Photodynamic Therapy of Disseminated Peritoneal Tumor Using New Photosensitizers

描述（由申请人提供）：播散性腹膜癌是由原发性上皮癌扩散引起的，这是由于脱落细胞随后植入腹膜内的其他组织和器官。它发生在癌症的晚期，但也是由于存在残留或接种（来自手术）疾病细胞而缺乏血行或淋巴转移的可切除肿瘤患者的肿瘤复发的原因。因此，需要对这种微转移进行辅助治疗，通常是化疗。然而，复发率仍然高得令人无法接受，而且治疗结果往往不确定。建议开发一种使用光敏剂进行光动力疗法的新辅助疗法，其在I期中已显示在体外光诱导杀死各种癌细胞系方面比Photofrin更有效。光动力疗法（PDT）是一种使用无毒光敏剂（PS）和可见光产生活性氧（ROS）杀死肿瘤细胞的方法。PDT的一个优点是其选择性水平，通过选择性靶向特定细胞或组织类型的PS实现，以及控制照明区域的能力。对于腹膜内PDT，腹膜充满光散射流体和PS。然后，在手术后立即将腔体直接照射到开放的腔体中，或者通过小切口用光纤电缆照射腔体。因为整个腔都得到了治疗，所以可以根除未检测到的微转移。PS的一个主要优点是不需要激光。此外，由于富勒烯不吸收红光，因此与深层组织穿透光相关的光毒性最小化。为了实现第二阶段的目标，我们将根据已建立的结构-活性关系合成新的化合物，并在体外筛选它们的PDT功效。然后，将在三种小鼠癌症模型中进行体内研究：卵巢癌、结直肠癌和网状细胞肉瘤。公共卫生相关性：各种形式的播散性腹膜癌每年影响成千上万的美国人。目前，手术后辅助化疗传统上是预防疾病复发的最佳防线。然而，由于5年生存率低得令人无法接受，因此需要开发光动力疗法等替代治疗方法。

DESCRIPTION (provided by applicant): Disseminated peritoneal cancer is caused by the spread of primary epithelial cancer as a result of shedding cells followed by implantation into other tissues and organs within the peritoneum. It occurs in late stages of cancer but is also responsible for tumor recurrence in patients with resectable tumors that lack hematogenous or lymphatic metastasis due to the presence of residual or seeded (from surgery) disease cells. Thus an adjuvant treatment for this micrometastasis, typically chemotherapy, is required. However, recurrence rates are still unacceptably high and the therapeutic outcome is often uncertain. It is proposed to develop a new adjunct therapy using photosensitizers for photodynamic therapy that have been shown in Phase I to be more efficacious than Photofrin at light induced killing of various cancer cell lines in vitro. Photodynamic therapy (PDT) is a procedure that uses a non-toxic photosensitizer (PS) and visible light to generate reactive oxygen species (ROS) that kill tumor cells. One advantage of PDT is its level of selectivity, achieved through PS that selectively target specific cell or tissue types, and the ability to control the illumination area. For intraperitoneal PDT, the peritoneum is filled with a light scattering fluid and PS. The cavity is then illuminated either immediately after surgery directly into the open cavity or with a fiber optic cable through a small incision. Because the entire cavity is treated, undetected micrometastases can be eradicated. One major advantage of our PS is that laser light is not needed. In addition, because fullerenes do not absorb red light, phototoxicity related to deep tissue penetrating light is minimized. To accomplish the goals of Phase II, we will synthesize new compounds based on established structure-activity relationships and screen them in vitro for PDT efficacy. The lead PS candidate along with the PS developed in Phase I will then be carried into in vivo studies in three mouse cancer models: ovarian, colorectal, and reticulum cell sarcoma PUBLIC HEALTH RELEVANCE: Disseminated peritoneal cancer of various forms affect thousands of Americans every year. Current adjuvant chemotherapy after surgery has traditionally been the best line of defense against disease recurrence. However, the unacceptably low 5-year survival rate necessitates the development of alternative treatments such as photodynamic therapy.