Size Polyethylene Glycol Research Articles

Therapeutic Pretargeting with Gold Nanoparticles as Drug Candidates for Boron Neutron Capture Therapy

AbstractBoron neutron capture therapy (BNCT) is a binary approach for cancer treatment in which boron‐10 atoms and thermal neutrons need to colocalize to become effective. Recent research in the development of BNCT drug candidates focuses increasingly on nanomaterials, with the advantages of high boron loadings and passive targeting due to the enhanced permeability and retention (EPR) effect. The use of small boron‐rich gold nanoparticles (AuNPs) in combination with a pretargeting approach is proposed. Small sized polyethylene glycol–stabilized AuNPs (core size 4.1 ± 1.5 nm), are synthesized and functionalized with thiolated cobalt bis(dicarbollide) and tetrazine. To enable in vivo tracking of the AuNPs by positron emission tomography (PET), the core is doped with [64Cu]CuCl2. For the pretargeting approach, the monoclonal antibody Trastuzumab is functionalized with trans‐cyclooctene‐N‐hydroxysuccinimide ester. After proving in vitro occurrence of the antibody conjugation onto the AuNPs by click reaction and the low toxicity of the AuNPs, the boron delivery system is evaluated in vivo using breast cancer xenograft bearing mice and PET imaging. Tumor uptake due to the EPR effect can be witnessed with ≈5% injected dose (ID) cm−3 at 24 h postinjection, but with slower clearance than expected. Therefore, no increased retention can be observed using the pretargeting strategy.

Engineering Enhanced Pore Sizes Using FhuA Δ1-160 from E. coli Outer Membrane as Template.

Biological membranes are the perfect example of a molecular filter using membrane channels to control the permeability of small water-soluble molecules. To allow filtering of larger hydrophilic molecules we started from the known mutant channel FhuA Δ1-160 in which the cork domain closing the channel had been removed. Here we further expand the pore diameter by copying the amino acid sequence of two β-strands in a stepwise manner increasing the total number of β-strands from 22 to 34. The pore size of the respective expanded channel protein was characterized by single-channel conductance. Insertion of additional β-strands increased the pore conductance but also induced more ion current flickering on the millisecond scale. Further, polymer exclusion measurements were performed by analyzing single-channel conductance in the presence of differently sized polyethylene glycol of known polymer random coil radii. The conclusion from channel conductance of small channel penetrating polymers versus larger excluded ones suggested an increase in pore radii from 1.6 nm for FhuA Δ1-160 up to a maximum of about 2.7 nm for +8 β insertion. Integration of more β-strand caused instability of the channel and exclusion of smaller sized polymer. FhuA Δ1-160 + 10 β and FhuA Δ1-160 + 12 β effective radius decreased to 1.4 and 1.3 nm, respectively, showing the limitations of this approach.

Separation of Silver Nanoparticles with Different Coatings by Capillary Electrophoresis Coupled to ICP-MS in Single Particle Mode.

The possibility of separating mixtures of Ag nanoparticles (NPs) with similar sizes but different surface coatings using capillary electrophoresis coupled to single particle inductively coupled mass-spectrometry (CE-SP-ICP-MS) was investigated. In two-component mixtures, it was possible to separate 40 nm sized polyvinylpirrolidone (PVP)- and citrate-coated NPs, 40 nm sized polyethylene glycol (PEG)- and citrate-coated NPs, and 60 nm sized PVP- and citrate-coated NPs. The separation of a more complex mixture containing NPs with the different coatings and sizes was successful, and each component, namely, 20, 40, and 60 nm sized citrate-coated and 40 and 60 nm sized PVP-coated NPs, could be distinguished. The theoretically expected migration order was confirmed by experimental results with selected Ag NPs. On the basis of the experimental observations, a separation mechanism that considers the effect of stable vs displaceable coatings during NP migration in CE is suggested. The ICP-MS was equipped with a prototype data acquisition system (μsDAQ) that provided 5 μs time resolution.

