a-piglet-model-of-neonatal-hypoxic-ischemic-encephalopathy

A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy

Birth asphyxia, which causes hypoxic-ischemic encephalopathy (HIE), accounts for 0.66 million deaths worldwide each year, about a quarter of the ...

Institute of Clinical Medicine, Aarhus University Hospital

High density lipoprotein (HDL) is an important natural nanoparticle that may be modified for biomedical imaging purposes. Here we developed a novel technique to create unique multimodality HDL mimicking nanoparticles by incorporation of gold, iron oxide, or quantum dot nanocrystals for computed tomography, magnetic resonance, and fluorescence imaging, respectively. By including additional labels in the corona of the particles, they were made multifunctional. The characteristics of these nanoparticles, as well as their in vitro and in vivo behavior, revealed that they closely mimic native HDL.

Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform.

Nanoparticles have become more and more prevalent in reports of novel contrast agents, especially for molecular imaging, the detection of cellular processes. The advantages of nanoparticles include their potency to generate contrast, the ease of integrating multiple properties, lengthy circulation times, and the possibility to include high payloads. As the chemistry of nanoparticles has improved over the past years, more sophisticated examples of nano-sized contrast agents have been reported, such as paramagnetic, macrophage targeted quantum dots or alpha(v)beta(3)-targeted, MRI visible microemulsions that also carry a drug to suppress angiogenesis. The use of these particles is producing greater knowledge of disease processes and the effects of therapy. Along with their excellent properties, nanoparticles may produce significant toxicity, which must be minimized for (clinical) application. In this review we discuss the different factors that are considered when designing a nanoparticle probe and highlight some of the most advanced examples.

Nanotechnology in medical imaging: probe design and applications.

Nanoemulsions are increasingly investigated for the delivery of hydrophobic drugs to improve their bioavailability or make their administration possible. In the current study, oil-in-water emulsions with three different mean diameters (30, 60, and 95 nm) were developed as a new multimodality nanoparticle platform for tumor targeting and imaging. To that aim, hydrophobically coated iron oxide particles were included in the soybean oil core of the nanoemulsions to enable their detection with magnetic resonance imaging (MRI), while the conjugation of a near infrared fluorophore allowed optical imaging. The accumulation of this novel nanocomposite in subcutaneous human tumors in nude mice was demonstrated with MRI and fluorescence imaging in vivo, and with Perl's staining of histological tumor sections ex vivo.

Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging.

Lipoproteins, natural nanoparticles, have a well-recognized biological role and are highly suitable as a platform for delivering imaging agents. The ease with which both the exterior and interior of the particles can be modified permits the creation of multifunctional nanoparticles for imaging as well as the delivery of therapeutics. Importantly, their endogenous nature may make them biocompatible and biodegradable and allows them to avoid the recognition of the reticuloendothelial system. In particular, high-density lipoproteins (HDL) are of interest, because of their small size they can easily cross the endothelium and penetrate the underlying tissue. We summarize here the progress in establishing HDL as a vector for delivering a variety of diagnostically active materials to vulnerable atherosclerotic plaques in mouse models of atherosclerosis. By loading various types of image-enhancing compounds into either the core or surface of HDL, they can be visualized by different imaging modalities (MRI, CT, optical). By rerouting of HDL away from plaque macrophages, imaging of biological processes in diseases besides atherosclerosis may also be achieved.

High-density lipoprotein-based contrast agents for multimodal imaging of atherosclerosis.

Multifunctional imaging nanoprobes have proven to be of great value in the research of pathological processes, as well as the assessment of the delivery, fate, and therapeutic potential of encapsulated drugs. Moreover, such probes may potentially support therapy schemes by the exploitation of their own physical properties, e.g., through thermal ablation. This review will present four classes of nanoparticulate imaging probes used in this area: multifunctional probes (1) that can be tracked with at least three different and complementary imaging techniques, (2) that carry a drug and have bimodal imaging properties, (3) that are employed for nucleic acid delivery and imaging, and (4) imaging probes with capabilities that can be used for thermal ablation. We will highlight several examples where the suitable combination of different (bio)materials like polymers, inorganic nanocrystals, fluorophores, proteins/peptides, and lipids can be tailored to manufacture multifunctional probes to accomplish nanomaterials of each of the aforementioned classes. Moreover, it will be demonstrated how multimodality imaging approaches improve our understanding of in vivo nanoparticle behavior and efficacy at different levels, ranging from the subcellular level to the whole body.

Multifunctional imaging nanoprobes.

Contrast-enhanced MRI of atherosclerosis can provide valuable additional information on a patient's disease state. As a result of the interactions of HDL with atherosclerotic plaque and the flexibility of its reconstitution, it is a versatile candidate for the delivery of contrast-generating materials to this pathogenic lesion. We herein discuss the reports of HDL modified with gadolinium to act as an MRI contrast agent for atherosclerosis. Furthermore, HDL has been modified with fluorophores and nanocrystals, allowing it to act as a contrast agent for fluorescent imaging techniques and for computed tomography. Such modified HDL has been found to be macrophage specific, and, therefore, can provide macrophage density information via noninvasive MRI. As such, modified HDL is currently a valuable contrast agent for probing preclinical atherosclerosis. Future developments may allow the application of this particle to further diseases and pathological or physiological processes in both preclinical models as well as in patients.

HDL as a contrast agent for medical imaging.

