Synthesis and Biological Evaluation of Radio and Dye Labeled Amino Functionalized Dendritic Polyglycerol Sulfates as Multivalent Anti-Inflammatory Compounds

被引：46

作者：

Groeger, Dominic ^{[1
]}

Paulus, Florian ^{[1
]}

Licha, Kai ^{[2
]}

Welker, Pia ^{[2
]}

Weinhart, Marie ^{[1
]}

Holzhausen, Cornelia ^{[3
]}

Mundhenk, Lars ^{[3
]}

Gruber, Achim D. ^{[3
]}

Abram, Ulrich ^{[1
]}

Haag, Rainer ^{[1
]}

机构：

[1] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

[2] Mivenion GmbH, D-10115 Berlin, Germany

[3] Free Univ Berlin, Dept Vet Pathol, D-14163 Berlin, Germany

来源：

BIOCONJUGATE CHEMISTRY | 2013年 / 24卷 / 09期

关键词：

HYPERBRANCHED POLYGLYCEROLS; L-SELECTIN; BIOCOMPATIBILITY; FLUORESCENCE; INFLAMMATION; INHIBITORS;

D O I：

10.1021/bc400047f

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Herein we describe a platform technology for the synthesis and characterization of partially aminated, S-35-labeled, dendritic polyglycerol sulfate (dPG(35)S amine) and fluorescent dPGS indocarbocyanine (ICC) dye conjugates. These polymer conjugates, based on a biocompatible dendritic polyglycerol scaffold, exhibit a high affinity to inflamed tissue in vivo and represent promising candidates for therapeutic and diagnostic applications. By utilizing a one-step sequential copolymerization approach, dendritic polyglycerol (M-n approximate to 4.5 kDa) containing 9.4% N-phthalimide protected amine functionalities was prepared on a large scale. Sulfation and simultaneous radio labeling with (SO3)-S-35 pyridine complex, followed by cleavage of the N-phthalimide protecting groups, yielded dPG(35)S amine as a beta emitting, inflammation specific probe with free amino functionalities for conjugation. Furthermore, efficient labeling procedures with ICC via iminothiolane modification and subsequent "Michael" addition of the maleimide functionalized ICC dye, as well as by amide formation via NHS derivatized ICC on a dPGS amine scaffold, are described. The dPGS-ICC conjugates were investigated with respect to their photophysical properties, and both the radiolabeled and fluorescent compounds were comparatively visualized in histological tissue sections (radio detection and fluorescence microscopy) of animals treated with dPGS. Furthermore, cellular uptake of dPGS-ICC was found in endothelial cord blood (HUVEC) and the epithelial lung cells (A549). The presented synthetic routes allow a reproducible, controlled synthesis of dPGS amine on kilogram scale applying a one-pot batch reaction process. dPGS amine can be used for analysis via radioactivity or fluorescence, thereby creating a new platform for inflammation specific, multimodal imaging purposes using other attachable probes or contrast agents.

引用

页码：1507 / 1514

页数：8

共 18 条

[11]

Nel AE, 2009, NAT MATER, V8, P543, DOI [10.1038/NMAT2442, 10.1038/nmat2442]

[12] Size-Dependant Cellular Uptake of Dendritic Polyglycerol [J].

Reichert, Stephanie ;

Welker, Pia ;

Calderon, Marcelo ;

Khandare, Jayant ;

Mangoldt, Dorothea ;

Licha, Kai ;

Kainthan, Rajesh K. ;

Brooks, Donald E. ;

Haag, Rainer .

SMALL, 2011, 7 (06) :820-829

[13] Hyperbranched Polyglycerols as Trimodal Imaging Agents: Design, Biocompatibility, and Tumor Uptake [J].

Saatchi, Katayoun ;

Soema, Peter ;

Gelder, Nikolaus ;

Misri, Ripen ;

McPhee, Kelly ;

Baker, Jennifer H. E. ;

Reinsberg, Stefan A. ;

Brooks, Donald E. ;

Haefeli, Urs O. .

BIOCONJUGATE CHEMISTRY, 2012, 23 (03) :372-381

[14] Controlled synthesis of hyperbranched polyglycerols by ring-opening multibranching polymerization [J].

Sunder, A ;

Hanselmann, R ;

Frey, H ;

Mülhaupt, R .

MACROMOLECULES, 1999, 32 (13) :4240-4246

[15] PREPARATION OF 35S-CHLOROSULPHONIC ACID FROM WASTE, BA35SO4 [J].

TUDBALL, N .

NATURE, 1962, 196 (4854) :580-&

[16] Dendritic polyglycerol sulfates as new heparin analogues and potent inhibitors of the complement system [J].

Türk, H ;

Haag, R ;

Alban, S .

BIOCONJUGATE CHEMISTRY, 2004, 15 (01) :162-167

[17] The Role of Dimension in Multivalent Binding Events: Structure-Activity Relationship of Dendritic Polyglycerol Sulfate Binding to L-Selectin in Correlation with Size and Surface Charge Density [J].

Weinhart, Marie ;

Groeger, Dominic ;

Enders, Sven ;

Riese, Sebastian B. ;

Dernedde, Jens ;

Kainthan, Rajesh K. ;

Brooks, Donald E. ;

Haag, Rainer .

MACROMOLECULAR BIOSCIENCE, 2011, 11 (08) :1088-1098

[18] Synthesis of Dendritic Polyglycerol Anions and Their Efficiency Toward L-Selectin Inhibition [J].

Weinhart, Marie ;

Groeger, Dominic ;

Enders, Sven ;

Dernedde, Jens ;

Haag, Rainer .

BIOMACROMOLECULES, 2011, 12 (07) :2502-2511

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