Functionalization of Mesoporous Silicon Nanoparticles for Targeting and Bioimaging Purposes

Carboxylic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi‐NP) were synthesized, and their opsonization and targeting properties were studied in vitro alongside with in vivo biodistribution. The carboxyl groups on UnTHCPSi were utilized to further functionalize the nanoparticles. In order to reduce the opsonization of the UnTHCPSi‐NPs, different sized polyethylene glycol (PEG) were conjugated or adsorbed to the NPs surface. The latter approach, based on hydrophobic interaction, turned out to be more effective in reducing the opsonization and improving the stability of the nanoparticle suspension. The most abundant opsonins after plasma incubation were fibrinogen precursors and IgG. Furthermore, the targeting properties of UnTHCPSi‐NPs were studied in vitro with antibodies against glutathione S‐transferase (anti‐GST). PEGylated NPs conjugated with anti‐GST bound to GST‐agarose in human plasma nearly 35‐fold compared to control NPs, indicating that UnTHCPSi‐NPs are suitable for targeting in physiological environment. The in vivo biodistribution in mice revealed that PEGylated UnTHCPSi‐NPs, accumulate fast into the liver and the spleen, regardless of the reduced opsonization in vitro. However, autoradiography and transmission electron microscopy showed that majority of the NPs still remained in hepatic blood vessels and sinusoids suggesting a possibility to utilize them as a sustained release platform for payload molecules.

Accumulation of magnetic iron oxide nanoparticles coated with variably sized polyethylene glycol in murine tumors

Iron oxide nanoparticles have found widespread applications in different areas including cell separation, drug delivery and as contrast agents. Due to water insolubility and stability issues, nanoparticles utilized for biological applications require coatings such as the commonly employed polyethylene glycol (PEG). Despite its frequent use, the influence of PEG coatings on the physicochemical and biological properties of iron nanoparticles has hitherto not been studied in detail. To address this, we studied the effect of 333-20,000 Da PEG coatings that resulted in larger hydrodynamic size, lower surface charge, longer circulation half-life, and lower uptake in macrophage cells when the particles were coated with high molecular weight (M(w)) PEG molecules. By use of magnetic resonance imaging, we show coating-dependent in vivo uptake in murine tumors with an optimal coating M(w) of 10,000 Da.

Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure

Lanthanum carbonate is a new phosphate binder that is poorly absorbed from the gastrointestinal tract and eliminated largely by the liver. After oral treatment, we and others had noticed 2-3 fold higher lanthanum levels in the livers of rats with chronic renal failure compared to rats with normal renal function. Here we studied the kinetics and tissue distribution, absorption, and subcellular localization of lanthanum in the liver using transmission electron microscopy, electron energy loss spectrometry, and X-ray fluorescence. We found that in the liver lanthanum was located in lysosomes and in the biliary canal but not in any other cellular organelles. This suggests that lanthanum is transported and eliminated by the liver via a transcellular, endosomal-lysosomal-biliary canicular transport route. Feeding rats with chronic renal failure orally with lanthanum resulted in a doubling of the liver levels compared to rats with normal renal function, but the serum levels were similar in both animal groups. These levels plateaued after 6 weeks at a concentration below 3 microg/g in both groups. When lanthanum was administered intravenously, thereby bypassing the gastrointestinal tract-portal vein pathway, no difference in liver levels was found between rats with and without renal failure. This suggests that there is an increased gastrointestinal permeability or absorption of oral lanthanum in uremia. Lanthanum levels in the brain and heart fluctuated near its detection limit with long-term treatment (20 weeks) having no effect on organ weight, liver enzyme activities, or liver histology. We suggest that the kinetics of lanthanum in the liver are consistent with a transcellular transport pathway, with higher levels in the liver of uremic rats due to higher intestinal absorption.

Biliary Excretion of 400– to 1,000–D Polyethylene Glycol Will Influence the Calculation of Small Intestinal Absorption in Portacaval–Shunted Rats