To investigate the potential of spectral computed tomography (CT) (popularly referred to as multicolor CT), used in combination with a gold high-density lipoprotein nanoparticle contrast agent (Au-HDL), for characterization of macrophage burden, calcification, and stenosis of atherosclerotic plaques.

Atherosclerotic plaque composition: analysis with multicolor CT and targeted gold nanoparticles.

&#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x548C;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x8D1F;&#x62C5;&#x76F8;&#x4FE1;&#x80FD;&#x591F;&#x5C06;&#x4E0E;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x6591;&#x5757;&#x5173;&#x8054;&#xFF0C;&#x56E0;&#x800C;&#x88AB;&#x8BA4;&#x4E3A;&#x662F;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x8BCA;&#x65AD;&#x548C;&#x6CBB;&#x7597;&#x7684;&#x91CD;&#x8981;&#x76EE;&#x6807;&#x3002;&#x8FD9;&#x4E9B;&#x5355;&#x5143;&#x683C;&#x7C7B;&#x578B;&#x7684;&#x7279;&#x70B9;&#x662F;&#x66B4;&#x9732;&#x7684;&#x78F7;&#x8102;&#x9170;&#x4E1D;&#x6C28;&#x9178; (PS) &#x5728;&#x5176;&#x8868;&#x9762;&#x3002;&#x5728;&#x672C;&#x7814;&#x7A76;&#x4E2D;&#xFF0C;&#x6211;&#x4EEC;&#x5F00;&#x53D1;&#x548C;&#x5E94;&#x7528;&#x5C0F;&#x80F6;&#x675F;&#x8367;&#x5149;&#x819C;&#x8054;&#x86CB;&#x767D; A5 &#x5B98;&#x80FD;&#x7EB3;&#x7C73;&#x7684;&#x65E0;&#x521B;&#x6027;&#x78C1;&#x5171;&#x632F;&#x6210;&#x50CF; &#xFF08;MRI&#xFF09; PS &#x63ED;&#x9732;&#x7EC6;&#x80DE;&#x5728;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x75C5;&#x53D8;&#x3002;&#x819C;&#x8054;&#x86CB;&#x767D;&#x4ECB;&#x5BFC; A5 &#x76EE;&#x6807;&#x7279;&#x5F02;&#x6027;&#x8BC1;&#x5B9E;&#x4E0E;&#x692D;&#x504F;&#x6CD5;&#x548C;&#x4F53;&#x5916;&#x7ED1;&#x5B9A;&#x5230; Jurkat &#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x3002;&#x4F53;&#x5185; T (1)-&#x8179;&#x4E3B;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316; ApoE(-/-) &#x5C0F;&#x9F20;&#x900F;&#x9732;&#x52A0;&#x6743;&#x7684; MRI &#x589E;&#x5F3A;&#x5438;&#x6536;&#x819C;&#x8054;&#x86CB;&#x767D;&#x7684; A5 &#x80F6;&#x675F;&#x63A7;&#x5236;&#xFF0C;&#x800C;&#x5176;&#x4E2D;&#x8BC1;&#x5B9E;&#x4E0E;&#x4E8B;&#x540E;&#x7684;&#x79BB;&#x4F53;&#x6574;&#x4E2A;&#x4E3B;&#x52A8;&#x8109;&#x4F53;&#x5185;&#x8FD1;&#x7EA2;&#x5916;&#x8367;&#x5149;&#x56FE;&#x50CF;&#x3002;&#x5171;&#x7126;&#x6FC0;&#x5149;&#x626B;&#x63CF;&#x663E;&#x5FAE;&#x955C; (CLSM) &#x8868;&#x660E;&#x6709;&#x9488;&#x5BF9;&#x6027;&#x7684;&#x4EE3;&#x7406;&#x4E0E;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x548C;&#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x76F8;&#x5173;&#x8054;&#x800C;&#x975E;&#x7279;&#x5F02;&#x6027;&#x63A7;&#x5236;&#x4EE3;&#x7406;&#x8868;&#x660E;&#x8FD9;&#x79CD;&#x7EC6;&#x80DE;&#x65E0;&#x660E;&#x663E;&#x5438;&#x6536;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x80F6;&#x819C;&#x8054;&#x86CB;&#x767D; A5 &#x5171;&#x8F6D;&#x53CC;&#x5CF0;&#x675F;&#x663E;&#x793A;&#x7684;&#x5355;&#x5143;&#x683C;&#x7C7B;&#x578B;&#x7684;&#x88AB;&#x89C6;&#x4E3A;&#x4E0D;&#x7A33;&#x5B9A;&#x6591;&#x5757;&#x4F5C;&#x51FA;&#x91CD;&#x5927;&#x8D21;&#x732E;&#xFF0C;&#x56E0;&#x6B64;&#x53EF;&#x80FD;&#x5728;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x75C5;&#x53D8;&#x8868;&#x578B;&#x7684;&#x8BC4;&#x4F30;&#x5F88;&#x6709;&#x4EF7;&#x503C;&#x7684;&#x65E0;&#x521B;&#x6027;&#x8BC4;&#x4F30;&#x7684;&#x6F5C;&#x529B;&#x3002;

&#x819C;&#x8054;&#x86CB;&#x767D; A5 &#x5B98;&#x80FD;&#x53CC;&#x5CF0;&#x7EB3;&#x7C73;&#x78C1;&#x5171;&#x632F;&#x6210;&#x50CF;&#x548C;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x6591;&#x5757;&#x7684;&#x8367;&#x5149;&#x6210;&#x50CF;&#x3002;

