生物发球成像：肿瘤发球，疾病传播和治疗效果的体系监测

监测原位实体瘤生长

过去20年里，凭借出色的有和的，勃利方法和工具的应临越，包括：蛋白质间相互作用，基因筛选，细胞细胞调节剂，寄生虫，干细胞植入，nk细胞迁移以及临床前前医学。大量研究说明，BLI成像可暂时评估肿瘤的发作。³当肿瘤生效法通话卡尺批量确定，并且依赖于体育减轻临床体征动物安乐死后负荷评估时，这一点尤。在下载中，有动物福利法在Aaalac认可的顾问中心行行，并经过iacuc协议协议和批准。

图2中的实例突出了非侵入性bli在监测监测组织肿瘤肿瘤发离方式的价值。将nci-h460-luc2人素肺癌异种移异种移物原位（ot）（OT）（1x10⁵细胞/小鼠）雌性裸鼠的左肺.bli（图2，左上）显示了最早在肿瘤细胞植入后8天就可以到胸腔肿瘤（在第28天可查看的最大信号阈值而在图片中不可见），而且肿瘤负荷在接接来的2周内增加。在整个整个程中，小屋的平面体系百分比为18.3％，可以能与有关（未未），并且小屋在肿瘤细胞细胞后28天安乐死。尸检揭示了原发行肿瘤的明显生活以及整个肿块实质性的实质性发布。在图2（左下）中，雌性雌性化病c57bl / 6小鼠颅内gl261-luc2同系鼠鼠神经胶质瘤（1x10⁶细胞/小鼠）。植入后7天，大众中可检测肿瘤。与疾病进展相关的体育在该模型中很常见，并且在植入肿瘤11天就可以检测到，而死亡中间时间约为21天。在雌性裸鼠中行行心内注射后，人均乳腺腺癌细胞系mda-mb-231-luc-d3h2ln形（1x10⁵细胞/小鼠）。在注射肿瘤细胞21天后，骨病变清晰可见，并且在接下来的3周内，肿瘤数量和肿瘤总负荷都有所增加（图2，右侧，顶部和底部）。到第32天，小鼠体重最多减轻16.2%。 体重减轻很大程度上与模型的侵袭性有关（未显示）。 The takeaway message from these studies is that BLI can be a powerful tool for investigating a variety of tumor types in real-time and non-invasively without relying solely on clinical signs of disease which may, or may not, accompany increasing tumor burden.

Imaging Hematologic Malignancies

经80多种独特的血液恶性肿瘤细胞系，景气引领了与市场相关的血液学恶性模型的行业，特别是在采用细胞疗法（ACT）中有关的相关性，也称为细胞免疫疗法，田间。⁴BLI is critically valuable when evaluating progression and treatment response in hematological disseminated malignancies. Longitudinal studies performed in 4 different human hematological cancer cells injected IV into NSG mice showed increased tumor burden over time in all models (Figure 3) underscoring BLI’s value in repeated assessment of disease progression and severity, as well as understanding the biodistribution of tumor signal throughout the body.

行为是不断发展的，为患者提供更好，更个性化的选择。Car-T细胞是自体或同种异体T细胞，特别是靶向肿瘤细胞表达的抗原或标记物。yaboapp体育官网临床体内在将这些新疗法转化为诊所之前，对Car-T细胞的功效和安全性评估至关重要。图4中所示的研究旨在测试在NSG小鼠中植入IV的人Raji-Lucb细胞淋巴瘤细胞中不同的Car-T制剂和剂量。3种不同的Car-T构建体显着抑制肿瘤负荷和延长的存活，突出了该价值BLI为这些新细胞免疫治疗的发展。

Monitoring Treatment Efficacy

放射

Clearly, one of the key advantages of BLI is the ability to track the efficacy of anti-tumor therapies over time in the same animal, leading to a reduction in the number of animal used. In the example shown in Figure 5, female nude mice were implanted intracranially with NCI-H1975-luc human non-small cell lung carcinoma in order to mimic lung metastasis to the brain. Mice received two courses of fractionated radiation (2Gy; 5 days on, two days off for two cycles), delivered by a RadSource RS-2000 irradiator. The control group was sham irradiated. BLI images were acquired over time and demonstrated that radiation significantly reduced tumor burden (Figure 5, p<0.05 on day 19) and increased life span by 160% (p<0.05, not shown). In this experiment, we were able to quantify treatment response体内, critical when monitoring efficacy as well as designing and refining new therapeutic approaches.

