Yellow Springs, OH, USA).…”

Section: Methodsmentioning

confidence: 99%

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P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model

et al. 2013

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The blood–brain barrier (BBB) is a specialized vascular interface that restricts the entry of many compounds into brain. This is accomplished through the sealing of vascular endothelial cells together with tight junction proteins to prevent paracellular diffusion. In addition, the BBB has a high degree of expression of numerous efflux transporters which actively extrude compounds back into blood. However, when a metastatic lesion develops in brain the vasculature is typically compromised with increases in passive permeability (blood-tumor barrier; BTB). What is not well documented is to what degree active efflux retains function at the BTB despite the changes observed in passive permeability. In addition, there have been previous reports documenting both increased and decreased expression of P-glycoprotein (P-gp) in lesion vasculature. Herein, we simultaneously administer a passive diffusion marker (14C-AIB) and a tracer subject to P-gp efflux (rhodamine 123) into a murine preclinical model of brain metastases of breast cancer. We observed that the metastatic lesions had similar expression (p > 0.05; n = 756–1214 vessels evaluated) at the BBB and the BTB. Moreover, tissue distribution of R123 was not significantly (p > 0.05) different between normal brain and the metastatic lesion. It is possible that the similar expression of P-gp on the BBB and the BTB contribute to this phenomenon. Additionally we observed P-gp expression at the metastatic cancer cells adjacent to the vasculature which may also contribute to reduced R123 uptake into the lesion. The data suggest that despite the disrupted integrity of the BTB, efflux mechanisms appear to be intact, and may be functionally comparable to the normal BBB. The BTB is a significant hurdle to delivering drugs to brain metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model

et al. 2013

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“…To accomplish this, we used the in situ brain perfusion technique, since it has several advantages in determining interactions of drugs with BBB transporters. Specifically, there is absolute control over the brain perfusate which helps determine accurate apparent permeability influx transport kinetics (Lockman et al, 2005a), efflux kinetics (Lockman et al, 2003b), inhibition constants for transporters (Lockman et al, 2001), and a direct measurement of the integrity of the BBB in healthy brain and in pathology (Lockman et al, 2003a, 2004, 2005b). …”

Section: Discussionmentioning

confidence: 99%

Quantitative fluorescence microscopy provides high resolution imaging of passive diffusion and P-gp mediated efflux at the in vivo blood–brain barrier

Mittapalli

Manda

Bohn

et al. 2013

Journal of Neuroscience Methods

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Quantitative fluorescent microscopy is an emerging technology that has provided significant insight into cellular dye accumulation, organelle function, and tissue physiology. However, historically dyes have only been used to qualitatively or semi-quantitatively (fold change) determine changes in blood–brain barrier (BBB) integrity. Herein, we present a novel method to calculate the blood to brain transfer rates of the dyes rhodamine 123 and Texas red across the in situ BBB. We observed that rhodamine 123 is subject to p-glycoprotein mediated efflux at the rat BBB and can be increased nearly 20-fold with p-glycoprotein inhibition. However, Texas Red appears to not be subject to MRP2 mediated efflux at the rat BBB, agreeing with literature reports suggesting MRP2 may lack functionality at the normal rat BBB. Lastly, we present data demonstrating that once dyes have crossed the BBB, diffusion of the dye molecule is not as instantaneous as has been previously suggested. We propose that future work can now be completed to (1) match BBB transfer coefficients to interstitial diffusion constants and (2) use dyes with specific affinities to cellular organelles or that have specific properties (e.g., subject to efflux transporters) to more fully understand BBB physiology.

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“…Nanoparticles have been widely studied in biomedical and biotechnological applications, particularly in drug delivery systems for drug targeting since their particle size (ranging from 10 to 1000 nm) is acceptable for intravenous injection [15–17]. In comparison with other colloidal carriers, polymeric nanoparticles possess both a higher stability in biological fluids and against enzymatic metabolism [18]. The higher stability of the nanoparticles is attributed to the reduced interactions and exchanges with blood components.…”

Section: Introductionmentioning

confidence: 99%

Rivastigmine Loaded L-Lactide-Depsipeptide Polymeric Nanoparticles: Decisive Formulation Variables Optimization

Pagar

Vavia²

2013

Sci. Pharm.

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The main aim of the investigation was to explore a novel L-lactide-depsipeptide copolymer for the development of rivastigmine-loaded polymeric nanoparticles. L-lactide-depsipeptide synthesis was based on the ring opening polymerization reaction of L-lactide with the cyclodepsipeptide, cyclo(Glc-Leu), using tin 2-ethyl hexanoate as an initiator. Rivastigmine-loaded nanoparticles were prepared by the single emulsion-solvent evaporation technique. The influence of various critical formulation variables like sonication time, amount of polymer, amount of drug, stabilizer concentration, drug-to-polymer ratio, and organic-to-aqueous phase ratio on particle size and entrapment efficiency was studied. The optimized formulation having a particle size of 142.2 ± 21.3 nm with an entrapment efficiency of 60.72 ± 3.72% was obtained. Increased rivastigmine entrapment within the polymer matrix was obtained with a relatively low organic-to-aqueous phase ratio and high drug-to-polymer ratio. A decrease in the average size of the nanoparticles was observed with a decrease in the amount of polymer added and an increase in the sonication time. Prolonged sonication time, however, decreased rivastigmine entrapment. From the different lyoprotectant tested, only trehalose was found to prevent nanoparticle aggregation upon application of the freeze-thaw cycle. Drug incorporation into the polymeric matrix was confirmed by the DSC and XRD study. The spherical nature of the nanoparticles was confirmed by the SEM study. The in vitro drug release study showed the sustained release of more than 90% of the drug up to 72 h. Thus, L-lactide-depsipeptide can be used as an efficient carrier for the nanoparticle preparation of rivastigmine.

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Abstract: The nanoparticle formulations appear to have no effect on primary BBB parameters in established in vitro and in vivo blood-brain barrier models.

Cited by 80 publications

References 20 publications

P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model

P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model

Quantitative fluorescence microscopy provides high resolution imaging of passive diffusion and P-gp mediated efflux at the in vivo blood–brain barrier

Rivastigmine Loaded L-Lactide-Depsipeptide Polymeric Nanoparticles: Decisive Formulation Variables Optimization

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