Development of anti-inflammatory nanodrug for endometriosis treatment

开发治疗子宫内膜异位症的抗炎纳米药物

• 批准号: 10709492
• 负责人: Jae-Wook Jeong
• 金额: $ 62.86万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709492
• 关键词: Affect; Age; Albumins; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Contrast Media; Development; Diagnosis; Disease; Elements; Endometrial; Enzymes; Estrogens; Excision; Extravasation; Fetal Development; Fluorescent Dyes; Functional disorder; Goals; Growth; Hormonal; Hormones; Human; Immunosuppression; Incidence; Indocyanine Green; Infertility; Inflammation; Inflammatory; Injections; Lesion; Macrophage; Mediating; Medical; Medicine; Menstrual cycle; Modeling; Molecular; Multimodal Imaging; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Optics; Pain; Permeability; Peroxidases; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Pregnancy; Process; Proteins; Recurrent disease; Reporting; Risk; Role; Signal Transduction; Stat3 protein; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Woman; angiogenesis; catalase; cerium oxide nanoparticle; chronic pelvic pain; endometriosis; endometriosis-related infertility; eutopic endometrium; fertility improvement; high risk; human tissue; image guided; immunoregulation; implantation; improved; in vivo imaging; inhibitor; innovation; insight; mineralization; mouse model; nano; nanodrug; nanoparticle; nanosized; novel; novel strategies; overexpression; pain reduction; pain relief; pain symptom; photoacoustic imaging; pre-clinical; real time monitoring; reduce symptoms; relapse risk; reproductive; side effect; targeted delivery; targeted treatment; theranostics; therapeutic evaluation; tool

Project Summary Endometriosis affects 10-15% of women of reproductive age, and the incidence increases to 50-60% in women with chronic pelvic pain and infertility. The current treatments include surgical removal of lesions or hormonal suppression; however, these may have many side effects and high risks of relapse. Precision-targeted therapy with a non-hormonal drug can successfully eradicate endometriosis lesions and alleviate pain symptoms while reducing its off-target toxicity. pSTAT3 signaling plays a crucial role in immunosuppression and inflammation in endometriosis. A potential therapeutic approach then is to downregulate the endometriosis-specific inflammation using antioxidant drugs. Cerium oxide nanoparticles (nanoceria) are potent STAT3 inhibitors due to their anti-inflammatory and immunomodulatory effects. The small-sized nanoceria can accumulate in endometriotic lesions by extravasation through permeable, angiogenic endometrial vasculature. Our preliminary results demonstrated pSTAT3 overexpression leads to estrogen-dependent inflammation in endometriosis, and our ROS scavenging nanoceria remarkably reduces the number of endometriotic lesions in a mouse model. The nanodrug (nanoceria), coated with albumin protein and conjugated with NIR fluorescent dye (indocyanine green), shows successful systemic endometrial tissue targeting under photoacoustic image guidance. We hypothesize the novel nanodrug (albumin-nanoceria-ICG) will significantly suppress endometriotic lesion growth and result in reduced pain and infertility. Multimodal imaging simultaneously offers real-time monitoring of endometriosis progression and pregnancy and fetal development in living animals. Aim 1 will investigate how pSTAT3 in endometriosis contributes to inflammatory and immunosuppressive conditions using our endometriosis mouse model and in vivo imaging. Aim 2 will evaluate the theranostic potential of nanoceria on endometriosis progression and pain alleviation. Aim 3 examines whether the nanodrug will improve fertility, endometrial receptivity, and implantation. The proposed studies will support uncovering the molecular mechanism of inflammation in endometriosis and lead to non-surgical and non-hormonal treatment.

项目摘要 子宫内膜异位症影响10-15%的育龄妇女，发病率增加到50-60%的妇女 患有慢性盆腔疼痛和不孕症目前的治疗方法包括手术切除病变或激素治疗。 抑制;然而，这些可能有许多副作用和复发的高风险。精确靶向治疗 与非激素类药物可以成功地根除子宫内膜异位症病变，减轻疼痛症状， 降低其脱靶毒性。pSTAT 3信号在免疫抑制和炎症中起着至关重要的作用。 子宫内膜异位症一种潜在的治疗方法是下调糖尿病特异性 使用抗氧化药物治疗炎症。氧化铈纳米颗粒（纳米二氧化铈）是有效的STAT 3抑制剂， 它们的抗炎和免疫调节作用。小尺寸的纳米二氧化铈可以聚集在 通过可渗透的血管生成性子宫内膜血管系统外渗的增生性病变。我们 初步结果表明，pSTAT 3过表达导致雌激素依赖性炎症， 子宫内膜异位症，我们的ROS清除纳米氧化铈显着减少子宫内膜异位症病变的数量， 一个老鼠模型。纳米药物（纳米氧化铈），与白蛋白蛋白质包被，并与NIR荧光标记物结合， 染料（吲哚菁绿色），在光声成像下显示成功的全身子宫内膜组织靶向 指导我们假设新的纳米药物（白蛋白-纳米氧化铈-ICG）将显著抑制 增生性病变的生长和结果减少疼痛和不孕症。多模式成像同时提供 实时监测活体动物子宫内膜异位症进展以及妊娠和胎儿发育。目的 1将研究子宫内膜异位症中pSTAT 3如何促进炎症和免疫抑制条件 使用我们的子宫内膜异位症小鼠模型和体内成像。目的2将评估的治疗诊断潜力 nanoceria对子宫内膜异位症进展和疼痛缓解的作用。目的3检查纳米药物是否会 改善生育力、子宫内膜容受性和着床。拟议的研究将有助于揭示 子宫内膜异位症炎症的分子机制，并导致非手术和非激素治疗。