Checkpoint Inhibition and Combination Therapy

检查点抑制，单独或与辐射组合的影响在植入甲虫中植入雌性白化C57BL / 6小鼠中的鼠同胞增量GL261-LUC2胶质瘤细胞。用小动物放射研究平台（SARRP; Xstrahl Inc.）递送的辐射治疗小鼠，以单一的7.5Gy剂量，抗小鼠PD-1（克隆RMP1-14,10mg / kg）或两种疗法的组合。如图6（左）所示，BLI信号已经检测到肿瘤后细胞植入后6天，并在未来几周内进行。所得生物发光信号（右）的定量显示治疗对肿瘤负担的影响。抗MPD-1治疗导致2.6天肿瘤生长延迟和1/8肿瘤游离幸存者（TFS），而辐射导致16.6天肿瘤生长延迟和2/8 TFS。辐射和抗MPD-1治疗的组合导致显着的38.6天肿瘤生长延迟和7/8小鼠完全缓解。在体内深入的恶性肿瘤中测量抗肿瘤反应的传统方法基于终端，经常，耗时的读出。如在这些例子中所示，整合体内BLI imaging has allowed us to shift from a “black box” of tumor therapy to real-time assessment of individual responses, providing the flexibility to adjust and refine treatments more rapidly.

Multimodality

BLI可以与其他成像方式耦合以询问不同的生物途径。为了说明这个应用程序，我们使用了Syngeneic 4T1-Luc2-1A4mouse breast adenocarcinoma cells injected OT into the mammary fat pad of immunologically competent BALB/c mice. When tumors reached ~300 mm³, a near-infrared imaging agent, ProSense^TM值750注射IV以检测与侵袭性乳腺癌生长相关的组织蛋白酶活性。pros^TM值750 is an optically silent agent which becomes fluorescent upon cleavage with cathepsins. As shown in Figure 7, BLI and FLI tumor signals were readily detectable in tumors. However, BLI and FLI signals were not perfectly superimposable which is expected given that luciferase is produced by all living tumor cells while the fluorescent signal is confined not only to tumor cells but also other tumor-associated cells, mainly macrophages, responsible for the cleavage and uptake of the cathepsin ProSense^TM值750探头。因此，可以使用多模来询问不同的生物学体内， 同时。

总结

Mouse models of deep-tissue cancer and cancer metastasis rely predominantly on terminal assessments like tissue weight, nodule counts, and/or histologic analysis for the assessment of tumor burden. Since its introduction well over 20 years ago, BLI has become an invaluable technique to track the growth dynamics of bioluminescently-tagged cancer cell lines over time and in response to various therapeutic approaches体内，最小化研究中的动物数量，因为可以随时间成像，而无需终端评估。除了提供替代建立的侵入性或放射性同位素依赖性非侵入性成像模式的替代方案之外，BLI还为各种科学领域产生了重大贡献。

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¹Contag CH, Spilman SD, Contag PR, Oshiro M, Eames B, Dennery P, Stevenson DK, Benaron DA. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol 1997; 66: 523–531.

²De Wet Jr，Wood KV，Helinski Dr，Deluca M.杀萤火虫荧光素酶cDNA的克隆以及活性荧光素酶的表达Escherichia coli。Proc。Natl。阿卡。SCI。U.S.A. 1985;82,7870-7873。

³Jenkins de，Oei Y，Hornig Ys，Yu Sf，Dusich J，Purnio T，Contag Pr。生物发球成像（BLI）可以改善和完善的鼠类生态和转移传统的“Clin Exp MetaStasis”，2003; 20（8）：733-744。

⁴https://www.cancerresearch.org/immunotherapy/troatment-types/adoptive-cell-therapy.

临床临床学位学

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