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Jorg Kreuter - One of the best experts on this subject based on the ideXlab platform.
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body distribution of Polysorbate 80 and doxorubicin loaded 14c poly butyl cyanoacrylate nanoparticles after i v administration in rats
Journal of Drug Targeting, 2005Co-Authors: Alessandra Ambruosi, Hiromitsu Yamamoto, Jorg KreuterAbstract:Previously it was shown that poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with Polysorbate 80 are able to cross the blood-brain barrier (BBB) after i.v. administration. The objective of the present study was to investigate the influence of Polysorbate 80 and doxorubicin-loading on the body distribution in rats. The biodistribution profile and brain concentration of 14C-radiolabeled PBCA nanoparticles, Polysorbate 80 coated 14C-PBCA nanoparticles, and doxorubicin-loaded 14C-PBCA nanoparticles were determined by radioactivity counting after i.v. administration in rats. The 14C-PBCA nanoparticles showed a significant accumulation in the organs of the reticuloendothelial system (RES). Polysorbate 80 coating of the 14C-PBCA nanoparticles decreased this accumulation to about 40% after 1 h post injection. The brain concentration was increased about 2-fold after Polysorbate 80-coating at this time point. The presence of doxorubicin in this preparation, however, decreased the brain concentration to levels...
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apolipoprotein mediated transport of nanoparticle bound drugs across the blood brain barrier
Journal of Drug Targeting, 2002Co-Authors: Jorg Kreuter, V E Petrov, D A Shamenkov, Peter Ramge, Klaus Cychutek, Claudia Kochbrandt, Renad N AlyautdinAbstract:Recent studies have shown that drugs that are normally unable to cross the blood-brain barrier (BBB) following intravenous injection can be transported across this barrier by binding to poly(butyl cyanoacrylate) nanoparticles and coating with Polysorbate 80. However, the mechanism of this transport so far was not known. In the present paper, the possible involvement of apolipoproteins in the transport of nanoparticle-bound drugs into the brain is investigated. Poly(butyl cyanoacrylate) nanoparticles loaded with the hexapeptide dalargin were coated with the apolipoproteins AII, B, CII, E, or J without or after precoating with Polysorbate 80. In addition, loperamide-loaded nanoparticles were coated with apolipoprotein E alone or again after precoating with Polysorbate 80. After intravenous injection to ICR mice the antinociceptive threshold was measured by the tail flick test. Furthermore, the antinociceptive threshold of Polysorbate 80-coated dalargin-loaded nanoparticles was determined in ApoEtm1Unc and C57BL/6J mice. The results show that only dalargin or loperamide-loaded nanoparticles coated with Polysorbate 80 and/or with apolipoprotein B or E were able to achieve an antinociceptive effect. This effect was significantly higher after Polysorbate-precoating and apolipoprotein B or E-overcoating. With the apolipoprotein E-deficient ApoEtm1Unc mice the antinociceptive effect was considerably reduced in comparison to the C57BL/6J mice. These results suggest that apolipoproteins B and E are involved in the mediation of the transport of drugs bound to poly(butyl cyanoacrylate) nanoparticles across the BBB. Polysorbate 80-coated nanoparticles adsorb these apolipoproteins from the blood after injection and thus seem to mimic lipoprotein particles that could be taken up by the brain capillary endothelial cells via receptor-mediated endocytosis. Bound drugs then may be further transported into the brain by diffusion following release within the endothelial cells or, alternatively, by transcytosis.
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significant transport of doxorubicin into the brain with Polysorbate 80 coated nanoparticles
Pharmaceutical Research, 1999Co-Authors: A E Gulyaev, Svetlana Gelperina, I N Skidan, Arkady S Antropov, Gregory Ya Kivman, Jorg KreuterAbstract:Purpose. To investigate the possibility of delivering of anticancer drugs into the brain using colloidal carriers (nanoparticles). Methods. Rats obtained 5 mg/kg of doxorubicin by i v. injection in form of 4 preparations : 1. a simple solution in saline, 2. a simple solution in Polysorbate 80 1% in saline, 3. bound to poly (butyl cyanoacrylate) nanoparticles, and 4. bound to poly(butyl cyanoacrylate) nanoparticles overcoated with 1% Polysorbate 80 (Tween® 80). After sacrifice of the animals after 10 min, 1, 2, 4, 6, and 8 hours, the doxorubicin concentrations in plasma, liver, spleen, lungs, kidneys, heart and brain were determined after extraction by HPLC. Results. No significant difference in the body distribution was observed between the two solution formulations. The two nanoparticle formulations very significantly decreased the heart concentrations. High brain concentrations of doxorubicin (>6 μg/g) were achieved with the nanoparticles overcoated with Polysorbate 80 between 2 and 4 hours. The brain concentrations observed with the other three preparations were always below the detection limit (< 0.1 |μg/g). Conclusions. The present study demonstrates that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant Polysorbate 80. It is highly probable that coated particles reached the brain intact and released the drug after endocytosis by the brain blood vessel endothelial cells.