Apoptosis and macrophage burden are believed to correlate with atherosclerotic plaque vulnerability and are therefore considered important diagnostic and therapeutic targets for atherosclerosis. These cell types are characterized by the exposure of phosphatidylserine (PS) at their surface. In the present study, we developed and applied a small micellar fluorescent annexin A5-functionalized nanoparticle for noninvasive magnetic resonance imaging (MRI) of PS exposing cells in atherosclerotic lesions. Annexin A5-mediated target-specificity was confirmed with ellipsometry and in vitro binding to apoptotic Jurkat cells. In vivo T(1)-weighted MRI of the abdominal aorta in atherosclerotic ApoE(-/-) mice revealed enhanced uptake of the annexin A5-micelles as compared to control-micelles, which was corroborated with ex vivo near-infrared fluorescence images of excised whole aortas. Confocal laser scanning microscopy (CLSM) demonstrated that the targeted agent was associated with macrophages and apoptotic cells, whereas the nonspecific control agent showed no clear uptake by such cells. In conclusion, the annexin A5-conjugated bimodal micelles displayed potential for noninvasive assessment of cell types that are considered to significantly contribute to plaque instability and therefore may be of great value in the assessment of atherosclerotic lesion phenotype.

Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques.

Charge l&#39;apoptose et macrophages sont cens&eacute;s mettre en corr&eacute;lation avec la vuln&eacute;rabilit&eacute; de la plaque d&#39;ath&eacute;roscl&eacute;rose et sont donc consid&eacute;r&eacute;s comme des cibles importantes de diagnostiques et th&eacute;rapeutiques de l&#39;ath&eacute;roscl&eacute;rose. Ces types de cellules sont caract&eacute;ris&eacute;es par l&#39;exposition de la phosphatidyls&eacute;rine (PS) &agrave; leur surface. Dans la pr&eacute;sente &eacute;tude, nous avons d&eacute;velopp&eacute; et appliqu&eacute; une petite micellaire fluorescente annexin fonctionnalis&eacute;s A5 nanoparticule pour non invasive magnetic resonance imaging (MRI) de cellules exposante de PS dans les l&eacute;sions ath&eacute;roscl&eacute;rotiques. Annexin A5-mediated cible-sp&eacute;cificit&eacute; a &eacute;t&eacute; confirm&eacute;e avec l&#39;ellipsom&eacute;trie et de la liaison in vitro &agrave; l&#39;apoptose des cellules Jurkat. T in vivo (1)-IRM pond&eacute;r&eacute;e de l&#39;aorte abdominale chez des souris ApoE(-/-) ath&eacute;roscl&eacute;reuses a r&eacute;v&eacute;l&eacute; am&eacute;lior&eacute; absorption des micelles-A5 ANNEXINES comparativement &agrave; contr&ocirc;le-micelles, qui a &eacute;t&eacute; corrobor&eacute;e par ex vivo images de fluorescence proche infrarouge des aortes entiers excis&eacute;s. Confocal laser scanning microscopy (CLSM) d&eacute;montre que l&#39;agent cibl&eacute; est associ&eacute;e avec les macrophages et les cellules apoptotiques, tandis que l&#39;agent de contr&ocirc;le non sp&eacute;cifiques ont montr&eacute; aucune absorption claire par ces cellules. En conclusion, l&#39;ANNEXINES micelles bimodales conjugu&eacute; A5 affichent possible d&#39;&eacute;valuation non invasive de types de cellules qui sont cens&eacute;es contribuer significativement &agrave; l&#39;instabilit&eacute; de la plaque et donc peut &ecirc;tre d&#39;une grande utilit&eacute; dans l&#39;&eacute;valuation du ph&eacute;notype des l&eacute;sions ath&eacute;roscl&eacute;reuses.

Annexin fonctionnalis&eacute;s A5 bimodale nanoparticules pour IRM et imagerie de fluorescence des plaques d&#39;ath&eacute;roscl&eacute;rose.

Apoptosis und Makrophagen Belastung werden geglaubt, um mit atherosklerotischen Plakette Schwachstelle korrelieren und gelten daher als wichtige diagnostische und therapeutische Ziele f&uuml;r Atherosklerose. Diesen Zelltypen zeichnen sich durch die Aufdeckung der Phosphatidylserin (PS) an ihrer Oberfl&auml;che. In der vorliegenden Studie, die wir entwickelt und eine kleine Mizellares fluoreszierende annexin A5-funktionalisierten Nanopartikeln f&uuml;r nicht-invasive Magnetresonanz-Bildgebung (MRI) PS verf&uuml;gbar machen Zellen in atherosklerotische L&auml;sionen angewandt. Annexin-A5-vermittelte Ziel-Spezifit&auml;t wurde mit Ellipsometrie und in-vitro-Bindung auf Apoptotic Jurkat Zellen best&auml;tigt. In-vivo-T (1)-gewichtete MRT der Abdominal-Aorta atherosklerotischen ApoE(-/-) M&auml;usen ergab verbesserte Aufnahme von annexin A5-Micellen im Vergleich zur Kontrolle-Mizellen, die mit ex-Vivo Nahinfrarotbereich Fluoreszenzbilder der excised ganze Aortas best&auml;tigt wurde. Konfokale Laser scanning Mikroskopie (CLSM) gezeigt, dass der gezielte Agent mit Makrophagen und Apoptotic Zellen, w&auml;hrend der unspezifische Control Agent keine klare Aufnahme durch solche Zellen zeigte. Abschlie&szlig;end angezeigt die annexin A5-konjugierten Bimodale Mizellen Potenzial f&uuml;r nicht-invasive Beurteilung der Zelltypen, die als wesentlich zur Plakette Instabilit&auml;t beitragen und daher m&ouml;glicherweise von gro&szlig;em Wert f&uuml;r die Beurteilung der atherosklerotischen L&auml;sion Ph&auml;notyp.

