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

基于纳米颗粒的子宫内膜异位症手术成像和术中治疗方法

• 批准号: 9893322
• 负责人: OV D SLAYDEN
• 金额: $ 26.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893322
• 关键词: Ablation; Adhesions; Affect; Aftercare; Anatomy; Animal Model; Blood Circulation; Cell Surface Receptors; Cell surface; Cells; Clinical; Contraceptive Agents; Disease; Encapsulated; Endometrial; Endometrium; Engineering; Etiology; Excision; Exposure to; Female of child bearing age; Fertility; Fluorescence; Future; Goals; Grant; Greater sac of peritoneum; Growth Factor Receptors; Gynecologic; Human; Hyaluronic Acid; Image; Image-Guided Surgery; KDR gene; Laparoscopic Surgical Procedures; Legal patent; Lesion; Light; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Malignant Neoplasms; Mammalian Oviducts; Mediating; Medical; Menstruation; Methods; Modeling; Mus; No Evidence of Disease; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pain; Patients; Pelvic Pain; Peptides; Permeability; Phototherapy; Polymers; Rattus; Reagent; Recurrence; Reporting; Residual state; Retrograde Menstruation; SCID Mice; Seeds; Signal Transduction; Silicon; Site; Specificity; Sum; Surface; Surgeon; Techniques; Testing; Thermal Ablation Therapy; Time; Tissue Grafts; Tissues; Uterine cavity; Uterus; Visualization; Woman; Work; Xenograft procedure; angiogenesis; base; cancer cell; cancer therapy; caprolactone; combinatorial; design; endometriosis; ethylene glycol; experimental study; fertility improvement; improved; innovation; intravenous injection; iron oxide nanoparticle; nanoparticle; nanoparticle delivery; nanoparticle exposure; nanotechnology platform; near infrared dye; nonhuman primate; operation; ovarian neoplasm; overexpression; particle; photothermal therapy; procedure safety; reproductive tract; subfertility; surgery outcome; targeted agent; theories; treatment choice

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.

项目摘要/摘要： 子宫内膜异位症是一种疼痛的疾病，子宫内膜样组织在宫腔外形成病变。 流行的理论，桑普森假说，是子宫内膜碎片通过 建立输卵管病变。尽管最近在药物治疗方面取得了进展，但仍然没有治愈的方法 对于许多女性来说，疾病和手术切除病变仍然是一种选择。不幸的是， 子宫内膜异位症术后复发率高，需要多次手术和内科治疗 治疗。导致复发的因素包括进一步的逆行月经和播种以及 手术中遗漏的微小子宫内膜异位症残留物。术中视觉化 这些微小的病变给妇科外科医生带来了成像方面的挑战。我们的目标是减少 手术后病情复发。我们已经创造了一种纳米平台并申请了专利，这种平台可以 术前全身应用实时近红外(NIR)勾画未切除组织 术中用荧光消融，并用光热消融消除未切除的残留物。平台是 最初是为癌症治疗开发的，适用于子宫内膜异位症。试剂由近红外光谱组成 可生物降解聚乙二醇聚乙二醇b-聚(ɛ-C)包埋的硅萘菁染料 己内酯))纳米粒。在靶细胞内被激活之前，这些颗粒是非荧光的。在……里面 初步研究，我们评估了近红外试剂在猕猴子宫内膜异位症移植到重度 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 猕猴异位内膜细胞，并在小鼠的病变中产生近红外荧光信号。近红外光谱 治疗还消融了子宫内膜异位移植物。我们的前提是纳米颗粒平台辅助 外科技术可以应用于临床，以实现术中可视化和消除 未切除的子宫内膜异位症。在这项授权中，我们建议我们现有平台的特殊性可以是 通过靶向子宫内膜异位症病变中的细胞表面受体而增强。这一改进是必不可少的一步。 创造新的外科技术，评估手术的安全性，并进行有效的 未来的实验。在特定的目标1中，我们将合成靶向血管内皮生长因子受体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度表达；评估人类细胞和 将该试剂与我们目前在猕猴组织中的平台进行比较。在具体目标2中，我们将验证新的 靶向药物可以全身注射，然后在人体皮损中特异性积聚。 靶向近红外治疗可导致异种移植物的光热消融。旧世界 非人灵长类动物，包括猕猴，会发生自发性子宫内膜异位症，并为 创造新的外科技术。为了推进这一模式，在具体目标3中，我们将把我们的研究扩展到测试 基于纳米颗粒的猕猴异位内膜消融术。