EPR and affinity studies of mannose–TEMPO functionalized PAMAM dendrimers

Samuelson, Lynn E.; Sebby, Karl B.; Walter, Éric; Singel, David J.; Cloninger, Mary J.

doi:10.1039/b411643g

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…Macrophage-specific targeting of mannose-coupled nanoparticles in various tumors has been described earlier, 45–47 and mannose-functionalized PAMAM dendrimers have mainly been developed for the study of protein-carbohydrate interactions. 48 Goonewardena et al, however, demonstrated uptake of mannose-conjugated G5 dendrimers by tumor-associated macrophages as well as activated bone marrow-derived monocyte-macrophages. 49 Taking advantage of the high expression of folate receptor on activated macrophages, earlier studies have used folate functionalized nanoparticles for macrophage targeting, 50 and this strategy is currently being favorably considered for rheumatoid arthritis therapy.…”

Section: Discussionmentioning

confidence: 99%

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis

Yuan

Bie

et al. 2018

Translational Research

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Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNPLXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR−/− mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque burden.

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Section: Discussionmentioning

confidence: 99%

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis

Yuan

Bie

et al. 2018

Translational Research

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“…[5] Isothiocyanates 13 b and 13 d were synthesized from the corresponding amines 12 b and 12 d by following ap rocedure by Munch. [12] Alternatively, amine 9 may also first be converted to the respective thiourea 11 by treatment with thiophosgene (10), [13] followed by addition of the respective amines 12.D epending on the accessibility of isothiocyanates 13,e ither route may be effectively applied. Final desulfuration of 14 with HgOthen gave the desired DCC analogues 1a-d.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, EPR‐Studies and Conformational Bias of Novel Spin‐Labeled DCC‐Analogues for the Highly Regioselective Labeling of Aliphatic and Aromatic Carboxylic Acids

Gölz

NejatyJahromy

Bauer

et al. 2016

Chemistry A European J

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Novel types of spin-labeled N,N'-dicyclohexylcarbodiimides (DCC) are reported that bear a 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) residue on one side and different aromatic and aliphatic cyclohexyl analogues on the other side of the diimide core. These readily available novel reagents add efficiently to aliphatic and aromatic carboxylic acids, forming two possible spin-labeled amide derivatives with different radical distances of the resulting amide. The addition of aromatic DCC analogues proceeds with excellent selectivity, giving amides where the carboxylic acid is exclusively connected to the aromatic residue, while little or no selectivity was observed for the aliphatic congeners. The usefulness of these adducts in structural studies was demonstrated by EPR (electron paramagnetic resonance) measurements of biradical adducts of biphenyl-4,4'-dicarboxylic acids. These analyses also reveal high degrees of conformational bias for aromatic DCC derivatives, which further underlines the powerfulness of these novel reagents. This observation was further corroborated by quantum chemical calculations, giving a detailed understanding of the structural dynamics, while detailed information on the solid state structure of all novel reagents was obtained by X-ray structure analyses.

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“…Once the glyco-silicas were synthesized, their ability to bind ConA was evaluated as an adequate methodology to characterize and determine their potential applicability as a chromatographic support. It has been previously proven that affinity chromatography is a valuable tool for the analysis of insoluble systems [37] since hemagglutination inhibition studies (HIA) and enzyme-linked lectin assays (ELLA) (that are the usual techniques for the analysis of carbohydrate-protein interactions) are restricted to assays in solution. The characterization was carried out by packing the glyco-silica in a column followed by saturating this column with a ConA solution in HEPES buffer and then washing with HEPES buffer to remove the unbonded protein.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Glyco‐Silicas by Cu(I)‐Catalyzed “Click‐Chemistry” and their Applications in Affinity Chromatography

et al. 2006

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The covalent immobilization of suitable alkyne/azide carbohydrate derivatives on complementarily functionalizated azide/alkyne silica was performed by click ligation througth the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of such compounds. The new glyco-silicas have shown to be efficient and valuable bio-selective affinity chromatographic supports for the purification of lectins as well as for the one-pot fluorescent labeling of those proteins. The synthetic methodology is simple, high yielding and flexible, allowing the preparation of tailored glyco-silicas with potential future applications in the inmobilization of other biomolecules.

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EPR and affinity studies of mannose–TEMPO functionalized PAMAM dendrimers

Cited by 19 publications

References 34 publications

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis

Design, Synthesis, EPR‐Studies and Conformational Bias of Novel Spin‐Labeled DCC‐Analogues for the Highly Regioselective Labeling of Aliphatic and Aromatic Carboxylic Acids

Synthesis of Glyco‐Silicas by Cu(I)‐Catalyzed “Click‐Chemistry” and their Applications in Affinity Chromatography

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