Annexin A5-funktionalisierten Bimodale Nanopartikel f&uuml;r MRI und Fluoreszenz-Bildgebung von atherosklerotischen Plaques.

Onere di apoptosi e dei macrofagi sono creduto per correlare con vulnerabilit&agrave; della placca aterosclerotica e sono pertanto considerati importanti obiettivi diagnostici e terapeutici per l&#39;aterosclerosi. Questi tipi di cellule sono caratterizzati dall&#39;esposizione della fosfatidilserina (PS) alla loro superficie. Nel presente studio, abbiamo sviluppato e applicato una piccola micellare fluorescente annexin A5-funzionalizzati nanoparticella per non invasiva risonanza magnetica (MRI) di cellule esposizione PS nelle lesioni aterosclerotiche. Annessina specificit&agrave; target A5-mediata &egrave; stata confermata con ellipsometry e associazione in vitro di cellule Jurkat apoptotic. T in vivo (1)-MRI pesata dell&#39;aorta addominale aterosclerotico ApoE(-/-) topi hanno rivelato enhanced uptake di annexin A5-micelle rispetto al controllo-micelle, che &egrave; stata confermata con ex vivo vicino infrarosso fluorescenza di escissa tutta aortas. Laser confocale microscopia (CLSM) hanno dimostrato che l&#39;agente mirato &egrave; stato associato con macrofagi e cellule apoptotiche, mentre l&#39;agente di controllo aspecifico ha mostrato nessun assorbimento chiaro da tali cellule. In conclusione, i annexin micelle bimodale A5-coniugato visualizzato potenziale per la valutazione non invasiva dei tipi di cellule che sono considerati significativamente contribuire alla instabilit&agrave; di placca e quindi pu&ograve; essere di grande valore nella valutazione del fenotipo lesione aterosclerotica.

Annessina A5-funzionalizzati bimodale nanoparticelle per la risonanza magnetica e formazione immagine di fluorescenza di placche aterosclerotiche.

