镓-68/钆无螯合剂共标记超小金纳米棒用于结直肠癌的PET-MRI诊断与图像介导的放疗增敏治疗

As one of cancers with the highest incidence and mortality, colorectal cancers have shown a significant increase of incidence rate in China recently. For colon cancer, exact local staging at the time of diagnosis is essential and is the basis for requirement of neoadjuvant treatment. Thus, imaging technique especially PET-MRI imaging with ultra-high sensitivity and soft tissues resolution is recognized as one of the best techniques for diagnosis of colorectal cancers. To improve the sensitivity of PET-MRI imaging furtherly, it is necessary to use PET-MRI contrast agent during imaging to meet clinical demand. In this project, we aim to construct a theranostic probe for the diagnosis and radiotherapy of colorectal cancers based on the characteristics of PET-MRI imaging. We first synthesized ultra-small gold nanorods (UGNRs) with a size of 5 nm, and chelator free co-labeled the radioisotope 68Ga and MRI contrast molecule Gd with the polydopamine coating on the surface of UGNRs. With the conjugation of acidic tumor microenvironment responded ligands, we hope the probe may able to specifically accumulate to tumor regions. With PET-MRI imaging, the lesion edge can be accurately distinguished, the tumor progression can be monitored, and the local radiotherapy sensitization treatment to tumor regions can be guided. In summary, this multi-modal theranostic probe could distinguish the lesion edge accurately and monitor tumor progression via PET-MRI imaging technique to improve treatment of colon cancer.

结直肠癌的发病率和死亡率高，近年来在我国呈现出发病率显著上升的趋势。结直肠癌在诊断过程中需要进行准确分期，也是后续综合性治疗的基础。因而，影像学手段特别是具有超高灵敏性和极高的软组织分辨率的PET-MRI成像，在这些方面有着独到的优势。为了进一步提高PET-MRI诊断灵敏度，研发能更好满足临床需求的PET-MRI造影剂就显得尤为必要。我们构建出了结直肠癌的诊疗一体化探针。首次合成了5 nm左右的超小金纳米棒，在其表面包裹多巴胺实现放射性核素镓-68及磁共振造影剂钆的无螯合剂共标记，并在表面接枝肿瘤微环境酸响应配体，以期望实现探针在肿瘤区域的特异性蓄积，实现病灶区域的精确界定与诊断，并监控肿瘤的发展状态，指导局部放疗增敏治疗。该探针有望利用PET-MRI成像技术，实现肿瘤区域的精准勾画和对肿瘤发展的监控，图像引导的治疗方案的优化，从而提高结直肠癌的治疗效果。

结直肠癌的发病率和死亡率高，近年来在我国呈现出发病率显著上升的趋势。对结直肠癌早期诊断并精准分期有助于提高后续综合性治疗的疗效。近年来，具有超高灵敏性和极高的软组织分辨率的PET-MRI成像在结直肠癌诊断方面有着独到的优势。为了进一步提高PET-MRI成像针对结直肠癌早期诊断的灵敏度和准确度，构建PET-MRI探针以满足临床需求就显得尤为必要。我们通过一步法合成超小金纳米棒，并构建出了可用于PET-MRI显像的肿瘤微环境酸响应的探针68Ga/Gd@UGNRs，经尾静脉注射，实现了探针在药物诱导的原位瘤和荷瘤鼠模型肿瘤区域特异性高剂量自聚集，以用于结直肠癌早期诊断和病灶区域勾画; 通过局部放疗增敏治疗，证实探针具备放疗增敏效果，显著抑制了结直肠癌的进展，并讨论了其抑制肿瘤进展的机理。具体结果如下：经PET/CT、MRI及光声成像，pH响应探针在肿瘤区域随着时间的推移逐渐增加，在注射后6小时达到高峰，而非pH响应的探针信号仅在注射后在肿瘤区域小幅升高（1.427 vs 1.135）。免疫组化染色结果证实探针特异性的蓄积在肿瘤间质中。采用6Gy的320kV X-射线进行局部放疗增敏治疗后，肿瘤曲线证明pH响应的探针组有显著的肿瘤生长抑制效果。流式细胞术和免疫荧光染色证实肿瘤治疗后，pH响应的探针组招募了更多的CD8+细胞毒性T淋巴细胞向肿瘤区域浸润，因而显示出更强的肿瘤抑制效果（7天： 21.11% vs 17.04% vs 11.66%；14天: 21.54% vs 7.55% vs 6.87%）。综上所述，我们基于PET/MR特性成功构建出pH响应的诊疗一体化探针68Ga/Gd@UGNRs，能够显著提高PET-MRI成像对结直肠癌诊断的灵敏度和准确度，并可以提高结直肠癌放疗增敏治疗效果，抑制肿瘤进展，达到了项目预期，有重大的科学意义和潜在应用价值。