A nanoparticle-based approach for surgical imaging and intraoperative treatment of endometriosis

项目概要/摘要： 子宫内膜异位症是一种疼痛的疾病，其中子宫内膜样组织在子宫腔外形成病变。 流行的理论，桑普森假说，是子宫内膜碎片通过[逆行]通过 输卵管来建立病变。尽管医学治疗取得了最新进展，但仍无法治愈 这种疾病和手术切除病变仍然是许多妇女的选择。可惜 子宫内膜异位症术后复发率高，患者需要多次手术和药物治疗。 治疗导致复发的因素包括进一步的逆行月经和播种以及 在手术过程中遗漏的微小残留物的存在。术中可视化 这些微小的病变对妇科外科医生提出了成像挑战。我们的目标是减少 手术后疾病复发。我们已经创建了一个纳米平台，并获得了专利， 手术前全身给药，以实时近红外（NIR）描绘未切除的组织 在手术过程中的荧光和消除未切除的残留物与光热消融。该平台 最初是为癌症治疗而开发的，适用于子宫内膜异位症。该试剂由NIR组成 染料，封装在可生物降解的PEG-PCL（聚（乙二醇）-b-聚（β-聚氧乙烯））中的硅萘（SiNc）， 己内酯））纳米颗粒。这些颗粒在靶细胞内被激活之前是非荧光的。在 初步研究，我们评估了近红外试剂在猕猴增生组织移植到严重的 联合免疫缺陷（SCID）小鼠。我们报告说，我们目前开发的纳米颗粒内化在 在小鼠的病变中产生NIR荧光信号。国家清单报告 治疗还消融了自体移植物。我们的前提是纳米粒子平台辅助 临床上可以采用外科技术以允许术中可视化和消除 未切除的子宫内膜异位症在这项拨款中，我们建议我们现有平台的特殊性可以 通过靶向细胞表面受体增强肿瘤病变。这种细化是必不可少的一步 致力于创造新的外科技术，评估手术的安全性， 未来的实验在具体目标1中，我们将合成靶向VEGF受体2的聚合物纳米颗粒， (KDR)，或其他细胞表面部分，在子宫内膜异位症中过表达;评估人细胞中的颗粒， 在猕猴组织中将试剂与我们目前的平台进行比较。在具体目标2中，我们将验证新的 靶向剂可以全身注射，然后特异性地积聚在移植到 在SCID小鼠中，靶向NIR治疗导致异种移植物的光热消融。旧世界 包括猕猴在内的非人灵长类动物发生自发性子宫内膜异位症，并为子宫内膜异位症提供了动物模型。 创造新的外科技术为了推进这一模型，在具体目标3中，我们将扩展我们的研究，以测试 基于纳米颗粒的猕猴异位子宫内膜消融。

Project Summary/ Abstract: Endometriosis is a painful disorder where endometrium-like tissue forms lesions outside of the uterine cavity. The prevalent theory, the Sampson Hypothesis, is that endometrial fragments pass [retrograde] through the fallopian tube to establish the lesions. Despite recent advances in medical therapy, there remains no cure for the disease and surgical removal of the lesions remains a choice for many women. Unfortunately, the recurrence rate for endometriosis after surgery is high with patients requiring multiple operations and medical treatment. Factors contributing to recurrence include further retrograde menstruation and seeding as well as the presence of minute endometriotic residues that are missed during surgery. Intraoperative visualization of these minute lesions poses an imaging challenge for gynecologic surgeons. Our goal is to reduce recurrence of the disease after surgery. We have created and patented a nanoplatform that can be administered systemically before surgery to delineate unresected tissue with real-time near infrared (NIR) fluorescence during surgery and eliminate unresected residues with photothermal ablation. The platform was originally developed for cancer therapy and is applicable to endometriosis. The reagent consists of the NIR dye, silicon naphthalocyanine (SiNc) encapsulated in biodegradable PEG-PCL (poly (ethylene glycol)-b-poly(ɛ- caprolactone)) nanoparticles. The particles are non-fluorescent until activated within the target cells. In preliminary studies, we assessed the NIR reagent in macaque endometriotic tissue grafted into severe combined immunodeficient (SCID) mice. We reported that our currently developed nanoparticles internalized in macaque endometriotic cells and generated a NIR fluorescence signal in lesions in the mice. The NIR treatment also ablated the endometriotic grafts. Our premise is that nanoparticle platform-assisted surgical techniques can be employed clinically to permit intraoperative visualization and elimination of the unresected endometriosis. In this grant, we propose that the specificity of our existing platform can be enhanced by targeting cell surface receptors in endometriotic lesions. This refinement is an essential step towards creating new surgical techniques, assessing the safety of the procedures, and conducting impactful future experiments. In specific aim 1, we will synthesize polymeric nanoparticles that target VEGF receptor 2 (KDR), or other cell surface moieties, overexpressed in endometriosis; assess the particles in human cells and compare the reagent to our current platform in macaque tissue. In specific aim 2 we will validate that the new targeted agent can be injected systemically and then specifically accumulate in human lesions engrafted into SCID mice, and that targeted NIR treatment results in photothermal ablation of the xenografts. Old-World nonhuman primates, including macaques develop spontaneous endometriosis and provide an animal model for creating new surgical techniques. To advance this model, in specific aim 3 we will extend our studies to test nanoparticle-based ablation of ectopic endometrium in macaques.