&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x3068;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306E;&#x8CA0;&#x62C5;&#x306F;&#x3001;&#x52D5;&#x8108;&#x786C;&#x5316;&#x30D7;&#x30E9;&#x30FC;&#x30AF;&#x306E;&#x8106;&#x5F31;&#x6027;&#x306B;&#x95A2;&#x9023;&#x3059;&#x308B;&#x3068;&#x8003;&#x3048;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x3001;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x30A2;&#x30C6;&#x30ED;&#x30FC;&#x30E0;&#x6027;&#x52D5;&#x8108;&#x786C;&#x5316;&#x306E;&#x305F;&#x3081;&#x306E;&#x91CD;&#x8981;&#x306A;&#x8A3A;&#x65AD;&#x3068;&#x6CBB;&#x7642;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3068;&#x898B;&#x306A;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30BB;&#x30EB; &#x30BF;&#x30A4;&#x30D7;&#x306F;&#x5F7C;&#x3089;&#x306E;&#x8868;&#x9762;&#x3067;&#x306E;&#x30DB;&#x30B9;&#x30D5;&#x30A1;&#x30C1;&#x30B8;&#x30EB;&#x30BB;&#x30EA;&#x30F3; (PS) &#x306E;&#x9732;&#x51FA;&#x306B;&#x3088;&#x3063;&#x3066;&#x7279;&#x5FB4;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x307E;&#x3059;&#x3002;&#x672C;&#x7814;&#x7A76;&#x3067;&#x958B;&#x767A;&#x3057;&#x3001;&#x5C0F;&#x3055;&#x306A;&#x30DF;&#x30BB;&#x30EB;&#x86CD;&#x5149;&#x30A2;&#x30CD;&#x30AD;&#x30B7;&#x30F3; A5 &#x6A5F;&#x80FD;&#x96C6;&#x7A4D;&#x5316;&#x30CA;&#x30CE; PS &#x516C;&#x958B;&#x7D30;&#x80DE;&#x52D5;&#x8108;&#x786C;&#x5316;&#x75C5;&#x5909;&#x306E;&#x975E;&#x4FB5;&#x8972;&#x7684;&#x78C1;&#x6C17;&#x5171;&#x9CF4;&#x753B;&#x50CF; &#xFF08;MRI&#xFF09; &#x3092;&#x9069;&#x7528;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30A2;&#x30CD;&#x30AD;&#x30B7;&#x30F3; A5 &#x3092;&#x4ECB;&#x3057;&#x305F;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x7279;&#x7570;&#x30A8;&#x30EA;&#x30D7;&#x30BD;&#x30E1;&#x30C8;&#x30EA;&#x30FC;&#x3068; Jurkat &#x7D30;&#x80DE;&#x306E;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x3078;&#x306E; in vitro &#x306E;&#x30D0;&#x30A4;&#x30F3;&#x30C9;&#x3067;&#x78BA;&#x8A8D;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;In vivo &#x3067; T (1)-&#x52A0;&#x91CD; MRI &#x660E;&#x3089;&#x304B;&#x306B;&#x52D5;&#x8108;&#x786C;&#x5316;&#x306E; ApoE(-/-) &#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8179;&#x90E8;&#x5927;&#x52D5;&#x8108;&#x306E;&#x62E1;&#x5F35;&#x3068; ex vivo &#x8FD1;&#x8D64;&#x5916;&#x86CD;&#x5149;&#x753B;&#x50CF;&#x5168;&#x4F53;&#x306E;&#x6458;&#x51FA;&#x5927;&#x52D5;&#x8108;&#x306E;&#x78BA;&#x8A3C;&#x3055;&#x308C;&#x305F;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB; &#x30DF;&#x30BB;&#x30EB;&#x3068;&#x6BD4;&#x8F03;&#x3059;&#x308B;&#x3068;&#x30A2;&#x30CD;&#x30AD;&#x30B7;&#x30F3; A5 &#x30DF;&#x30BB;&#x30EB;&#x306E;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x3002;&#x975E;&#x7279;&#x7570;&#x7684;&#x5236;&#x5FA1;&#x30A8;&#x30FC;&#x30B8;&#x30A7;&#x30F3;&#x30C8;&#x306F;&#x305D;&#x306E;&#x3088;&#x3046;&#x306A;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x660E;&#x78BA;&#x306A;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x3092;&#x793A;&#x3055;&#x306A;&#x304B;&#x3063;&#x305F;&#x306B;&#x5BFE;&#x3057;&#x5171;&#x7126;&#x70B9;&#x30EC;&#x30FC;&#x30B6;&#x30FC;&#x8D70;&#x67FB;&#x9855;&#x5FAE;&#x93E1; (CLSM) &#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8; &#x30A8;&#x30FC;&#x30B8;&#x30A7;&#x30F3;&#x30C8; &#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x3068;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x7D30;&#x80DE;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x7D50;&#x8AD6;&#x3068;&#x3057;&#x3066;&#x3001;&#x30A2;&#x30CD;&#x30AD;&#x30B7;&#x30F3; A5 &#x5171;&#x5F79;&#x30D0;&#x30A4;&#x30E2;&#x30FC;&#x30C0;&#x30EB; &#x30DF;&#x30BB;&#x30EB; &#x30D7;&#x30E9;&#x30FC;&#x30AF;&#x306E;&#x4E0D;&#x5B89;&#x5B9A;&#x6027;&#x306B;&#x5927;&#x304D;&#x304F;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x3068;&#x8003;&#x3048;&#x3089;&#x308C;&#x3001;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x8868;&#x73FE;&#x578B;&#x52D5;&#x8108;&#x786C;&#x5316;&#x75C5;&#x5909;&#x306E;&#x8A55;&#x4FA1;&#x306B;&#x5927;&#x304D;&#x306A;&#x4FA1;&#x5024;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x30BB;&#x30EB;&#x578B;&#x306E;&#x975E;&#x4FB5;&#x8972;&#x7684;&#x8A55;&#x4FA1;&#x306E;&#x53EF;&#x80FD;&#x6027;&#x3092;&#x8868;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30A2;&#x30CD;&#x30AD;&#x30B7;&#x30F3; A5 &#x4FEE;&#x98FE;&#x30CA;&#x30CE; &#x30D0;&#x30A4;&#x30E2;&#x30FC;&#x30C0;&#x30EB;&#x7C92;&#x5B50; MRI &#x3068;&#x52D5;&#x8108;&#x786C;&#x5316;&#x6027;&#x30D7;&#x30E9;&#x30FC;&#x30AF;&#x306E;&#x86CD;&#x5149;&#x30A4;&#x30E1;&#x30FC;&#x30B8;&#x30F3;&#x30B0;&#x3002;

