Stabilization of Substances in Circulation

Monfardini, Cristina; Veronese, Francesco M.

doi:10.1021/bc970184f

Cited by 209 publications

(171 citation statements)

References 325 publications

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“…These findings are in line with the idea that protein PEGylation enhances circulatory longevity by forming a shielding cloud around the modified protein which thereby prevents access to receptors involved in protein clearance, and by increasing the overall molecular size of the modified protein and thus which preventing or decreasing its glomerular filtration (Monfardini and Veronese, 1998). These studies point towards the potential ability to utilize recombinant human AChE produced in bacterial production systems, and therefore lack all eukaryotic-related post translation modifications, as a cost-effective source for large-scale amounts of enzyme which can be thereby be efficiently PEGylated to generate circulatory longlived enzyme species for therapeutic use.…”

Section: Pegylated -Deglycosylated-achesupporting

confidence: 86%

Generation of Recombinant Human Ache Op-Scavengers With Extended Circulatory Longevity

Shafferman¹

2004

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of infomation. Send co.mments regarding this burden estimate or any other aspect of this colledion of information, including suggestions for reducing this burden to Washington Headquarters Sen/ices, Directorate Ibr Infbmialion Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Papenvork Reduction Project (0704-01881, Washington, DC 20503 Agency Use Only (Leave blank). 11. Supplementary Notes (i.e., report contains color photos, report contains appendix in non-print form, etc.)Original contains color plates: All DTIC reproductions will be in black and white. 12a. Distribution/Availability Statement)Approved for public release; distribution unlimited Abstract {Maximum 200 Words) 12b. Distribution Code (Leave Blank)The use of recombinant human acetylcholinesterase as an effective bioscavenger of organophosphorus compounds requires that it reside in the circulation for sufficiently long periods of time. We have demonstrated in the past that extension of the circulatory lifetime of AChE can be achieved either by optimizing post-translation-related enzyme processing or by chemical conjugation of polyethylene glycol (PEG) moieties to the enzyme. To delineate the interrelationship between these two modes of AChE modulation with regard to pharmacokinetic behavior, an array of AChE molecules differing in their post-translation-related processing was subjected to PEG-conjugation and monitored for their pharmacokinetic performance. In all cases tested to date, PEG-conjugation was found to give rise to enzyme species which reside for very long periods of time in the circulation of mice in a nearly equal manner. We have now found a novel mode of AChE circulatory elimination based on the recognition of specific amino acid-related epitopes. This unique clearance mechanism can also be efficiently overcome by enzyme PEGylation. These findings indicate that the circulatory residence is dictated primarily by the PEG appendage, and that cost-effective microorganisms-based production systems which do not support animal-cell-related enzyme processing, may be utilized for large-scale AChE production. In line with this notion, we have constructed a synthetic human AChE gene designed for optimal expression in microorganism-based production systems, which will now be tested for its ability to sustain human AChE production.14. Subject Terms (keywords previously assigned to proposal abstract or terms which apply to this award) I. GENERAL INTRODUCTIONThe primary role of acetylcholinesterase (acetylcholine acetylhydrolase 3.1.1.7, AChE) is the termination of impulse transmission in cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylchoUne (ACh). The enzyme has been th...

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Section: Pegylated -Deglycosylated-achesupporting

confidence: 86%

Generation of Recombinant Human Ache Op-Scavengers With Extended Circulatory Longevity

Shafferman¹

2004

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“…Neither far-red fluorogen was designed with consideration of biodistribution in animals, and we have not yet explored parameters such as the rate of clearance in mice. We expect that the in vivo labeling effectiveness of these fluorogens could be improved by attaching chemical substituents known to alter small molecule retention within living animals (43). Coupling to polyethylene glycol, for example, may increase the solubility and circulation time of the molecule and consequently decrease the quantity of fluorogen required for effective labeling.…”

Section: Discussionmentioning

confidence: 99%

Fluoromodule-based reporter/probes designed for in vivo fluorescence imaging

Zhang¹,

Chakraborty²,

Sampath³

et al. 2015

Journal of Clinical Investigation

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“…Instead, a large proportion of circulating nanoparticles are nonspecifically captured by macrophages and specialized endothelial cells residing in the liver, spleen, and bone marrow 31 . Early efforts to evade the mononuclear phagocyte system, such as the addition of non-ionic surfactants and polymer macromolecules to the surface of drug carriers, have been shown to extend blood-circulation time while reducing macrophage uptake [31][32][33][34] . Such innovations have allowed nanoparticle-based chemotherapeutics to show enhanced efficacy over freely administered drugs.…”

Section: Visualization Of Nanoparticle Transport and Uptake In The Livermentioning

confidence: 99%

Real-time intravital microscopy of individual nanoparticle dynamics in liver and tumors of live mice

Ven¹,

Yun²,

Kim³

et al. 2013

Protocol Exchange

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Intravital microscopy is emerging as an important experimental tool for the research and development of multi-functional therapeutic nanoconstructs. The direct visualization of nanoparticle dynamics within live animals provides invaluable insights into the mechanisms that regulate nanotherapeutics transport and cell-particle interactions. Here we present a protocol to image the dynamics of nanoparticles within the liver and tumors of live mice immediately following systemic injection using a high-speed (30-400 fps) confocal or multi-photon laserscanning fluorescence microscope. Techniques for quantifying the real-time accumulation and cellular association of individual particles with a size ranging from several tens of nanometers to micrometers are described, as well as an experimental strategy for labeling Kupffer cells in the liver in vivo. Experimental design considerations and controls are provided, as well as minimum equipment requirements. The entire protocol takes approximately 4-8 hours and yields quantitative information. These techniques can serve to study a wide range of kinetic parameters that drive nanotherapeutics delivery, uptake, and treatment response.

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Stabilization of Substances in Circulation

Cited by 209 publications

References 325 publications

Generation of Recombinant Human Ache Op-Scavengers With Extended Circulatory Longevity

Generation of Recombinant Human Ache Op-Scavengers With Extended Circulatory Longevity

Fluoromodule-based reporter/probes designed for in vivo fluorescence imaging

Real-time intravital microscopy of individual nanoparticle dynamics in liver and tumors of live mice

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