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

项目摘要/摘要 晚期卵巢癌治疗的一个主要挑战是播散性卵巢癌的存在。 腹膜腔内有微小肿瘤结节。尽管进行了手术和辅助化疗，AS 多达50%的患者可以表现出隐匿性播散性疾病，但存活率只有43%。此外， 全身化疗可能会有毒副作用。因此，最近的努力旨在提高检测 以及微粒子的治疗。化学光疗法(CPT)--化疗和光动力的结合 治疗，是一种新兴的癌症治疗方式，可以提供两种治疗方法的协同疗效。这个 总的目标是实施一种量化的腹腔镜成像和治疗方法 微粒子的检测及靶向销毁卵巢微粒子和减灭剂的CPT优化 毒副作用。定量荧光腹腔镜成像将提供高灵敏度和高分辨率 检测微粒子以及图像引导的药物输送。叶酸受体α(FA)将被用作 有希望成为靶点，因为它对上皮性卵巢癌具有高度的特异性。拟议的有针对性的CPT 化合物具有~6倍的肿瘤特异性，提供增强的荧光对比度。这些以叶酸为靶标的 利用近红外(NIR)光直接触发卟啉-磷脂掺杂脂质体。这将激活 抗癌光敏剂外层，释放抗癌剂阿霉素(Dox)。虽然这件事 纳米载体有望提高对微粒子的检测，组织吸收和在活组织中的散射可以 混淆的荧光对比度。基于空间频域成像的定量成像可以 消除这些混杂影响，并提供定量对比以实现更灵敏的检测 与原始荧光或白光可视化相比。此外，这种量化能力可以发挥作用 近乎实时地提供药物释放的反馈，从而实现图像引导的治疗优化 光，以确保药物在每个肿瘤内充分释放。在目标1中，一种广视场双通道腹腔镜，快速 将实施和优化量化算法和靶向脂质体纳米构建。在目标2中， 该平台将在体内进行验证，以改进对微粒子的检测，而不是原始荧光和白光。 在Aim 3中，将在体内验证该平台在摧毁靶向肿瘤中的微粒子方面的有效性 减少对周围正常组织的毒性。这一方法的成功完成预计将导致 改进了微粒子的检测和治疗，减少了副作用。预计这最终将导致 降低复发率，总体提高存活率。尽管这种成像方法侧重于上皮细胞 卵巢癌的诊断和治疗，它可以适用于多种上皮性疾病，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.