Apoptosis&#xC640; macrophage &#xBD80;&#xB2F4; &#xB3D9;&#xB9E5; &#xACBD; &#xD654;&#xC131; &#xD50C; &#xB77C;&#xD06C; &#xCDE8;&#xC57D;&#xC810;&#xC744; &#xC5F0;&#xAD00; &#xC2DC;&#xD0AC; &#xAC83;&#xC73C;&#xB85C; &#xCD94;&#xC815; &#xB41C;&#xB2E4; &#xACE0; &#xB530;&#xB77C;&#xC11C; &#xB3D9;&#xB9E5; &#xACBD;&#xD654; &#xC99D;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC694; &#xD55C; &#xC9C4;&#xB2E8; &#xBC0F; &#xCE58;&#xB8CC; &#xB300;&#xC0C1; &#xC774;&#xB77C;&#xACE0; &#xC5EC;&#xACA8;&#xC9C4;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC140; &#xD615;&#xC2DD;&#xC758; phosphatidylserine (PS) &#xADF8;&#xB4E4;&#xC758; &#xD45C;&#xBA74;&#xC5D0; &#xB178;&#xCD9C;&#xC5D0; &#xC758;&#xD574; &#xD2B9;&#xC9D5;. &#xD604;&#xC7AC;&#xC758; &#xC5F0;&#xAD6C;&#xC5D0; &#xC6B0;&#xB9AC;&#xB294; &#xAC1C;&#xBC1C;&#xACFC; &#xB098;&#xB178;&#xB294; &#xC791;&#xC740; micellar &#xD615;&#xAD11; annexin a 5 functionalized &#xC785;&#xC790; &#xB3D9;&#xB9E5; &#xACBD; &#xD654;&#xC131; &#xBCD1; &#xBCC0;&#xC5D0;&#xC11C; PS &#xB178;&#xCD9C; &#xC140;&#xC758; &#xBE44; &#xCE68; &#xD22C; &#xC801;&#xC778; &#xC790;&#xAE30; &#xACF5;&#xBA85; &#xC601;&#xC0C1; (MRI)&#xC5D0; &#xB300; &#xD55C; &#xC801;&#xC6A9;. A5-&#xC911;&#xC7AC; &#xB300;&#xC0C1; &#xD2B9;&#xC774;&#xC131; annexin ellipsometry&#xC640; apoptotic Jurkat &#xC138;&#xD3EC;&#xC5D0; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; &#xBC14;&#xC778;&#xB529;&#xC744; &#xD655;&#xC778; &#xB410;&#xB2E4;. Vivo&#xC5D0;&#xC11C; T (1)-&#xACF5;&#xAC1C; &#xB3D9;&#xB9E5; &#xACBD; &#xD654;&#xC131; ApoE(-/-) &#xC950;&#xC5D0; &#xBCF5; &#xBD80; &#xB300;&#xB3D9;&#xB9E5;&#xC758;&#xAC00; &#xC911;&#xB41C; MRI &#xAC15;&#xD654; &#xB41C; ex vivo &#xC0AD;&#xC81C; &#xC804;&#xCCB4; aortas&#xC758; &#xADFC; &#xC801;&#xC678;&#xC120; &#xD615;&#xAD11; &#xC774;&#xBBF8;&#xC9C0;&#xC640; &#xB4B7;&#xBC1B;&#xCE68; &#xD588;&#xB2E4; &#xC81C;&#xC5B4; micelles&#xC5D0; &#xBE44;&#xD574; annexin a 5 micelles&#xC758; &#xD1B5;&#xD48D; &#xAD00;. Confocal &#xB808;&#xC774;&#xC800; &#xC2A4;&#xCE90;&#xB2DD; &#xD604;&#xBBF8;&#xACBD; &#xAC80;&#xC0AC; &#xBC95; (CLSM) &#xBC18;&#xBA74; &#xC77C;&#xBC18; &#xC81C;&#xC5B4; &#xC5D0;&#xC774;&#xC804;&#xD2B8; &#xBCF4;&#xC600;&#xB2E4; &#xAC19;&#xC740; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xBD84;&#xBA85; &#xC544;&#xB2C8; &#xAE00;&#xADC0;&#xB97C; &#xB300;&#xC0C1;&#xB41C; &#xC5D0;&#xC774;&#xC804;&#xD2B8; apoptotic &#xC138;&#xD3EC;, &#xB300; &#xC2DD; &#xC138;&#xD3EC;&#xC640; &#xAD00;&#xB828;&#xC774; &#xC788;&#xC5C8;&#xB2E4;&#xC744; &#xC2DC;&#xC5F0; &#xD588;&#xB2E4;. &#xB05D;&#xC73C;&#xB85C;, annexin a 5 conjugated &#xBAA8;&#xB2EC; micelles &#xD45C;&#xC2DC; &#xD50C; &#xB77C;&#xD06C; &#xBD88;&#xC548;&#xC815;&#xC5D0; &#xD06C;&#xAC8C; &#xAE30;&#xC5EC;&#xD560; &#xAC83;&#xC73C;&#xB85C; &#xAC04;&#xC8FC; &#xB429;&#xB2C8;&#xB2E4; &#xB530;&#xB77C;&#xC11C; &#xB3D9;&#xB9E5; &#xACBD; &#xD654;&#xC131; &#xBCD1; &#xBCC0; &#xD615; &#xD3C9;&#xAC00;&#xC5D0; &#xD070; &#xAC00;&#xCE58;&#xAC00; &#xC788;&#xC744; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC140; &#xD615;&#xC2DD;&#xC758; &#xBE44; &#xCE68; &#xD22C; &#xC801;&#xC778; &#xD3C9;&#xAC00; &#xB300; &#xD55C; &#xAC00;&#xB2A5;&#xC131;.

A5 functionalized &#xBAA8;&#xB2EC; &#xB098;&#xB178; MRI &#xBC0F; &#xB3D9;&#xB9E5; &#xACBD; &#xD654;&#xC131; &#xD50C; &#xB77C;&#xD06C;&#xC758; &#xD615;&#xAD11; &#xC774;&#xBBF8;&#xC9D5; annexin.

