Simultaneous In Vivo Fluorescent Markers for Perfusion, Protoporphyrin Metabolism, and EGFR Expression for Optically Guided Identification of Orthotopic Glioma.
Simultaneous In Vivo Fluorescent Markers for Perfusion, Protoporphyrin Metabolism, and EGFR Expression for Optically Guided Identification of Orthotopic Glioma.
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DOI：
10.1158/1078-0432.ccr-16-1400
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发表时间：
2017-05-01
期刊：
影响因子：
--
通讯作者：
Pogue BW
中科院分区：
文献类型：
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作者：
Elliott JT;Marra K;Evans LT;Davis SC;Samkoe KS;Feldwisch J;Paulsen KD;Roberts DW;Pogue BW
虽然肿瘤切除范围是胶质瘤预后的重要预测因素，但由于肿瘤和正常实质之间缺乏内在对比，边缘勾画仍然具有挑战性。放射性引导的手术因其通过外源性荧光团增强对比度的能力而有希望，然而，潜在的对比机制和肿瘤递送和摄取的特异性和灵敏度在批准的和新兴的药剂中变化很大。具有原位F98野生型和F98 EGFR阳性胶质瘤的大鼠分别接受IRDye 680 RD、5-aminioleuvulinic acid和ABY-029-灌注、原卟啉代谢和EGFR表达的标记物的体内给药。离体成像证明了对比机制依赖的空间异质性，并能够在动物体内比较肿瘤与背景比（TBR）。通常，ABY-029在F98 EGFR原位肿瘤边缘和核心中优于PpIX（分别高50%和60%的TBR）。PpIX在F98 wt边缘中优于ABY-029 60%，但在大块肿瘤中提供等同的对比度。IRDye 680 RD提供的对比度很小，平均TBR为1.7 ± 0.2。每种药物的独特空间模式被组合成一个单一的度量-多机制荧光对比指数（MFCI）。ABY-029在EGFR+肿瘤中表现最好（91%准确率），而PpIX在野生型肿瘤中表现最好（87%准确率）。在所有组中，ABY-029和PpIX的表现相似（分别为80%和84%），但MFCI的准确率为91%，支持肿瘤基因型未知时的多药物成像。人类使用ABY-029进行神经胶质瘤切除应该增强EGFR+肿瘤的切除，并且可以并入当前的PpIX策略中以进一步增强一般神经胶质瘤病例中的治疗。比较在大鼠原位胶质瘤中使用灌注、原卟啉代谢和EGFR细胞表面表达标记物获得的对比度，证明在荧光引导手术中使用替代对比机制的额外成像剂的价值。
While extent of tumor resection is an important predictor of outcome in glioma, margin delineation remains challenging due to lack of inherent contrast between tumor and normal parenchyma. Fluorescence-guided surgery is promising for its ability to enhance contrast through exogenous fluorophores, however, the specificity and sensitivity of the underlying contrast mechanism and tumor delivery and uptake vary widely across approved and emerging agents. Rats with orthotopic F98 wild-type and F98 EGFR-positive gliomas received in vivo administration of IRDye680RD, 5-aminioleuvulinic acid, and ABY-029—markers of perfusion, protoporphyrin metabolism, and EGFR expression, respectively. Ex vivo imaging demonstrates the contrast mechanism-dependent spatial heterogeneity and enables within-animal comparisons of tumor-to-background ratio (TBR). Generally, ABY-029 outperformed PpIX in F98EGFR orthotopic tumor margins and core (50% and 60% higher TBR, respectively). PpIX outperformed ABY-029 in F98wt margins by 60% but provided equivalent contrast in the bulk tumor. IRDye680RD provided little contrast, having an average TBR of 1.7 ± 0.2. The unique spatial patterns of each agent were combined into a single metric—the multimechanistic fluorescence-contrast index (MFCI). ABY-029 performed best in EGFR+ tumors (91% accuracy), while PpIX performed best in wild-type tumors (87% accuracy). Across all groups, ABY-029 and PpIX performed similarly (80% and 84%, respectively) but MFCI was 91% accurate, supporting multi-agent imaging when tumor genotype is unknown. Human use of ABY-029 for glioma resection should enhance excision of EGFR+ tumors and could be incorporated into current PpIX strategies to further enhance treatment in the general glioma case. Comparison of contrast obtained using perfusion, protoporphyrin metabolism and EGFR cell-surface expression markers in rat orthotopic gliomas, demonstrating value of additional imaging agents using alternative contrast mechanisms in fluorescence guided surgery.