Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, USA.
Nucl Med Biol. 2021 Jan;92:107-114. doi: 10.1016/j.nucmedbio.2020.02.013. Epub 2020 Mar 5.
Blood-brain barrier (BBB) disruption and subsequent neuro-inflammation occur following traumatic brain injury (TBI), resulting in a spectrum of human nervous system disorders. [Tc]Tc-tilmanocept is a receptor-binding radiopharmaceutical FDA-approved for sentinel lymph node mapping. We hypothesize that after an intravenous (i.v.) injection, [Tc]Tc-tilmanocept, will traverse a disrupted BBB and bind to CD206-bearing microglial cells.
Age-matched mice were divided into three groups: 5-days post TBI (n = 4), and 5-days post sham (n = 4), and naïve controls (n = 4). IRDye800CW-labeled [Tc]Tc-tilmanocept (0.15 nmol per gram body weight) and FITC-labeled bovine serum albumin (FITC-BSA) were injected (i.v.) into each mouse. Mice were imaged with a high-resolution gamma camera for 45 min. Immediately after imaging, the brains were perfused with fixative, excised, imaged with a fluorescence scanner, assayed for radioactivity, and prepared for histology.
In vivo nuclear imaging, ex vivo fluorescence imaging, ex vivo gamma well counting, and histo-microscopy demonstrated enhanced tilmanocept uptake in the TBI region. The normalized [Tc]Tc-tilmanocept uptake value from nuclear imaging and the maximum pixel intensity from fluorescence imaging of the TBI group (1.12 ± 0.12 and 2288 ± 278 a.u., respectively) were significantly (P < 0.04) higher than the sham group (0.64 ± 0.28 and 1708 ± 101 a.u., respectively) and the naive group (0.76 ± 0.24 and 1643 ± 391 a.u., respectively). The mean [Tc]Tc-tilmanocept scaled uptake in the TBI brains (0.058 ± 0.013%/g) was significantly (P < 0.010) higher than the scaled brain uptake of the sham group (0.031 ± 0.011%/g) and higher (P = 0.04) than the uptake of the naïve group (0.020 ± 0.002%/g). Fluorescence microscopy demonstrated increased uptake of the IRDye800CW-tilmanocept and FITC-BSA in the TBI brain regions.
[Tc]Tc-tilmanocept traverses disrupted blood-brain barrier and localizes within the injured region. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [Tc]Tc-tilmanocept could serve as an imaging biomarker for TBI-associated neuroinflammation and any disease process that involves a disruption of the blood-brain barrier.
颅脑创伤（TBI）后会发生血脑屏障（BBB）破坏和随后的神经炎症，导致一系列人类神经系统疾病。[Tc]Tc- tilmanocept 是一种受体结合放射性药物，已获得美国食品和药物管理局批准用于前哨淋巴结绘图。我们假设，静脉注射（i.v.）后，[Tc]Tc- tilmanocept 将穿过受损的 BBB 并与 CD206 阳性的小胶质细胞结合。
将年龄匹配的小鼠分为三组：TBI 后 5 天（n=4），假手术（n=4）和正常对照组（n=4）。IRDye800CW 标记的[Tc]Tc- tilmanocept（每克体重 0.15nmol）和 FITC 标记的牛血清白蛋白（FITC-BSA）被静脉注射（i.v.）到每只小鼠体内。用高分辨率伽马相机对小鼠进行 45 分钟的成像。成像后立即用固定剂灌注大脑，取出，用荧光扫描仪成像，用伽马计数器进行放射性测定，并进行组织学处理。
体内核成像、体外荧光成像、体外伽马井计数和组织显微镜显示，TBI 区域的 tilmanocept 摄取增加。TBI 组核成像的[Tc]Tc- tilmanocept 摄取归一化值（1.12±0.12）和荧光成像的最大像素强度（2288±278 a.u.）显著（P<0.04）高于假手术组（0.64±0.28 和 1708±101 a.u.）和正常对照组（0.76±0.24 和 1643±391 a.u.）。TBI 脑内[Tc]Tc- tilmanocept 的平均摄取比例（0.058±0.013%/g）显著（P<0.010）高于假手术组（0.031±0.011%/g），也高于正常对照组（P=0.04，0.020±0.002%/g）。荧光显微镜显示 TBI 脑区 IRDye800CW-tilmanocept 和 FITC-BSA 的摄取增加。
[Tc]Tc- tilmanocept 穿过受损的血脑屏障并定位于损伤区域。知识的进展及其对患者护理的影响：[Tc]Tc- tilmanocept 可用作 TBI 相关神经炎症和任何涉及血脑屏障破坏的疾病过程的成像生物标志物。