Carga de apoptosis y macr&oacute;fagos se cree que se correlacionan con la vulnerabilidad de la placa de ateroma y por lo tanto se consideran objetivos importantes de diagn&oacute;sticos y terap&eacute;uticos para la ateroesclerosis. Estos tipos de c&eacute;lulas se caracterizan por la exposici&oacute;n de fosfatidilserina (PS) en su superficie. En el presente estudio, hemos desarrollado y hab&iacute;a aplicado una peque&ntilde;a micelar fluorescente anexina A5-funcionalizados nanopart&iacute;cula para no invasiva resonancia magn&eacute;tica (MRI) de la c&eacute;lulas de exposici&oacute;n de PS en las lesiones ateroscler&oacute;ticas. Anexina A5-mediada blanco-especificidad fue confirmada con Elipsometr&iacute;a y Uni&oacute;n in vitro a c&eacute;lulas Jurkat de apoptosis. T in vivo (1)-MRI ponderada de la aorta abdominal en ratones de ApoE(-/-) ateroscler&oacute;ticas revelada mejorado la absorci&oacute;n de las anexinas A5-micelas en comparaci&oacute;n con el control-micelas, que fue corroborada con ex vivo im&aacute;genes de fluorescencia de infrarrojo cercano de aortas todo suprimidas. L&aacute;ser confocal de microscop&iacute;a (CLSM) demostraron que el agente espec&iacute;fico se asoci&oacute; con macr&oacute;fagos y c&eacute;lulas apopt&oacute;ticas, mientras que el agente de control inespec&iacute;fico no demostr&oacute; ninguna absorci&oacute;n clara por tales c&eacute;lulas. En conclusi&oacute;n, las micelas bimodales anexinas A5-conjugado muestran potencial para la evaluaci&oacute;n no invasiva de tipos celulares que se consideran a contribuir significativamente a la inestabilidad de la placa y por lo tanto puede ser de gran valor en la evaluaci&oacute;n del fenotipo de la lesi&oacute;n ateroscler&oacute;tica.

Anexina A5-funcionalizados bimodales nanopart&iacute;culas para MRI e im&aacute;genes de fluorescencia de placas ateroscler&oacute;ticas.

An important challenge in medical diagnostics is to design all-in-one contrast agents that can be detected with multiple techniques such as magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), single photon emission tomography (SPECT) or fluorescence imaging (FI). Although many dual labeled agents have been proposed, mainly for combined MRI/FI, constructs for three imaging modalities are scarce. Here gold/silica nanoparticles with a poly(ethylene glycol), paramagnetic and fluorescent lipid coating were synthesized, characterized and applied as trimodal contrast agents to allow for nanoparticle-enhanced imaging of macrophage cells in vitro via MRI, CT and FI, and mice livers in vivo via MRI and CT. This agent can be a useful tool in a multitude of applications, including cell tracking and target-specific molecular imaging, and is a step in the direction of truly multi-modal imaging.

A fluorescent, paramagnetic and PEGylated gold/silica nanoparticle for MRI, CT and fluorescence imaging.

Lipoproteins are a family of plasma nanoparticles responsible for the transportation of lipids throughout the body. High-density lipoprotein (HDL), the smallest of the lipoprotein family, measures 7-13 nm in diameter and consists of a cholesteryl ester and triglyceride core that is covered with a monolayer of phospholipids and apolipoproteins. We have developed an iron oxide core HDL nanoparticle (FeO-HDL), which has a lipid based fluorophore incorporated in the phospholipid layer. This nanoparticle provides contrast for optical imaging, magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Consequently, FeO-HDL can be visualized on the anatomical, cellular and sub-cellular level. In the current study we show that the biophysical features of FeO-HDL closely resemble those of native HDL and that FeO-HDL possess the ability to mimic HDL characteristics both in vitro as well as in vivo. We demonstrate that FeO-HDL can be applied to image HDL interactions and to investigate disease settings where HDL plays a key function. More generally, we have demonstrated a multimodal approach to study the behavior of biomaterials in vitro as well as in vivo. The approach allowed us to study nanoparticle dynamics in circulation, as well as nanoparticle targeting and uptake by tissues and cells of interest. Moreover, we were able to qualitatively assess nanoparticle excretion, critical for translating nanotechnologies to the clinic.

The biological properties of iron oxide core high-density lipoprotein in experimental atherosclerosis.

The study of lipoproteins, natural nanoparticles comprised of lipids and apolipoproteins that transport fats throughout the body, is of key importance to better understand, treat, and prevent cardiovascular disease. In the current study, we have developed a lipoprotein-based nanoparticle that consists of a quantum dot (QD) core and Cy5.5 labeled lipidic coating. The methodology allows judicious tuning of the QD/Cy5.5 ratio, which enabled us to optimize Förster resonance energy transfer (FRET) between the QD core and the Cy5.5-labeled coating. This phenomenon allowed us to study lipoprotein-lipoprotein interactions, lipid exchange dynamics, and the influence of apolipoproteins on these processes. Moreover, we were able to study HDL-cell interactions and exploit FRET to visualize HDL association with live macrophage cells.

Quantum dot and Cy5.5 labeled nanoparticles to investigate lipoprotein biointeractions via Förster resonance energy transfer.

There are many liver diseases that could be treated with delivery of therapeutics such as DNA, proteins, or small molecules. Nanoparticles are often proposed as delivery vectors for such therapeutics; however, achieving nanoparticle accumulations in the therapeutically relevant hepatocytes is challenging. In order to address this issue, we have synthesized polymer coated, fluorescent iron oxide nanoparticles that bind and deliver DNA, as well as produce contrast for magnetic resonance imaging (MRI), fluorescence imaging, and transmission electron microscopy (TEM). The composition of the coating can be varied in a facile manner to increase the quantity of poly(ethylene glycol) (PEG) from 0% to 5%, 10%, or 25%, with the aim of reducing opsonization but maintaining DNA binding. We investigated the effect of the nanoparticle coating on DNA binding, cell uptake, cell transfection, and opsonization in vitro. Furthermore, we exploited MRI, fluorescence imaging, and TEM to investigate the distribution of the different formulations in the liver of mice. While MRI and fluorescence imaging showed that each formulation was heavily taken up in the liver at 24 h, the 10% PEG formulation was taken up by the therapeutically relevant hepatocytes more extensively than either the 0% PEG or the 5% PEG, indicating its potential for delivery of therapeutics to the liver.

