Molecular Contrast Agents Based on Gold Nanocages for OCT Imaging of Cancer

描述（由申请人提供）：本提案是一个多学科项目，涉及华盛顿大学生物工程系、化学系、病理学和医学系的研究人员。目的是开发和验证一类基于生物可偶联金纳米笼的新型分子纳米造影剂，以提高光学相干断层扫描（OCT）在早期癌症检测中的能力。癌症的发展需要几年的时间，在转移之前经历分子和结构的变化。早期癌症检测仍然是提高生存率和治疗效果的关键临床目标。OCT是最近发展起来的一种非侵入性技术，可以通过活体和实时组织显微解剖的横断面成像进行“光学活检”。OCT提供出色的空间分辨率；然而，目前它在早期癌症检测中的成功有限，主要原因是正常组织与早期癌症的内在光学对比较弱，缺乏分子特异性。本提案的假设是新型分子造影剂可以增强OCT成像对比度和分子特异性，用于早期癌症检测。与其他金属纳米颗粒不同，金纳米笼在近红外范围内表现出非常强的可调谐光学共振，同时保持小尺寸（35-65纳米）。金纳米笼可以为OCT成像提供强度和光谱对比度增强，并且可以方便地偶联分子识别剂进行靶向。具体目标是：(1)利用电替代纳米化学技术制备近红外强吸收或强散射的金纳米笼，并优化合成条件，实现规模化生产；(2)表征纳米笼的光学特性，将结果与基于离散偶极子近似的理论计算结果进行比较，并量化强度和光谱OCT对比度增强；(3)进行体内动物模型研究，定量评估OCT在生物偶联纳米笼辅助下早期癌症检测的能力；(4)应用分子造影剂探讨OCT对人食管切除术标本的异常增生和早期癌的检测能力。如果成功，分子对比OCT可以提高我们发现早期癌症的能力，指导活检和癌症手术。此外，分子造影剂还可用于其他光学成像和光谱学技术。

DESCRIPTION (provided by applicant): This proposal is a multidisciplinary program involving researchers from the Departments of Bioengineering, Chemistry, Pathology and Medicine at the University of Washington. The objective is to develop and validate a new class of molecular nano contrast agents based on biocojugatible gold nanocages for improving the ability of optical coherence tomography (OCT) in early cancer detection. Cancers develop over a period of several years and experience molecular and structural changes prior to metastasis. Early cancer detection remains a critical clinical objective to improve survival rates and treatment outcomes. OCT is a recently developed non-invasive technique that can perform "optical biopsy" by cross-sectional imaging of tissue microanatomy in vivo and in real time. OCT offers excellent spatial resolution; however, currently it has limited success in early cancer detection mainly because of the weak intrinsic optical contrast between normal tissue and early cancer and its lack of molecular specificity. The hypothesis of this proposal is that novel molecular contrast agents can enhance OCT imaging contrast and molecular specificity for early cancer detection. Unlike other metallic nanoparticles, gold nanocages exhibit very strong, tunable optical resonance in the near infrared range while remaining a small size (35-65 nm). Gold nanocages can provide both intensity and spectroscopic contrast enhancement for OCT imaging and they permit facile conjugation of molecular recognition agents for targeting. The specific aims are to: (1) develop gold nanocages with strong absorption or scattering in the near-infrared range using galvanic replacement nanochemistry and optimize synthesis conditions for scaling-up production; (2) characterize the optical properties of nanocages, compare the results with theoretical calculations based on discrete dipole approximation, and quantify intensity and spectroscopic OCT contrast enhancement; (3) perform in vivo animal model studies to quantitatively evaluate the ability of OCT for early cancer detection with assistance of bioconjugated nanocages; and (4) investigate the ability of OCT in detecting dysplasia and early cancer on human esophagectomy specimens using molecular contrast agents. If successful, molecular contrast enabled OCT can improve our ability to detect early cancers, guide biopsy and cancer surgery. In addition, the molecular contrast agents can also be used for other optical imaging and spectroscopy techniques.