Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques.
Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques.
复制标题
DOI：
10.1161/circresaha.111.300576
复制
发表时间：
2013-03-01
影响因子：
20.1
通讯作者：
Nahrendorf M
中科院分区：
文献类型：
--
作者：
Majmudar MD;Yoo J;Keliher EJ;Truelove JJ;Iwamoto Y;Sena B;Dutta P;Borodovsky A;Fitzgerald K;Di Carli MF;Libby P;Anderson DG;Swirski FK;Weissleder R;Nahrendorf M
动脉粥样硬化斑块中的骨髓细胞含量与破裂和血栓形成有关。因此，病变单核细胞和巨噬细胞（Mo/M β）的成像可以作为疾病进展和治疗干预的生物标志物。采用葡聚糖纳米颗粒促进的混合PET/MR成像无创评估斑块炎症。使用临床批准的构建模块，我们系统地开发了由交联短链葡聚糖组成的13 nm聚合物纳米颗粒，其用去铁胺修饰用于锆-89放射性标记（89 Zr-DNP）和近红外荧光染料（VT 680）用于显微镜和细胞验证。从切除的主动脉中分离的细胞的流式细胞术显示，Mo/M（76.7%）主要吸收DNP，而来自其他白细胞（例如中性粒细胞和淋巴细胞）的信号较低（11.8%和0.7%，p<0.05，相对于Mo/M）。免疫组化显示DNP与髓系细胞标志物CD 11b共定位。PET/MRI显示ApoE−/−小鼠的主动脉根中89 Zr-DNP的高摄取（标准摄取值，ApoE−/−小鼠与野生型对照，1.9±0.28 vs 1.3±0.03，p<0.05），通过离体闪烁计数和放射自显影证实。用siRNA治疗性沉默单核细胞募集受体CCR 2降低了89 Zr-DNP斑块信号（p<0.05）和炎性基因表达（p<0.05）。使用13 nm DNP的混合PET/MR成像能够无创评估实验性动脉粥样硬化斑块中的炎症，并报告抗炎治疗的疗效。
Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocyte and macrophages (Mo/Mϕ) could serve as a biomarker of disease progression and therapeutic intervention. To noninvasively assess plaque inflammation with dextran nanoparticle-facilitated hybrid PET/MR imaging. Using clinically approved building blocks, we systematically developed 13nm polymeric nanoparticles consisting of crosslinked short chain dextrans which were modified with desferoxamine for zirconium-89 radiolabeling (89Zr-DNP) and a near infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in Mo/Mϕ (76.7%) and lower signal originating from other leukocytes such as neutrophils and lymphocytes (11.8% and 0.7%, p<0.05 versus Mo/Mϕ). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of 89Zr-DNP in the aortic root of ApoE−/− mice (standard uptake value, ApoE−/− mice versus wild type controls, 1.9±0.28 versus 1.3±0.03, p<0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor CCR2 with siRNA decreased 89Zr-DNP plaque signal (p<0.05) and inflammatory gene expression (p<0.05). Hybrid PET/MR imaging with a 13nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.