A versatile and tunable coating strategy allows control of nanocrystal delivery to cell types in the liver.

Lipoproteins are natural nanoparticles composed of phospholipids and apolipoproteins that transport lipids throughout the body. As key effectors of lipid homeostasis, the functions of lipoproteins have been demonstrated to be crucial during the development of cardiovascular diseases. Therefore various strategies have been used to study their biology and detect them in vivo. A recent approach has been the production of lipoprotein biomimetic particles loaded with diagnostically active nanocrystals in their core. These include, but are not limited to: quantum dots, iron oxide or gold nanocrystals. Inclusion of these nanocrystals enables the utilization of lipoproteins as probes for a variety of imaging modalities (computed tomography, magnetic resonance imaging, fluorescence) while preserving their biological activity. Furthermore as some lipoproteins naturally accumulate in atherosclerotic plaque or specific tumor tissues, nanocrystal core lipoprotein biomimetics have been developed as contrast agents for early diagnosis of these diseases.

Nanocrystal Core Lipoprotein Biomimetics for Imaging of Lipoproteins and Associated Diseases.

Lipid coated nanocrystal assemblies are among the most extensively investigated nanoparticle platforms for biomedical imaging and therapeutic purposes. However, very few efforts have been addressed to the lipid coating exchange dynamics in such systems, which is key to our understanding of the nanoparticles' coating stability and their interactions with the environment. Here, we apply the Förster resonance energy transfer (FRET) from quantum dot (QD) core to Cy5.5 dye labeled lipids at the surface to monitor the lipid exchange dynamics in situ and to study its dependence on concentration, temperature and solvent. A kinetic model is developed to describe the experimental data, allowing the rate constants and the activation energy for lipid exchange to be determined. The activation energy for lipid exchange on QD micelles is 155 kJ/mol in saline environment and 130 kJ/mol in pure water. The findings presented here provide basic knowledge on these self-assembled structures and contribute to understanding their performance and to further design of nanomedicine.

Probing lipid coating dynamics of quantum dot core micelles via Förster resonance energy transfer.

Abstract Morning reports offer opportunities for intensive work-based learning. In this controlled study, we measured learning processes and outcomes with the report of paediatric emergency room patients. Twelve specialists and 12 residents were randomised into four groups and discussed the same two paediatric cases. The groups differed in their presentation modality (verbal only vs. verbal + text) and the use of buzz groups (with vs. without). The verbal interactions were analysed for clinical reasoning processes. Perceptions of learning and judgment of learning were reported in a questionnaire. Diagnostic accuracy was assessed by a 20-item multiple-choice test. Combined bimodal presentation and buzz groups increased the odds ratio of clinical reasoning to occur in the discussion of cases by a factor of 1.90 (p = 0.013), indicating superior reasoning for buzz groups working with bimodal materials. For specialists, a positive effect of bimodal presentation was found on perceptions of learning (p < 0.05), and for residents, a positive effect of buzz groups was found on judgment of learning (p < 0.005). A positive effect of bimodal presentation on diagnostic accuracy was noted in the specialists (p < 0.05). Combined bimodal presentation and buzz group discussion of emergency cases improves clinicians' clinical reasoning and learning.

Article	Year
Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform. Nano letters\| PubMed ID: 18939808	2008
Nanotechnology in medical imaging: probe design and applications. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 19057023	2009
Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging. Biomaterials\| PubMed ID: 19783295	2009
High-density lipoprotein-based contrast agents for multimodal imaging of atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 19815819	2010
Multifunctional imaging nanoprobes. Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology\| PubMed ID: 20039335	2010
HDL as a contrast agent for medical imaging. Clinical lipidology\| PubMed ID: 20352038	2009
Atherosclerotic plaque composition: analysis with multicolor CT and targeted gold nanoparticles. Radiology\| PubMed ID: 20668118	2010
Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques. Bioconjugate chemistry\| PubMed ID: 20804153	2010
A fluorescent, paramagnetic and PEGylated gold/silica nanoparticle for MRI, CT and fluorescence imaging. Contrast media & molecular imaging\| PubMed ID: 20812290	2010
The biological properties of iron oxide core high-density lipoprotein in experimental atherosclerosis. Biomaterials\| PubMed ID: 20926130	2011
Quantum dot and Cy5.5 labeled nanoparticles to investigate lipoprotein biointeractions via Förster resonance energy transfer. Nano letters\| PubMed ID: 21087054	2010
A versatile and tunable coating strategy allows control of nanocrystal delivery to cell types in the liver. Bioconjugate chemistry\| PubMed ID: 21361312	2011
Nanocrystal Core Lipoprotein Biomimetics for Imaging of Lipoproteins and Associated Diseases. Current cardiovascular imaging reports\| PubMed ID: 23687557	2013
Probing lipid coating dynamics of quantum dot core micelles via Förster resonance energy transfer. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 24343988	2014
Combining bimodal presentation schemes and buzz groups improves clinical reasoning and learning at morning report. Medical teacher\| PubMed ID: 25496711	2014

Torjus Skajaa

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