Quantitative Fluorescence Imaging-Guided Detection and Targeted Therapy Monitoring Platform for Ovarian Cancer Micrometastases

项目概要/摘要 晚期卵巢癌治疗的一个主要挑战是存在播散性卵巢癌。 腹腔内的显微镜下肿瘤结节。尽管手术和辅助化疗， 多达50%的患者可表现为隐匿性播散性疾病，仅有43%的存活率。此外，委员会认为， 全身化疗可能具有毒副作用。因此，最近的努力旨在改善检测 和微转移的治疗。化学光疗法（CPT），化学疗法和光动力学的组合 治疗是一种新兴的癌症治疗方式，可以提供两种治疗的协同功效。的 总体目标是实施一种定量腹腔镜成像和治疗方法， 检测微小转移瘤并优化CPT，以靶向破坏卵巢微小转移瘤， 毒副作用定量荧光腹腔镜成像将提供高灵敏度和分辨率， 检测微小转移瘤以及图像引导的药物递送。叶酸受体α（FA）将被用作 因为它对上皮性卵巢癌具有高度特异性，因此是一个很有前景的靶点。拟议的有针对性的CPT 化合物具有约6倍的肿瘤特异性，提供增强的荧光对比度。这些叶酸靶向的， 卟啉-磷脂掺杂的脂质体直接由近红外（NIR）光触发。这将激活 抗癌光敏剂外层并释放抗癌剂阿霉素（Dox）。虽然这 纳米载体有望改善微转移的检测，活组织中的组织吸收和散射可 混淆荧光对比度。基于空间频域成像的定量成像可以 消除这些混杂效应，并提供定量对比，以实现更灵敏的检测 与原始荧光或白色光可视化相比。此外，这种定量能力可以发挥作用， 以提供关于药物释放的反馈，从而允许图像引导的治疗优化 光，以确保每个肿瘤内的药物充分释放。在目标1中，宽视野双通道腹腔镜，快速 将实施和优化定量算法和靶向脂质体纳米构建体。在目标2中， 将在体内验证该平台相对于原始荧光和白色光的微转移的改进检测。 在目标3中，将在体内验证该平台的功效，以破坏靶向肿瘤中的微转移， 减少对周围正常组织的毒性。成功完成这一方法预计将导致 改善微小转移瘤的检测和治疗，减少副作用。预计这最终将导致 降低复发率和提高总体生存率。虽然这种成像方法主要集中在上皮细胞， 卵巢癌的诊断和治疗，它可以适用于广泛的上皮性疾病，如 口腔癌、肺癌和胃肠癌。

PROJECT SUMMARY/ABSTRACT A major challenge in the management of advanced ovarian cancer is the presence of disseminated microscopic tumor nodules within the intraperitoneal cavity. Despite surgery and adjuvant chemotherapy, as many as 50% of patients can show occult disseminated disease, with only a 43% survival rate. Furthermore, systemic chemotherapy can have toxic side effects. Thus, recent efforts have aimed at improving detection and treatment of micromets. Chemophototherapy (CPT), the combination of chemotherapy and photodynamic therapy, is an emerging cancer treatment modality that can provide synergistic efficacy of both therapies. The overall goal is to implement a quantitative laparoscopic imaging and treatment approach for advanced detection of micromets and optimization of CPT for targeted destruction of ovarian micromets and reduced toxic side effects. Quantitative fluorescence laparoscopic imaging will provide high sensitivity and resolution for detecting micromets as well as image guided drug delivery. Folate receptor alpha (FA) will be used as a promising target because it is highly specific of epithelial ovarian cancer. The proposed targeted CPT compound has a ~6-fold tumor-specificity providing enhanced fluorescence contrast. These folate-targeted, porphyrin-phospholipid doped liposomes are triggered directly by near infrared (NIR) light. This activates the anti-cancer photosensitizer outer layer and releases the anti-cancer agent Doxorubicin (Dox). While this nanocarrier is expected to improve detection of micromets, tissue absorption and scattering in living tissue can confound fluorescence contrast. Quantitative imaging based on spatial frequency domain imaging can eliminate these confounding effects and provide quantitative contrasts to enable more sensitive detection compared to raw fluorescence or white light visualization. Furthermore, this quantitative capability can function in near-real-time to provide feedback on drug release, thus allowing image-guided optimization of treatment light to ensure full drug release within each tumor. In Aim 1, a wide-field dual-channel laparoscope, fast quantification algorithms and targeted liposomal nano-construct will be implemented and optimized. In Aim 2, the platform will be validated in vivo for improved detection of micromets vs. raw fluorescence and white light. In Aim 3, the platform’s efficacy will be validated in vivo for destroying micromets in targeted tumors while reducing toxicity to surrounding normal tissues. Successful completion of this approach is expected to result in improved detection and treatment of micromets with reduced side effects. This is ultimately expected to lead to reduced recurrence rates and overall improved survival. Although this imaging approach focuses on epithelial ovarian cancer diagnosis and treatment, it can be applicable to a wide range of epithelial diseases, such as oral, lung, and gastrointestinal cancers.