Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel alpha(nu)beta3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging.
Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel alpha(nu)beta3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging.
复制标题
DOI：
--
复制
发表时间：
2003
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
中科院分区：
文献类型：
--
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
实体瘤及其支持的新血管系统的早期无创检测和表征是有效治疗干预的基本先决条件，特别是抗血管生成治疗方案。新兴的分子成像技术现在可以在出现总体病理变化之前识别早期的生化、生理和解剖学变化。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(nu)β(3)-整合素仍然是一个有吸引力的生化表位，它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，我们报告了首次体内使用磁共振（MR）分子成像纳米颗粒，以使用常见的临床场强（1.5T）灵敏地检测和空间表征兔Vx-2肿瘤植入引起的新生血管。新鲜 Vx-2 肿瘤 (2 x 2 x 2 mm(3)) 植入后 12 天，新西兰白兔 (2 kg) 被随机分为三个治疗组之一：(a) α(nu)beta(3) 靶向顺磁制剂； (b) 非靶向、顺磁性制剂； (c) α(nu)β(3) 靶向非顺磁性纳米粒子，然后是 (2 小时) α(nu)β(3) 靶向顺磁性制剂，以竞争性阻断磁共振成像 (MRI) 信号增强。静脉注射后全身注射（0.5ml纳米颗粒/kg），使用动态T(1)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。注射后 2 小时，α(nu)β(3) 靶向顺磁纳米颗粒使主要位于肿瘤周边的不对称分布区域的 MRI 信号增加了 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。尽管纳米粒子尺寸相对较大，但它们渗透到渗漏的肿瘤新血管系统中，但没有明显迁移到间质中，导致 2 小时时 MR 信号增加 56%。 α(nu)β(3)-整合素与非顺磁性纳米粒子的预靶向竞争性地阻断了α(nu)β(3)靶向顺磁性纳米粒子的特异性结合，将MR信号增强(50%)降低至可归因于局部外渗的水平。 α(nu)β(3)靶向剂或对照顺磁剂均未改变相邻后肢肌肉或对侧对照组织的MR信号。 α(nu)β(3)-整合素的免疫组织化学证实了 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具有使用临床1.5特斯拉MRI扫描仪检测和表征微小实体瘤诱导的早期血管生成（生化和形态学）的潜力，促进新生癌症或转移瘤的定位，并提供对治疗患者群体进行表型分类和分段的工具，并纵向跟踪抗肿瘤治疗方案的有效性。
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 alpha(nu)beta(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 x 2 x 2 mm(3)) were randomized into one of three treatment groups: (a) alpha(nu)beta(3)-targeted, paramagnetic formulation; (b) nontargeted, paramagnetic formulation; and (c) alpha(nu)beta(3)-targeted nonparamagnetic nanoparticles followed by (2 h) the alpha(nu)beta(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, alpha(nu)beta(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 alpha(nu)beta(3)-integrin with nonparamagnetic nanoparticles competitively blocked the specific binding of alpha(nu)beta(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 alpha(nu)beta(3)-targeted or control paramagnetic agents. Immunohistochemistry of alpha(nu)beta(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.