Departments of Biomedical Engineering and Chemistry, Boston University , Boston, Massachusetts 02215, United States.
Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.
ACS Nano. 2017 Feb 28;11(2):1466-1477. doi: 10.1021/acsnano.6b06777. Epub 2017 Feb 1.
A current challenge in the treatment of peritoneal carcinomatosis is the inability to detect, visualize, and resect small or microscopic tumors of pancreatic, ovarian, or mesothelial origin. In these diseases, the completeness of primary tumor resection is directly correlated with patient survival, and hence, identifying small sub-millimeter tumors (i.e., disseminated disease) is critical. Thus, new imaging techniques and probes are needed to improve cytoreductive surgery and patient outcomes. Highly fluorescent rhodamine-labeled expansile nanoparticles (HFR-eNPs) are described for use as a visual aid during cytoreductive surgery of pancreatic carcinomatosis. The covalent incorporation of rhodamine into ∼30 nm eNPs increases the fluorescent signal compared to free rhodamine, thereby affording a brighter and more effective probe than would be achieved by a single rhodamine molecule. Using the intraperitoneal route of administration, HFR-eNPs localize to regions of large (∼1 cm), sub-centimeter, and sub-millimeter intraperitoneal tumor in three different animal models, including pancreatic, mesothelioma, and ovarian carcinoma. Tumoral localization of the HFR-eNPs depends on both the material property (i.e., eNP polymer) as well as the surface chemistry (anionic surfactant vs PEGylated noncharged surfactant). In a rat model of pancreatic carcinomatosis, HFR-eNP identification of tumor is validated against gold-standard histopathological analysis to reveal that HFR-eNPs possess high specificity (99%) and sensitivity (92%) for tumors, in particular, sub-centimeter and microscopic sub-millimeter tumors, with an overall accuracy of 95%. Finally, as a proof-of-concept, HFR-eNPs are used to guide the resection of pancreatic tumors in a rat model of peritoneal carcinomatosis.
当前，在治疗腹膜癌转移方面存在一个挑战，即无法检测、可视化和切除胰腺、卵巢或间皮来源的小或微肿瘤。在这些疾病中，原发性肿瘤切除的完整性与患者的生存直接相关，因此，识别小至亚毫米级的肿瘤（即播散性疾病）至关重要。因此，需要新的成像技术和探针来改善细胞减灭术和患者的预后。本文描述了可被用于胰腺癌转移的细胞减灭术中的可视化辅助手段——高荧光罗丹明标记的膨胀纳米颗粒（HFR-eNPs）。与游离罗丹明相比，将罗丹明共价结合到约 30nm 的 eNPs 中可增加荧光信号，从而使探针比单个罗丹明分子更亮、更有效。通过腹腔内给药途径，HFR-eNPs 可在三种不同的动物模型（包括胰腺、间皮瘤和卵巢癌）中定位到大型（约 1cm）、亚厘米级和亚毫米级的腹腔内肿瘤部位。HFR-eNPs 的肿瘤定位取决于材料特性（即 eNP 聚合物）和表面化学性质（阴离子表面活性剂与 PEG 化非带电表面活性剂）。在胰腺癌转移的大鼠模型中，通过与金标准组织病理学分析的对比，验证了 HFR-eNP 对肿瘤的识别，结果表明 HFR-eNPs 对肿瘤具有高特异性（99%）和高敏感性（92%），特别是对亚厘米级和显微镜下的亚毫米级肿瘤，总体准确率为 95%。最后，作为概念验证，HFR-eNPs 用于指导大鼠腹膜癌转移模型中胰腺肿瘤的切除。
