Image-guided surgery and sonodynamic therapy with stroma-targeted theranostic nanoclusters

使用基质靶向治疗诊断纳米簇进行图像引导手术和声动力治疗

• 批准号: 10541160
• 负责人: Andrew Tsourkas
• 金额: $ 36.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541160
• 关键词: Ablation; Address; Azides; Binding; Biological Markers; Breast Cancer Model; Breast Cancer Patient; Breast-Conserving Surgery; Cancer Etiology; Carcinoma; Cell-Mediated Cytolysis; Cells; Cessation of life; Clinical; Clinical Research; Contrast Media; Diagnosis; Diameter; Drug Kinetics; Excision; Extracellular Matrix; Extravasation; Fibroblasts; Fluorescent Dyes; Frequencies; Generations; Genetic Engineering; Goals; Human; Image; Image-Guided Surgery; In Vitro; Indocyanine Green; Ligands; Light; Localized Disease; Magnetic Resonance; Magnetic Resonance Imaging; Mammary Neoplasms; Modeling; Monoclonal Antibodies; Mus; Nanotechnology; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Optics; PUVA Photochemotherapy; Pathology; Patients; Penetration; Photosensitizing Agents; Physicians; Process; Proteins; Radiologic Finding; Reactive Oxygen Species; Recombinant Antibody; Recombinants; Recurrence; Regimen; Relapse; Residual Cancers; Residual Neoplasm; Safety; Site; Specificity; Stromal Cells; Surface; Therapeutic; Time; Tissues; Toxic effect; Tumor Expansion; Visual; Woman; analog; cancer cell; cancer therapy; chemical property; clinical investigation; contrast enhanced; cytotoxicity; design; image guided; imaging properties; improved; innovation; insight; iron oxide nanoparticle; malignant breast neoplasm; mouse model; nanocluster; nanoformulation; nanoparticle; novel; optical imaging; pharmacokinetics and pharmacodynamics; prevent; response; superparamagnetism; theranostics; trend; tumor; tumor initiation; ultrasound; uptake

The majority of women with breast cancer undergo breast-conserving surgery, but in >20% of the cases it is post-surgically determined that the margins are not tumor free and additional surgery is necessary. One potential solution is the use of optical image-guided surgery to improve intraoperative margin assessment. We recently found that the near-infrared fluorescent dye, indocyanine green (ICG), can be used to help differentiate breast tumor tissue from normal tissue in clinical investigations; however, a low specificity was found to lead to false-positives. We hypothesize that targeted nanoparticles capable of carrying large payloads of ICG could be used to confer additional specificity (and sensitivity) during surgery. A recent trend in more aggressive cancer therapies involves treating patients with photodynamic therapy (PDT) as anadjunct to surgery. Clinical studies have shown that this can improve overall survival. However, PDT is hampered by the poor specificity of photosensitizers and the limited depth penetration of the excitation light. We propose to utilize targeting ligands to overcome the poor selectivity of sensitizing agents and ultrasound, instead of light, to activate the sensitizing agents to improve tissue penetration, i.e. sonodynamic therapy (SDT). ICG will be used as the sensitizer, thus allowing a single agent to be used for both imaging and therapy. The goal of this proposal is to develop multifunctional, targeted nanoparticles that allow intraoperative image- guided surgery and SDT to be performed in a novel combination regimen for treating breast cancer. Multifunctional nanoparticles will be prepared with ICG and superparamagnetic iron oxide nanoparticles (SPIONs) in a single nanoformulation. The nanoparticles will be designed to target fibroblast activating protein (FAP) on the tumor stroma. We hypothesize that stromal cells will be a favorable target because they are located at the invasive front of the tumor, they are genetically stable, and they are required for expansion of tumor initiating cells. Superparamagnetic iron oxide nanoparticle (SPION)-enhanced MR imaging is expected to enable preoperative radiologic findings to be directly related to the visual presentation of pathology during surgery. ICG-enhanced intraoperative image-guided surgery will enable more complete resection, resulting in fewer residual cancer cells after surgery. SDT will enable the ablation of any residual disease. We believe that this innovative nanotechnology will profoundly improve the ability of physicians to completely eradicate local disease in breast cancer patients, resulting in fewer re-excisions and an improvement in survival. The specific aims of this proposal are (1) . Synthesize and characterize the physical-chemical properties of FAP-targeted ICG-coated SPION nanoclusters.; (2) . Characterize binding, uptake and cytotoxicity of ICG- coated SPION nanoclusters in vitro; and (3) Evaluate the pharmacokinetics, contrast enhancement, and ability of ICG-coated SPION nanoclusters to enhance intraoperative image-guided resection and SDT in a murine model of breast cancer.

大多数患有乳腺癌的女性接受保乳手术，但在>20%的病例中， 手术后确定边缘不是无肿瘤的，需要进行额外的手术。一 潜在的解决方案是使用光学图像引导手术来改善术中边缘评估。我们 最近发现，近红外荧光染料，吲哚菁绿色（ICG），可以用来帮助 在临床研究中区分乳腺肿瘤组织和正常组织;然而， 导致假阳性。我们假设能够携带大载荷的靶向纳米颗粒 ICG可用于在手术过程中提供额外的特异性（和灵敏度）。 最近的一个趋势是更积极的癌症治疗涉及治疗患者的光动力疗法（PDT） as anadjuvant辅助to surgery手术.临床研究表明，这可以提高总生存率。然而，PDT是 受到光敏剂的特异性差和激发光穿透深度有限的阻碍。 我们建议利用靶向配体来克服敏化剂和超声的选择性差， 以激活敏化剂来改善组织穿透，即声动力疗法 （SDT）。ICG将用作敏化剂，从而允许将单一药剂用于成像和治疗。 该提案的目标是开发多功能的靶向纳米颗粒，允许术中成像- 引导手术和SDT在治疗乳腺癌的新组合方案中进行。 将ICG与超顺磁性氧化铁纳米粒子一起制备多功能纳米粒子 （SPION）在单一纳米制剂中。纳米颗粒将被设计为靶向成纤维细胞活化蛋白 (FAP)在肿瘤间质上。我们假设，基质细胞将是一个有利的目标，因为他们是 位于肿瘤的侵袭性前沿，它们在遗传上是稳定的，并且它们是肿瘤扩张所必需的。 肿瘤起始细胞超顺磁性氧化铁纳米颗粒（SPION）增强MR成像有望 为了使术前放射学发现能够直接与手术期间病理的视觉表现相关， 手术ICG增强的术中图像引导手术将实现更完整的切除， 手术后残留癌细胞较少。SDT将能够消融任何残留疾病。我们认为 这种创新的纳米技术将大大提高医生完全根除局部 乳腺癌患者的疾病，导致更少的再切除和生存率的提高。 本建议的具体目标是（1）。合成并表征了 FAP靶向ICG涂层SPION纳米团簇(2) .表征ICG的结合、摄取和细胞毒性- 体外包被SPION纳米团簇;和（3）评价药物动力学、对比增强和能力 ICG涂层SPION纳米簇增强小鼠术中图像引导切除和SDT 乳腺癌的模型。