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利用自组装肽两亲胶束主动靶向早期和中期动脉粥样硬化斑块。

Active targeting of early and mid-stage atherosclerotic plaques using self-assembled peptide amphiphile micelles.

机构信息

Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720, USA; Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.

Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.

出版信息

Biomaterials. 2014 Oct;35(30):8678-86. doi: 10.1016/j.biomaterials.2014.06.054. Epub 2014 Jul 16.

Abstract

Inflammatory cell adhesion molecules expressed by endothelial cells on the luminal surface of atherosclerotic plaques, such as vascular cell adhesion molecule-1 (VCAM-1), provide a rational target for diagnostic and therapeutic delivery vehicles. Therefore, the potential of using spherical, self-assembled micelles synthesized from VCAM-1 targeted peptide amphiphile molecules was examined for the ability to specifically bind to both early and mid-stage atherosclerotic plaques. In vitro, cells incubated with VCAM-1 targeted and dye-labeled micelles show enhanced fluorescence signal as compared to cells incubated with a PEG micelle control. In vivo, VCAM-1 targeted and Cy7-labeled peptide amphiphile micelles were shown to specifically accumulate at atherosclerotic plaques in both early and mid-stage ApoE -/- mice through co-localization of Cy7 signal with anti-VCAM-1 antibody staining in fixed tissue. No specific accumulation was observed with a PEG micelle control. Histological analysis of excised tissue provided evidence for the in vivo biocompatibility of these micelle formulations as no tissue damage was observed. These results demonstrate that VCAM-1 targeted micelles have potential as a platform for targeted drug delivery to multiple stages of atherosclerotic plaque formation due to their established specificity and safety.

摘要

内皮细胞在动脉粥样硬化斑块的管腔表面表达的炎症细胞黏附分子,如血管细胞黏附分子-1(VCAM-1),为诊断和治疗药物输送载体提供了合理的靶向目标。因此,研究了由 VCAM-1 靶向肽两亲分子合成的球形自组装胶束在特异性结合早期和中期动脉粥样硬化斑块方面的潜力。在体外,与孵育有聚乙二醇(PEG)胶束对照的细胞相比,孵育有 VCAM-1 靶向和荧光染料标记胶束的细胞显示出增强的荧光信号。在体内,通过与固定组织中的抗 VCAM-1 抗体染色共定位,VCAM-1 靶向和 Cy7 标记的肽两亲胶束显示出在 ApoE-/- 小鼠的早期和中期动脉粥样硬化斑块中特异性积累,而 PEG 胶束对照则没有观察到特异性积累。切除组织的组织学分析为这些胶束制剂的体内生物相容性提供了证据,因为没有观察到组织损伤。这些结果表明,由于其既定的特异性和安全性,VCAM-1 靶向胶束有可能成为针对动脉粥样硬化斑块形成多个阶段的靶向药物递送的平台。

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