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analgesic activity of the hexapeptide dalargin adsorbed on the surface of Polysorbate 80 coated poly butyl cyanoacrylate nanoparticles
European Journal of Pharmaceutics and Biopharmaceutics, 1995Co-Authors: Renad N Alyautdin, D Gothier, V E Petrov, D A Kharkevich, Jorg KreuterAbstract:Drug targeting to the brain using Polysorbate 80-coated nanoparticles was investigated. The leu-enkephalin analogue dalargin was used as a model drug for the investigation of drug penetration through the blood-brain barrier. Nociceptive threshold was measured by means of the tail flick test. Intravenous injection of dalargin bound by sorption to poly(butyl cyanoacrylate) nanoparticles that were subsequently coated with Polysorbate 80 induced an analgesic effect at doses of 5.0 mg kg -1 and 7.5 mg kg -1 . Pretreatment with naloxone prevented this effect. Other controls, including: a dalargin solution (10 mg kg -1 , i.v.); dalargin bound to nanoparticles without coating with Polysorbate 80; and a simple mixture of dalargin, nanoparticles and Polysorbate 80 mixed directly before i.v. injection, also exhibited no analgesic activity
Krishna M. G. Mallela - One of the best experts on this subject based on the ideXlab platform.
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effect of Polysorbate 20 and Polysorbate 80 on the higher order structure of a monoclonal antibody and its fab and fc fragments probed using 2d nuclear magnetic resonance spectroscopy
Journal of Pharmaceutical Sciences, 2017Co-Authors: Surinder M Singh, Swati Bandi, David N M Jones, Krishna M. G. MallelaAbstract:Abstract We examined how Polysorbate 20 (PS20; Tween 20) and Polysorbate 80 (PS80; Tween 80) affect the higher-order structure of a monoclonal antibody (mAb) and its antigen-binding (Fab) and crystallizable (Fc) fragments, using near-UV circular dichroism and 2D nuclear magnetic resonance (NMR). Both Polysorbates bind to the mAb with submillimolar affinity. Binding causes significant changes in the tertiary structure of mAb with no changes in its secondary structure. 2D 13 C- 1 H methyl NMR indicates that with increasing concentration of Polysorbates, the Fab region showed a decrease in crosspeak volumes. In addition to volume changes, PS20 caused significant changes in the chemical shifts compared to no changes in the case of PS80. No such changes in crosspeak volumes or chemical shifts were observed in the case of Fc region, indicating that Polysorbates predominantly affect the Fab region compared to the Fc region. This differential effect of Polysorbates on the Fab and Fc regions was because of the lesser thermodynamic stability of the Fab compared to the Fc. These results further indicate that PS80 is the preferred Polysorbate for this mAb formulation, because it offers higher protection against aggregation, causes lesser structural perturbation, and has weaker binding affinity with fewer binding sites compared to PS20.
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effect of Polysorbate 20 and Polysorbate 80 on the higher order structure of a monoclonal antibody and its fab and fc fragments probed using 2d nmr
Journal of Pharmaceutical Sciences, 2017Co-Authors: Surinder M Singh, Swati Bandi, David N M Jones, Krishna M. G. MallelaAbstract:Abstract We examined how Polysorbate 20 (PS20; Tween 20) and Polysorbate 80 (PS80; Tween 80) affect the higher order structure of a monoclonal antibody (mAb) and its Fab and Fc fragments, using near-UV circular dichroism and 2D NMR. Both Polysorbates bind to the mAb with sub-millimolar affinity. Binding causes significant changes in the tertiary structure of mAb with no changes in its secondary structure. 2D 13 C- 1 H methyl NMR indicates that with increasing concentration of Polysorbates, the Fab region showed a decrease in crosspeak volumes. In addition to volume changes, PS20 caused significant changes in the chemical shifts compared to no changes in the case of PS80. No such changes in crosspeak volumes or chemical shifts were observed in the case of Fc region, indicating that Polysorbates predominantly affect the Fab region compared to the Fc region. This differential effect of Polysorbates on the Fab and Fc regions was because of the lesser thermodynamic stability of the Fab compared to the Fc. These results further indicate that PS80 is the preferred Polysorbate for this mAb formulation, because it offers higher protection against aggregation, causes lesser structural perturbation, and has weaker binding affinity with fewer binding sites compared to PS20.