HepatologyVolume 25, Issue 2 p. 500-500 CorrespondenceFree Access Biliary excretion of 400- to 1,000-d polyethylene glycol will influence the calculation of small intestinal absorption in portacaval-shunted rats S Friman, S FrimanSearch for more papers by this authorJ Svanvik, J SvanvikSearch for more papers by this author S Friman, S FrimanSearch for more papers by this authorJ Svanvik, J SvanvikSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510250243Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Panzar N, Bergqvist P, Bugge M, Olaison G, Lundin S, Jeppsson B, Weström B, et al. Small intestine absorption of polyetethylene glycol 400 to 1,000 in the portacaval shunted rat. Hepatology 1995; 21: 1167– 1173. 2 Friman S, Leanderson P, Tagesson C, Svanvik J. Biliary excretion of different sized polyethylene glycols in the cat. J Hepatol 1990; 11: 215– 220. 3 Friman S, Egestad B, Sjövall J, Svanvik J. Hepatic excretion and metabolism of polyethylene glycols and mannitol in the cat. J Hepatol 1993; 17: 48– 55. 4 Lake JR, Licko V, van Dyke RN, Scharschmidt BF. Biliary secretion of fluid–markers by the isolated perfused rat liver. J Clin Invest 1985; 76: 676– 684. 5 Friman S, Rådberg G, Svanvik J. Hepatic clearance of polyethylene glycol 900 and mannitol in the pig. Digestion 1988; 29: 172– 180. 6 Friman S, Persson H, Karlberg I, Svanvik J. The bile acid independent flow is reduced in the transplanted liver. Transplant Int 1992; 5: S163– S167. Citing Literature Volume25, Issue2February 1997Pages 500-500 ReferencesRelatedInformation

Reduced intestinal permeability measured by differently sized polyethylene glycols in acute uremic rats.

The effect of experimental acute renal failure on the intestinal permeability measured by differently sized polyethylene glycols (PEG) was studied in rats. The permeability was assessed by analysing the 24-hour urinary recovery of PEG molecules (size 326-1,162 D). Acute renal failure was induced by clamping the left renal artery and right-sided nephrectomy. The overall urinary recovery of PEG was decreased in the uremic rats. However, the relative recovery of larger molecules (range 590-1,162 D) was further reduced in the uremic rats. The results which are compared with a computer simulation by a multicompartment model, suggest that the intestinal permeability especially towards larger PEG is decreased in acute uremic rats.

Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure.

The intestinal mucosa plays a fundamental role as the site for absorption of nutrients, and as an important barrier from potentially harmful agents in the intestinal lumen. Little is known of the permeability properties of the intestinal mucosa in uraemic patients. The intestinal permeability to differently sized polyethylene glycols (PEGs; range 326-1254 daltons) was studied in nine patients with chronic renal failure (24 hour endogeneous creatinine clearance 5-24 ml/minute). The maximum 24 hour urinary recovery of PEGs was decreased in the uraemic patients but relatively more of the larger than the smaller PEGs were found in these patients. The results suggest a reduced urinary recovery of PEGs caused by renal dysfunction but also a relatively increased intestinal permeability to larger PEGs in the uraemic patients.

Intestinal permeability in patients with yersinia triggered reactive arthritis.

The passive intestinal permeability of patients with yersinia triggered reactive arthritis was studied using different sized polyethylene glycols (PEGs) contained in a mixture of PEG 400 and PEG 1000. The investigation was carried out at least one year after the onset of yersinia infection, and patients had neither acute gastrointestinal nor joint symptoms. The control groups included patients with uncomplicated yersiniosis as well as healthy subjects who were either HLA-B27 positive or negative. An altered intestinal barrier function to PEG molecules was detected in patients with a history of yersinia infection compared with healthy controls. No significant differences in the permeability were found between patients with or without reactive arthritis, nor was there any association of increased permeability with HLA-B27. The passive permeability of the intestinal mucosa to the larger molecules was increased for an unexpectedly long time after the acute yersinia infection, probably contributing to the perpetuation of joint symptoms in subjects susceptible to a chronic joint disease.

Biliary excretion of different sized polyethylene glycols in the cat

Polyethylene glycol (PEG) 900 is excreted more extensively into bile than mannitol and erythritol. In this study, the biliary recovery of intravenously injected marker molecules was analysed in anaesthetised cats with ligated renal pedicles. It was demonstrated that among polyethylene glycols sized 292-1250 Da, the species sized 1074 Da was maximally excreted in the bile. After 5 h, about 12% of the injected amount of this molecular species was recovered in bile. Both larger and smaller polyethylene glycol molecules had a lower biliary excretion. The distribution of different sized PEGs in the range 766-1250 Da in serum was fairly constant and cannot explain the recovery profile in bile. 14C-Labelled mannitol was recovered in bile to the extent of 0.7% of the amount given i.v. after 5 h, a figure that corresponds to that obtained for polyethylene glycol with a size of 370 Da. Bile/plasma ratios during steady state conditions of labelled PEG 450, PEG 900, PEG 2500 and PEG 4000 were 10, 36, 3 and 4, respectively. The results may be tentatively explained by restricted passage of the larger PEG molecules into the canaliculi, and leakage of the smaller molecules from bile back to plasma.

