Online monitoring and image-guided treatment of chemoresistant micrometastases

描述（由申请人提供）：尽管在细胞减少手术和化疗方面取得了进展，但转移性上皮性卵巢癌和胰腺导管腺癌的生存率仍然很低，部分原因是传统成像方式无法检测到化疗耐药微转移。这两种疾病都涉及腹膜癌，即腹膜腔及其常驻器官的广泛肿瘤。为了解决这些“看不见”的肿瘤，我们引入了一系列针对癌细胞的、可激活的成像和治疗剂，并结合了细胞分辨率、多分子荧光显微内镜。我们开发了近红外光细胞毒性免疫偶联物（PICs），其靶向癌细胞过度表达的细胞膜分子，包括表皮生长因子受体，作为成像探针和联合光动力和抗分子治疗剂，用于肿瘤靶向，可激活光免疫治疗（taPIT）。在癌细胞结合、内化和加工过程中，光动力和荧光成分被去淬灭（激活）。这种策略克服了脱靶光毒性，包括肠道光毒性，这是光激活治疗复杂部位（如盆腔）的主要临床障碍。我们之前的研究表明，PIC在体内结合卵巢微转移瘤具有93%的敏感性和93%的特异性，能够准确识别小至30 μ m的肿瘤并选择性地破坏微转移瘤。我们建议进一步开发这个平台，专门针对化疗耐药微转移，这代表了癌症治疗的一个关键利基。目前的临床成像技术无法解决手术和化疗留下的显微肿瘤沉积物，并且对于复发性化疗耐药肿瘤患者的治疗选择有限。我们期待这种显微内镜引导下的taPIT新模式将补充目前晚期疾病患者和接受补救性治疗的患者的治疗模式。

DESCRIPTION (provided by applicant): Despite advances in cytoreductive surgery and chemotherapy, survival of metastatic epithelial ovarian cancer and pancreatic ductal adenocarcinoma remain dismal due in part to chemoresistant micrometastases undetectable by traditional imaging modalities. Both of these diseases involve peritoneal carcinomatosis, that is, extensive tumor studding of the peritoneal cavity and its resident organs. To address these "invisible" tumors, we introduce a series of cancer cell-targeted, activatable imaging and therapeutic agents integrated with cellular-resolution, multi-molecular fluorescence microendoscopy. We developed near-infrared photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells, including the epidermal growth factor receptor, to serve as an imaging probe and combined photodynamic and anti-molecular therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic and fluorescence components become de-quenched (activated) upon cancer cell binding, internalization and processing. This strategy overcomes off-target phototoxicity-including bowel phototoxicity-the major clinical obstacle for photoactivated treatments in complex sites such as the pelvic cavity. This proposal builds on our prior work that shows the PIC binds ovarian micrometastases with 93% sensitivity and 93% specificity in vivo, enabling accurate recognition of tumors as small as 30 �m and selective destruction of micrometastases. We propose to further develop this platform to specifically address chemoresistant micrometastases, which represent a critical niche in cancer therapy. Current clinical imaging technologies cannot resolve microscopic tumor deposits left behind by surgery and chemotherapy, and there are limited treatment options for patients with recurrent, chemoresistant tumors. We anticipate that this new paradigm for microendoscopy-guided taPIT will complement current treatment modalities for patients with advanced-stage disease and those receiving salvage therapies.