Taylor Zhang - One of the best experts on this subject based on the ideXlab platform.
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Mixed-mode and reversed-phase liquid chromatography-tandem mass spectrometry methodologies to study composition and base hydrolysis of Polysorbate 20 and 80.
Journal of Chromatography A, 2010Co-Authors: Daniel Hewitt, Melissa Alvarez, Kathryn Robinson, Junyan Ji, Y. John Wang, Taylor ZhangAbstract:Abstract Polysorbate 20 (polyoxyethylenesorbitan monolaurate) and Polysorbate 80 (polyoxyethylenesorbitan monooleate) used in protein drug formulations are complex mixtures that have been difficult to characterize. Here, two HPLC methods are used with evaporative light scattering detection (ELSD) and mass spectrometry (MS) to characterize Polysorbate from commercial vendors. The first HPLC method used a mixed-mode stationary phase (Waters Oasis MAX, mixed-mode anion exchange and reversed-phase sorbent) with a step gradient to quantify both the total polyoxyethylene sorbitan ester and polyoxyethylene sorbitan (POE sorbitan, a non-surfactant) in Polysorbate. The results indicated POE sorbitan was present from 16.0 to 27.6 and 11.1 to 14.5% (w/w) in Polysorbate 20 and 80, respectively. The second HPLC method used a reversed-phase stationary phase (Zorbax SB-300 C8) with a shallow gradient to separate, identify, and quantify the multiple ester species present in Polysorbate. For all lots of Polysorbate 20 analyzed, only 18–23% of the material was the expected structure, polyoxyethylenesorbitan monolaurate. Up to 40% and 70% (w/w) di- and triesters were found in Polysorbate 20 and Polysorbate 80 respectively. Likewise, polyoxyethylenesorbitan monooleate accounted for only 20% of Polysorbate 80. A variability of 3–5% was observed for each ester species between multiple lots of Polysorbate 20. The reversed-phase method was then used to determine the rate of hydrolysis for each polyoxyethylene sorbitan ester of Polysorbate 20 in basic solution at room temperature. Increasing rates of hydrolysis were observed with decreasing aliphatic chain lengths in Polysorbate 20.
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quantitation of Polysorbate 20 in protein solutions using mixed mode chromatography and evaporative light scattering detection
Journal of Chromatography A, 2008Co-Authors: Daniel P Hewitt, Taylor ZhangAbstract:An HPLC assay requiring no complex sample preparation for the measurement of Polysorbate 20 in protein solutions was developed. An on-off chromatography technique was employed involving a mixed-mode stationary phase (Waters Oasis MAX, mixed-mode anion-exchange and reversed-phase sorbent) to quantify Polysorbate 20 in solutions containing >100mg/mL of protein. With 2% formic acid mobile phase, proteins are typically positive charged and are not retained because of electrostatic repulsions from the quaternary amine in the mixed-mode resin. Other formulation components elute in void volume because of their hydrophilicity. Hydrophobic Polysorbate 20 is retained, eluted with a step gradient and quantified as a single peak using an evaporative light scattering detector. The performance of the assay is evaluated according to International Conference on Harmonisation (ICH) guidelines and shown to be suitable for Polysorbate quantitation. Accuracy (96-108%) and repeatability (2.3% RSD) were demonstrated using protein samples spiked with Polysorbate 20. This method was used to accurately measure Polysorbate 20 in at least 25 different protein solutions spanning a wide range of formulations. Although the majority of the data reported here target Polysorbate 20, this methodology can also be used to assay other common non-ionic surfactants such as Polysorbate 80, Brij, Igepal, and Triton X-100.
Alex Sparreboom - One of the best experts on this subject based on the ideXlab platform.
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simultaneous analysis of docetaxel and the formulation vehicle Polysorbate 80 in human plasma by liquid chromatography tandem mass spectrometry
Analytical Biochemistry, 2004Co-Authors: Sharyn D Baker, Jaap Verweij, Michael A. Carducci, Ping He, Ming Zhao, Alex SparreboomAbstract:Abstract An analytical procedure for the simultaneous determination of the anticancer agent docetaxel (Taxotere) and its formulation vehicle Polysorbate 80 (Tween 80) in human plasma samples is described. Sample pretreatment involved a double liquid–liquid extraction step with a mixture of acetonitrile/n-butyl chloride (1/4, v/v). Separation of the compounds of interest, including the internal standard paclitaxel, was achieved on a reversed-phase Waters X-Terra mass spectrometry (MS) column (50×2.1 mm internal diameter) packed with a 3.5-μm octadecyl stationary phase, using isocratic elution. Detection of docetaxel and Polysorbate 80 was performed using tandem MS detection with electrospray ionization. Validation results indicated that the method is accurate and precise and has lower limits of quantitation of 0.500 nM (∼0.4 ng/ml) and 1.00 μg/ml for docetaxel and Polysorbate 80, respectively. The method was subsequently used to measure concentrations of docetaxel and Polysorbate 80 in plasma samples in support of a project to assess the influence of Polysorbate 80 concentrations on the disposition and toxicity profile of docetaxel in cancer patients receiving Taxotere.