Urinary Excretion of Differently Sized Polyethylene Glycols after Intravenous Administration in Uremic and Control Rats: Effects of Low- and High-Protein Diets

The intestine constitutes a barrier towards potentially harmful agents in the intestinal lumen. Different-sized polyethylene glycols (PEGs; range 326-1,1162 Da) have been used to study the intestinal permeability properties in 5/6-nephrectomized rats on either a high- (22%) or low-protein (8%) diet. PEGs were administered intravenously, and the urinary recovery was measured. The 24-hour urinary recovery of PEGs was significantly reduced in the uremic groups. The ratios between different sizes of PEGs, indicating a size-selective escape of molecules from blood, were decreased in the uremic groups. The urinary recovery was in general increased in the control group on the high-protein diet compared to the control group on the low-protein diet. The results provide evidence for an increased permeability of larger PEGs (range 634-1,162 Da) in uremic rats and that the protein content of the diet might affect the permeability properties.

Increased Intestinal Permeability to Differently Sized Polyethylene Glycols in Uremic Rats: Effects of Low- and High-Protein Diets

Intestinal mucosa forms an important barrier towards harmful agents in the intestinal lumen, besides being the site for absorption of nutrients. Little is known about the intestinal permeability properties in chronic uremia. The permeability toward differently sized polyethylene glycols (PEGs; range 326-1,162 Da) was studied in uremic groups compared to the control groups. The urinary recovery was also recovery of PEGs was increased in the uremic groups compared to the control groups. The urinary recovery was also increased in the groups on the high-protein diet compared to the corresponding group on the low-protein diet. This study suggests an increased permeability of PEG molecules in the range of 546-1,162 Da in uremic rats and a decreased intestinal permeability after a low-protein diet in both a uremic and nonuremic state. Thus, in chronic renal failure the intestinal barrier is impaired but returns towards normal with low-protein diets.

Characterization of size-dependent exchange of PEG molecules between the blood and extravascular space in the pig

Different sized polyethylene glycols (PEGs) have been used as probe molecules in studies of size-dependent permeation through the intestinal wall and the glomerular membranes. We have curve-fitted a three-compartment model to the urinary recovery data following intravenous injection of different sized PEG molecules in the pig. The rate constants to and from the extravascular space demonstrate a strong size-dependent selectivity for PEG molecules less than 502 Da, but the rate constants to the urine are almost the same for all PEG molecules. This is discussed in relation to the selectivity in the glomerular filtration, distribution volume, and the use of PEG molecules as tracers in the permeability studies.

The effect of concanavalin A and wheat germ agglutinin on the ultrastructure and permeability of rat intestine. A possible model for an intestinal allergic reaction.

Sprague-Dawley rats were exposed to lectins, either concanavalin A (Con A) or wheat germ agglutinin (WGA). The lectins were instilled into a ligated segment of the distal small intestine together with permeability markers, fluoresceinated dextran (MW 3,000) or a mixture of differently sized polyethylene glycols (MW 400, 600 and 1,000). WGA-treated rats showed a decreased permeability to small molecules (MW less than 600) of polyethylene glycol but an increase for a larger dextran molecule (MW 3,000). These effects as well as the morphological findings might mimic the situation in patients with food allergy or celiac disease. Con A-treated rats had decreased intestinal permeability to the larger dextran molecules (MW 3,000), whereas the passage of small molecules was unaffected and the ultrastructural effects were minute. The Con A-induced changes could result from a mucotractive effect, associated with a low-grade gut allergy. These observations suggest that lectins can affect both the ultrastructure and the permeability of the intestine, in a way assumed to mimic allergic reactions to food constituents.

Bile formation in guinea pigs: analysis with inert solutes of graded molecular radius.

