Molecular Imaging of Angiogenesis in Nascent Vx-2 Rabbit Tumors Using a Novel ανβ3-targeted Nanoparticle and 1.5 Tesla Magnetic Resonance Imaging
Molecular Imaging of Angiogenesis in Nascent Vx-2 Rabbit Tumors Using a Novel ανβ3-targeted Nanoparticle and 1.5 Tesla Magnetic Resonance Imaging
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发表时间：
2003-09
期刊：
影响因子：
11.2
通讯作者：
P. Winter;S. Caruthers;A. Kassner;T. Harris;L. Chinen;J. Allen;E. K. Lacy;Huiying Zhang;J. D. Robertson;S. Wickline;G. Lanza
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作者：
P. Winter;S. Caruthers;A. Kassner;T. Harris;L. Chinen;J. Allen;E. K. Lacy;Huiying Zhang;J. D. Robertson;S. Wickline;G. Lanza
实体瘤及其支持性新生血管的早期非侵入性检测和表征是有效治疗干预，特别是抗血管生成治疗方案的基本先决条件。新兴的分子成像技术，现在允许识别早期的生化，生理和解剖结构的变化之前，表现出严重的病理变化。尽管新的肿瘤、血管、细胞外基质和淋巴生物标志物不断被发现，但α ν β 3 -整联蛋白仍然是一种有吸引力的生物化学表位，其在活化的新生血管内皮细胞上高度表达，而在成熟的静止细胞上基本上不存在。在这项研究中，我们报告了第一次在体内使用的磁共振（MR）分子成像纳米粒子，灵敏地检测和空间特征的新生血管诱导的兔Vx-2肿瘤植入使用一个共同的临床场强（1.5T）。新西兰白色兔（2 kg）新鲜Vx-2肿瘤植入后12天（2 × 2 × 2 mm 3）随机分为三个治疗组之一：（a）α ν β 3靶向顺磁性制剂;（B）非靶向顺磁性制剂;和（c）α ν β 3靶向的非顺磁性纳米颗粒，随后（2 h）α ν β 3靶向的顺磁性制剂，以竞争性地阻断磁共振成像（MRI）信号增强。静脉内全身注射（0.5ml纳米颗粒/kg）后，使用动态T1加权MRI在空间和时间上确定肿瘤和邻近组织（包括骨骼肌）中的纳米颗粒沉积。在注射后2小时，α ν β 3靶向的顺磁性纳米颗粒使主要在肿瘤周边的不对称分布区域中的MRI信号增加126%。在靠近肿瘤的一些血管壁内也观察到MR对比度的类似增加。尽管它们的尺寸相对较大，但纳米颗粒渗透到渗漏的肿瘤新生血管中，但没有明显迁移到肿瘤中，导致2小时时MR信号增加56%。用非顺磁性纳米颗粒预靶向α ν β 3 -整联蛋白竞争性地阻断了α ν β 3 -靶向的顺磁性纳米颗粒的特异性结合，将MR信号增强（50%）降低至可归因于局部外渗的水平。相邻后肢肌肉或对侧对照组织的MR信号未被α ν β 3靶向或对照顺磁性剂改变。α ν β 3 -整联蛋白的免疫组织化学证实了通过MRI观察到的新生血管的程度和不对称分布。这些研究证明了这种靶向分子成像剂检测和表征（生物化学和形态学）通过临床1.5特斯拉MRI扫描仪由微小实体肿瘤诱导的早期血管生成，促进新生癌症或转移灶的定位，以及提供用于对患者群体进行表型分类和分段以进行治疗以及纵向跟踪抗肿瘤治疗的有效性的工具养生法
Early noninvasive detection and characterization of solid tumors and their supporting neovasculature is a fundamental prerequisite for effective therapeutic intervention, particularly antiangiogenic treatment regimens. Emerging molecular imaging techniques now allow recognition of early biochemical, physiological, and anatomical changes before manifestation of gross pathological changes. Although new tumor, vascular, extracellular matrix, and lymphatic biomarkers continue to be discovered, the α ν β 3 -integrin remains an attractive biochemical epitope that is highly expressed on activated neovascular endothelial cells and essentially absent on mature quiescent cells. In this study, we report the first in vivo use of a magnetic resonance (MR) molecular imaging nanoparticle to sensitively detect and spatially characterize neovascularity induced by implantation of the rabbit Vx-2 tumor using a common clinical field strength (1.5T). New Zealand White rabbits (2 kg) 12 days after implantation of fresh Vx-2 tumors (2 × 2 × 2 mm 3 ) were randomized into one of three treatment groups: ( a ) α ν β 3 -targeted, paramagnetic formulation; ( b ) nontargeted, paramagnetic formulation; and ( c ) α ν β 3 -targeted nonparamagnetic nanoparticles followed by (2 h) the α ν β 3 -targeted, paramagnetic formulation to competitively block magnetic resonance imaging (MRI) signal enhancement. After i.v. systemic injection (0.5 ml of nanoparticles/kg), dynamic T 1 -weighted MRI was used to spatially and temporally determine nanoparticle deposition in the tumor and adjacent tissues, including skeletal muscle. At 2-h postinjection, α ν β 3 -targeted paramagnetic nanoparticles increased MRI signal by 126% in asymmetrically distributed regions primarily in the periphery of the tumor. Similar increases in MR contrast were also observed within the walls of some vessels proximate to the tumor. Despite their relatively large size, nanoparticles penetrated into the leaky tumor neovasculature but did not appreciably migrate into the interstitium, leading to a 56% increase in MR signal at 2 h. Pretargeting of the α ν β 3 -integrin with nonparamagnetic nanoparticles competitively blocked the specific binding of α ν β 3 -targeted paramagnetic nanoparticles, decreasing the MR signal enhancement (50%) to a level attributable to local extravasation. The MR signal of adjacent hindlimb muscle or contralateral control tissues was unchanged by either the α ν β 3 -targeted or control paramagnetic agents. Immunohistochemistry of α ν β 3 -integrin corroborated the extent and asymmetric distribution of neovascularity observed by MRI. These studies demonstrate the potential of this targeted molecular imaging agent to detect and characterize (both biochemically and morphologically) early angiogenesis induced by minute solid tumors with a clinical 1.5 Tesla MRI scanner, facilitating the localization of nascent cancers or metastases, as well as providing tools to phenotypically categorize and segment patient populations for therapy and to longitudinally follow the effectiveness of antitumor treatment regimens.