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simultaneous analysis of docetaxel and the formulation vehicle Polysorbate 80 in human plasma by liquid chromatography tandem mass spectrometry
Analytical Biochemistry, 2004Co-Authors: Sharyn D Baker, Jaap Verweij, Michael A. Carducci, Ming Zhao, Alex SparreboomAbstract:An analytical procedure for the simultaneous determination of the anticancer agent docetaxel (Taxotere) and its formulation vehicle Polysorbate 80 (Tween 80) in human plasma samples is described. Sample pretreatment involved a double liquid-liquid extraction step with a mixture of acetonitrile/n-butyl chloride (1/4, v/v). Separation of the compounds of interest, including the internal standard paclitaxel, was achieved on a reversed-phase Waters X-Terra mass spectrometry (MS) column (50 x 2.1mm internal diameter) packed with a 3.5-microm octadecyl stationary phase, using isocratic elution. Detection of docetaxel and Polysorbate 80 was performed using tandem MS detection with electrospray ionization. Validation results indicated that the method is accurate and precise and has lower limits of quantitation of 0.500 nM (approximately 0.4 ng/ml) and 1.00 microg/ml for docetaxel and Polysorbate 80, respectively. The method was subsequently used to measure concentrations of docetaxel and Polysorbate 80 in plasma samples in support of a project to assess the influence of Polysorbate 80 concentrations on the disposition and toxicity profile of docetaxel in cancer patients receiving Taxotere.
Rainer H. Müller - One of the best experts on this subject based on the ideXlab platform.
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Polysorbate stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns
Journal of Drug Targeting, 2005Co-Authors: Torsten M Goppert, Rainer H. MüllerAbstract:Plasma proteins enriched on the surface of drug-delivery-purpose nanoparticles are regarded as key factors for determination of in vivo organ distribution after intravenous injection. Polysorbate 80-coated polybutylcyanoacrylate (PBCA) nanoparticles, preferentially adsorbing apolipoprotein E (apoE) on their surface, have previously been considered to deliver various drugs to the brain. In the present study, in vivo well tolerable solid lipid nanoparticles (SLN) using different types of Polysorbates as stabilizers were produced. The influence of the different surfactants on in vitro adsorption of human plasma proteins was investigated using two-dimensional polyacrylamide gel electrophoresis (2-DE). Possible correlations of different amounts of adsorbed apoE to the hydrophilic–lipophilic balance (HLB) of the Polysorbates are shown and discussed. Apolipoprotein C-II, albumin and immunoglobulin G, which are also decisive plasma proteins with regard to site-specific drug delivery of intravenously injected carr...
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Polysorbate stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns
Journal of Drug Targeting, 2005Co-Authors: Torsten M Goppert, Rainer H. MüllerAbstract:Plasma proteins enriched on the surface of drug-delivery-purpose nanoparticles are regarded as key factors for determination of in vivo organ distribution after intravenous injection. Polysorbate 80-coated polybutylcyanoacrylate (PBCA) nanoparticles, preferentially adsorbing apolipoprotein E (apoE) on their surface, have previously been considered to deliver various drugs to the brain. In the present study, in vivo well tolerable solid lipid nanoparticles (SLN) using different types of Polysorbates as stabilizers were produced. The influence of the different surfactants on in vitro adsorption of human plasma proteins was investigated using two-dimensional polyacrylamide gel electrophoresis (2-DE). Possible correlations of different amounts of adsorbed apoE to the hydrophilic-lipophilic balance (HLB) of the Polysorbates are shown and discussed. Apolipoprotein C-II, albumin and immunoglobulin G, which are also decisive plasma proteins with regard to site-specific drug delivery of intravenously injected carriers to the brain, are compared with regard to adsorption. Moreover, certain similarities to the plasma protein adsorption patterns of previously analysed brain-specific PBCA nanoparticles could be detected. Despite some differences in adsorption behavior of proteins on the surface of Polysorbate-stabilized SLN and PBCA nanoparticles, we conclude that in both cases Polysorbate 80 might have the highest potential to deliver drugs to the brain.