靶向 uMUC1 的磁共振成像在结直肠癌异体移植瘤模型中的疗效评估
uMUC1-Targeting Magnetic Resonance Imaging of Therapeutic Response in an Orthotropic Mouse Model of Colon Cancer.
机构信息
Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, 775 Woodlot Dr., Rm. 3.111, East Lansing, MI, 48823, USA.
Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
出版信息
Mol Imaging Biol. 2019 Oct;21(5):852-860. doi: 10.1007/s11307-019-01326-5.
PURPOSE
Noninvasive assessment of chemotherapeutic response in colon cancer would tremendously aid in therapeutic intervention of cancer patients and improve outcomes. The aim of the study was to evaluate the feasibility of a noninvasive assessment of chemotherapeutic response by magnetic resonance imaging utilizing underglycosylated mucin 1 (uMUC1) tumor antigen as a biomarker of therapeutic response in a colon cancer mouse model.
PROCEDURES
The study was performed by applying molecular imaging approach based on targeting uMUC1 with specific dual-modality imaging probe (MN-EPPT). The probe consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT) and was used for magnetic resonance imaging (MRI) and fluorescence optical imaging. An orthotopic murine model of colon cancer expressing human uMUC1 peptide (MC38 MUC1) was created along with the control model devoid of the antigen (MC38 neo). Animals received chemotherapy with 5-fluorouracil (5-FU) followed by MN-EPPT-enhanced MR and optical imaging.
RESULTS
In vivo imaging of animals with uMUC1 expressing tumors after 5-FU therapy showed that the average deltaT2 was reduced by 7.27 ms (p = 0.045) compared with animals in control groups indicating lower accumulation of MN-EPPT caused by uMUC1 downregulation. In vivo optical imaging, biodistribution, and fluorescence microscopy confirmed the MRI findings. Interestingly, we found that the group of animals that did not respond to chemotherapy ("progressive disease" per RECIST) showed higher accumulation of MN-EPPT compared to the group of responders ("stable disease") consistent with proliferating tumor cells and increased antigen availability.
CONCLUSIONS
We believe that in application to over 50 % of human cancers expressing uMUC1, our results could provide insight into overall assessment of therapeutic response based on its expression as defined by non-invasive MN-EPPT-enhanced MRI.
目的
非侵入性评估结肠癌的化疗反应将极大地帮助癌症患者的治疗干预，并改善治疗效果。本研究旨在评估利用低聚糖黏蛋白 1（uMUC1）肿瘤抗原作为治疗反应生物标志物，通过磁共振成像（MRI）对结肠癌小鼠模型进行非侵入性化疗反应评估的可行性。
方法
本研究通过应用基于靶向 uMUC1 的分子成像方法，使用特异性双模态成像探针（MN-EPPT）进行。该探针由葡聚糖包裹的氧化铁纳米粒子与近红外荧光染料 Cy5.5 和 uMUC1 特异性肽（EPPT）偶联而成，用于 MRI 和荧光光学成像。建立了表达人 uMUC1 肽（MC38 MUC1）的结肠癌原位模型，以及缺乏抗原的对照模型（MC38 neo）。动物接受氟尿嘧啶（5-FU）化疗，随后进行 MN-EPPT 增强 MRI 和光学成像。
结果
5-FU 治疗后表达 uMUC1 的肿瘤动物的体内成像显示，与对照组相比，平均 deltaT2 降低了 7.27ms（p=0.045），表明 uMUC1 下调导致 MN-EPPT 积累减少。体内光学成像、生物分布和荧光显微镜证实了 MRI 结果。有趣的是，我们发现对化疗无反应的动物组（根据 RECIST 为“进展性疾病”）与对化疗有反应的动物组（“稳定疾病”）相比，MN-EPPT 的积累更高，这与增殖的肿瘤细胞和增加的抗原可用性一致。
结论
我们认为，对于超过 50%表达 uMUC1 的人类癌症，我们的结果可以提供基于其表达的非侵入性 MN-EPPT 增强 MRI 进行整体治疗反应评估的见解。
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