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

大多数患有乳腺癌的女性都会接受保乳手术，但这一比例为20%。 手术后确定边缘不是无肿瘤的，需要额外的手术。一 可能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青绿(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，特异性较低 被发现导致假阳性。我们假设目标是能够携带大有效载荷的纳米颗粒 ICG可用于在手术中提供额外的特异性(和敏感性)。 在更具侵略性的癌症治疗中，最近的一个趋势是用光动力疗法(Pdt)治疗病人。 作为手术的辅助手段。临床研究表明，这可以提高总体存活率。然而，PDT是 由于光敏剂的特异性差和激发光的穿透深度有限而受到阻碍。 我们建议利用靶向配体来克服敏化剂和超声波选择性差的问题， 代替光，激活敏化剂以提高组织穿透性，即声动力疗法 (SDT)。ICG将被用作增敏剂，从而允许一种试剂同时用于成像和治疗。 这项提议的目标是开发多功能、靶向的纳米颗粒，使术中成像- 以一种新的联合方案进行引导手术和SDT治疗乳腺癌。 利用ICG和超顺磁性氧化铁纳米颗粒制备多功能纳米颗粒 (SPION)在单一纳米配方中。这种纳米颗粒将被设计成针对成纤维细胞激活蛋白。 (FAP)在肿瘤间质。我们假设基质细胞将是一个有利的靶点，因为它们 它们位于肿瘤的侵袭性前沿，在基因上是稳定的，它们是肿瘤扩张所必需的。 肿瘤始动细胞。超顺磁性纳米氧化铁(SPION)增强磁共振成像有望实现 使术前放射学发现与手术期间病理的视觉表现直接相关。 做手术。ICG增强的术中图像引导手术将实现更完全的切除，从而导致 术后残留癌细胞较少。SDT将能够消融任何残留的疾病。我们相信 这项创新的纳米技术将深刻提高医生彻底根除局部 减少乳腺癌患者的再次切除，提高存活率。 这项建议的具体目的是(1)。化合物的合成及物化性质表征 FAP靶向ICG包裹的Spion纳米团簇；ICG-的结合、摄取和细胞毒性的表征 (3)评价药物动力学、对比剂增强和能力。 ICG包被Spion纳米团簇增强术中图像引导下的小鼠切除和SDT 乳腺癌的模型。

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.