High sensitivity: high-resolution SPECT-CT/MR molecular imaging of angiogenesis in the Vx2 model.
High sensitivity: high-resolution SPECT-CT/MR molecular imaging of angiogenesis in the Vx2 model.
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DOI：
10.1097/rli.0b013e31818935eb
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发表时间：
2009-01
影响因子：
6.7
通讯作者：
Lanza GM
中科院分区：
文献类型：
--
作者：
Lijowski M;Caruthers S;Hu G;Zhang H;Scott MJ;Williams T;Erpelding T;Schmieder AH;Kiefer G;Gulyas G;Athey PS;Gaffney PJ;Wickline SA;Lanza GM
抗血管生成治疗与传统化疗联合使用在癌症管理中越来越多，但这些靶向药物的最佳获益仅限于治疗人群的一部分。改进的成像探针，允许灵敏的检测和高分辨率表征肿瘤血管生成，可以改善患者的风险-受益分层。这些实验的首要目标是开发一种双重模式的αvβ3靶向纳米颗粒分子成像剂，其提供灵敏的核检测以及肿瘤血管生成的高分辨率MR表征。在第1部分中，荷瘤14 d的新西兰白色兔（n = 21）接受11、22或44 MBq/kg剂量的αvβ3靶向99 mTc纳米颗粒、22 MBq/kg剂量的非靶向99 mTc纳米颗粒或与未标记αv β3纳米颗粒竞争性抑制的αvβ3靶向99 mTc纳米颗粒（22 MBq/kg）。所有动物在2小时内用平面照相机使用针孔准直器动态成像。在第2部分中，使用临床SPECT-CT成像技术证明了αvβ3靶向99 mTc纳米颗粒在家兔模型中的有效性。接下来，通过将亲脂性钆螯合物纳入外磷脂层，将MR功能纳入αvβ3靶向99 mTc纳米颗粒中，并使用连续SPECT-CT和MR分子成像与3D新生血管标测显示肿瘤血管生成的高灵敏度-高分辨率检测和表征概念。αvβ3靶向99 mTc纳米粒子在22 MBq/kg剂量下产生最高的肿瘤-肌肉对比度（8.56 ± 0.13，TMR），而11 MBq/kg剂量（7.32 ± 0.12）和44 MBq/kg剂量（6.55 ± 0.07），（P < 0.05）。22.2MBq/kg非靶向颗粒的TMR（5.48 ± 0.09）低于等效剂量的αvβ3靶向99 mTc纳米颗粒（P < 0.05）。竞争性抑制22.2 MBq/kg的99 mTc αvβ3-整合素靶向纳米颗粒使TMR（5.31 ± 0.06）降低（P < 0.05）至非靶向对照对比剂水平。多层螺旋CT成像无法区分植入腘窝的肿瘤与同一窝或对侧腿部的淋巴结。然而，99 mTc αvβ3-纳米颗粒与SPECT-CT联合使用产生了来自肿瘤的清晰的新生血管信号，而非植入后腿中不存在该信号。使用αvβ3靶向99 mTc-钆纳米颗粒，将对T272肿瘤的灵敏检测扩展到允许对小肿瘤中的血管生成进行MR分子成像和3D绘图，揭示了沿癌症周边沿着不对称分布的片状新血管。αvβ3靶向99 mTc-钆纳米粒子的双模态分子成像可以提供肿瘤血管生成的高度敏感和特异性定位，可以通过高分辨率MR新生血管标测进一步表征，这可以预测抗血管生成治疗的反应性。
The use of antiangiogenic therapy in conjunction with traditional chemotherapy is becoming increasingly in cancer management, but the optimal benefit of these targeted pharmaceuticals has been limited to a subset of the population treated. Improved imaging probes that permit sensitive detection and high-resolution characterization of tumor angiogenesis could improve patient risk-benefit stratification. The overarching objective of these experiments was to develop a dual modality αvβ3-targeted nanoparticle molecular imaging agent that affords sensitive nuclear detection in conjunction with high-resolution MR characterization of tumor angiogenesis. In part 1, New Zealand white rabbits (n = 21) bearing 14d Vx2 tumor received either αvβ3-targeted 99mTc nanoparticles at doses of 11, 22, or 44 MBq/kg, nontargeted 99mTc nanoparticles at 22 MBq/kg, or αvβ3-targeted 99mTc nanoparticles (22 MBq/kg) competitively inhibited with unlabeled αvβ3-nanoparticles. All animals were imaged dynamically over 2 hours with a planar camera using a pinhole collimator. In part 2, the effectiveness of αvβ3-targeted 99mTc nanoparticles in the Vx2 rabbit model was demonstrated using clinical SPECT-CT imaging techniques. Next, MR functionality was incorporated into αvβ3-targeted 99mTc nanoparticles by inclusion of lipophilic gadolinium chelates into the outer phospholipid layer, and the concept of high sensitivity – high-resolution detection and characterization of tumor angiogenesis was shown using sequential SPECT-CT and MR molecular imaging with 3D neovascular mapping. αvβ3-Targeted 99mTc nanoparticles at 22 MBq/kg produced the highest tumor-to-muscle contrast ratio (8.56 ± 0.13, TMR) versus the 11MBq/kg (7.32 ± 0.12) and 44 MBq/kg (6.55 ± 0.07) doses, (P < 0.05). TMR of nontargeted particles at 22.2 MBq/kg (5.48 ± 0.09) was less (P < 0.05) than the equivalent dosage of αvβ3-targeted 99mTc nanoparticles. Competitively inhibition of 99mTc αvβ3-integrin-targeted nanoparticles at 22.2 MBq/kg reduced (P < 0.05) TMR (5.31 ± 0.06) to the nontargeted control contrast level. Multislice CT imaging could not distinguish the presence of Vx2 tumor implanted in the popliteal fossa from lymph nodes in the same fossa or in the contralateral leg. However, the use of 99mTc αvβ3-nanoparticles with SPECT-CT produced a clear neovasculature signal from the tumor that was absent in the nonimplanted hind leg. Using αvβ3-targeted 99mTc-gadolinium nanoparticles, the sensitive detection of the Vx2 tumor was extended to allow MR molecular imaging and 3D mapping of angiogenesis in the small tumor, revealing an asymmetrically distributed, patchy neovasculature along the periphery of the cancer. Dual modality molecular imaging with αvβ3-targeted 99mTc-gadolinium nanoparticles can afford highly sensitive and specific localization of tumor angiogenesis, which can be further characterized with high-resolution MR neovascular mapping, which may predict responsiveness to antiangiogenic therapy.