ARTICLESBile formation in guinea pigs: analysis with inert solutes of graded molecular radiusEL ForkerEL ForkerPublished Online:01 Jul 1968https://doi.org/10.1152/ajplegacy.1968.215.1.56MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByCholangiocyte anion exchange and biliary bicarbonate excretionWorld Journal of Gastroenterology, Vol. 12, No. 22Fetal excretion of the fluorescent bile acid derivative cholylglycylamido-fluorescein (FITC-GC) by the rat placenta-maternal liver tandemPlacenta, Vol. 19, No. 1Ursodeoxycholate-induced hypercholeresis in cirrhotic rats: Further evidence for cholehepatic shuntingHepatology, Vol. 20, No. 4Hepatic excretion and metabolism of polyethylene glycols and mannitol in the catJournal of Hepatology, Vol. 17, No. 1The pattern of vasopressin-induced reduction in biliary output of cholephilic probes in the rat can be mimicked by dialysisHepatology, Vol. 14, No. 1Adrenergic influence on bile secretion-an experimental study in the catActa Physiologica Scandinavica, Vol. 140, No. 2Biliary excretion of different sized polyethylene glycols in the catJournal of Hepatology, Vol. 11, No. 2Demonstration of vesicular-dependent bile flow in the sucrose-loaded ratGastroenterology, Vol. 99, No. 2The effects of hypertonic glucose solutions on hepatic bile formationJournal of Hepatology, Vol. 11, No. 1Cellular Mechanisms of Hepatic Fluid and Electrolyte Transport1 January 2011Effect of molecular charge on para- and transcellular access of horseradish peroxidase into rat bileHepatology, Vol. 9, No. 6The Passage of Molecules into Bile: Paracellular and Transcytotic PathwaysBiliary clearance of inert carbohydratesGastroenterology, Vol. 94, No. 1Mechanisms of Bile Secretion and Hepatic TransportPermeability characteristics of the guinea pig biliary apparatusHepatology, Vol. 6, No. 6Mechanisms of Bile Secretion and Hepatic TransportPostnatal development of hepatic bile formation in the rabbitDigestive Diseases and Sciences, Vol. 30, No. 6Relation between molecular weight and pulmonary absorption rate of lipid-insoluble compounds in neonatal and adult ratsBiochemical Pharmacology, Vol. 32, No. 17Cellular mechanisms of bile formationGastroenterology, Vol. 82, No. 2Effect of Ethanol on Formation of Bile1 February 2008 | Alcoholism: Clinical and Experimental Research, Vol. 5, No. 1Tissue Distribution and Metabolism of Drugs V: Effect of Secretin and Pancreozymin on Drug Transport in Rabbit PancreasJournal of Pharmaceutical Sciences, Vol. 69, No. 1Evaluation of hepatobiliary function in the rat by the segmented retrograde intrabiliary injection techniqueBiochemical Pharmacology, Vol. 29, No. 2Characteristics of inert solute clearance by the monkey liverGastroenterology, Vol. 76, No. 2Phalloidin-induced cholestasis in the rat: Relation to changes in microfilamentsGastroenterology, Vol. 75, No. 3Erythritol and mannitol clearances with taurocholate and secretin-induced cholereses.J L Barnhart, and B Combes1 February 1978 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 234, No. 2Die LeberHepatic Bile FormationNew England Journal of Medicine, Vol. 295, No. 26Canalicular Bile Production in ManEuropean Journal of Clinical Investigation, Vol. 5, No. 1Principles of Biliary SecretionBiliäre Clearance und intrahepatische Verteilung von Sucrose und Natrium-Ferrocyanid bei Äthinylöstradiol-CholestaseEffect of osmotic pressure on spontaneous afferent discharge in the nerves of the perfused rabbit liverPfl�gers Archiv European Journal of Physiology, Vol. 361, No. 1Mechanisms and Control of Secretion of Bile Water and ElectrolytesGastroenterology, Vol. 66, No. 2Bile SecretionClinics in Gastroenterology, Vol. 2, No. 1The influence of secretin on the elimination of14C-Edrophonium in bileExperientia, Vol. 28, No. 11Excretion of 14C-edrophonium and its metabolites in bile: role of the liver cell and the peribiliary vascular plexus19 July 2012 | British Journal of Pharmacology, Vol. 44, No. 3Canalicular Bile flow and Bile Secretory PressureGastroenterology, Vol. 59, No. 6Rapid passage of mannitol into liver and bileLife Sciences, Vol. 9, No. 17Pathophysiology of cholestasisHuman Pathology, Vol. 1, No. 1 More from this issue > Volume 215Issue 1July 1968Pages 56-62 Copyright & PermissionsCopyright © 1968 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1968.215.1.56PubMed5659343History Published online 1 July 1968 Published in print 1 July 1968 Metrics

Canalicular bile production in dogs.

Canalicular bile production in dogs.