Synthesis, characterization, and biological evaluation of integrin αvβ3-targeted PAMAM dendrimers
Synthesis, characterization, and biological evaluation of integrin αvβ3-targeted PAMAM dendrimers
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DOI：
10.1021/mp800022a
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发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
Brechbiel, Martin W.
中科院分区：
文献类型：
--
作者：
Boswell, C. Andrew;Eck, Peter K.;Brechbiel, Martin W.
配体大小和配价强烈影响受体的摄取和肿瘤血管生成显像剂的清除。成功的显像剂的结构表现出高度的可变性，包括含有小的单价精氨酸-甘氨酸-天冬氨酸（RGD）肽、多价RGD低聚物和抗整合素α -v- β -3 (α (v) β(3))的单克隆抗体。我们已经追求了一种纳米尺度的血管生成成像方法，使用合理设计的共价修饰rgd -环肽的聚胺胺（PAMAM）树状大分子。采用正交肟-连接策略将PAMAM树状大分子与rgd -环肽进行化学选择性偶联，以靶向α (v) β(3)。用于光学成像的荧光染料和用于钆基磁共振（MR）成像的螯合剂随后被添加到创建健壮的多模态大分子显像剂中。荧光显微镜显示，携带RGD肽的树状大分子与空螯合物选择性结合到表达α (v) β(3)的细胞上，但在Gd（III）络合后，选择性有所降低。预期的Gd（III）离子螯合物不完全饱和允许放射性金属络合，M21黑色素瘤荷瘤小鼠体内组织分布主要显示肾和网状内皮积聚，肿瘤：血比在注射后2小时达到峰值（3.30 +/- 0.03）。
Ligand size and valency strongly influence the receptor uptake and clearance of tumor angiogenesis imaging agents. The structures of successful imaging agents exhibit a high degree of variability, encompassing small monovalent arginine-glycine-aspartic acid (RGD)-containing peptides, multivalent RGD-oligomers, and a monoclonal antibody against integrin alpha-v-beta-3 (alpha(v)beta(3)). We have pursued a nanoscale approach to imaging of angiogenesis using rationally designed polyamidoamine (PAMAM) dendrimers covalently adorned with RGD-cyclopeptides. An orthogonal oxime-ligation strategy was applied to chemoselectively effect conjugation of the PAMAM dendrimers with RGD-cyclopeptides for targeting alpha(v)beta(3). Fluorescent dyes for optical imaging and chelates for gadolinium-based magnetic resonance (MR) imaging were subsequently appended to create robust multimodal macromolecular imaging agents. Fluorescence microscopy revealed selective binding of the resulting RGD peptide-bearing dendrimer with empty chelates to alpha(v)beta(3)-expressing cells, but somewhat reduced selectivity was observed following Gd(III) complexation. The expected incomplete saturation of chelates with Gd(III) ions permitted radiometal complexation, and an in vivo tissue distribution of the resulting agent in M21 melanoma tumor-bearing mice showed mostly renal and reticuloendothelial accumulation, with the tumor:blood ratio peaking (3.30 +/- 0.03) at 2 h postinjection.