Nanoparticle Enabled Intraoperative Imaging and Therapy

描述（由申请人提供）：在过去的三十年中，脑肿瘤治疗的改进对结果几乎没有影响。我们建议开发靶向的多功能纳米颗粒，旨在通过提高手术效率和介导辅助光动力治疗来提高脑肿瘤患者的生存率。通过光学成像肿瘤边缘，靶向多功能纳米颗粒将实现最大程度的手术切除，同时最大限度地减少邻近组织损伤。此外，同样的纳米颗粒将被用于术中介导光动力治疗，从而根除隐匿或不可切除的肿瘤。这种结合提出了一种独特的方法，实现了高度显著的实际结果，在恶性脑癌患者的生存统计数据方面有了很大的定量改善。例如，小儿低/高级别胶质瘤的生存率有望提高至100%。具体来说，我们建议合成染料标记的纳米颗粒，可以静脉注射并选择性靶向脑肿瘤，以优化神经外科医生描绘肿瘤和健康神经组织的能力。此外，有人提出，相同靶向纳米颗粒内的光动力成分将能够根除手术切除后的残留肿瘤。为切除而进行的手术暴露，将为可见光有效地传递到不可切除或隐匿的肿瘤提供通道，进行光动力治疗。多功能纳米颗粒将由可生物降解的聚丙烯酰胺核心组成，内含蓝色描绘染料和光敏剂。纳米颗粒尺寸（30-70纳米）被设计成允许外渗穿过血脑屏障破裂的区域，这是肿瘤的特征，同时最小化穿过完整血脑屏障的通道。通过在纳米颗粒表面包裹肿瘤归巢肽F3，可以优化纳米颗粒在肿瘤部位的定位。我们先前证明了类似纳米颗粒的高治疗指数，无毒性和生物消除。靶向多功能纳米颗粒在术中光学描绘和光动力治疗（PDT）方面的能力将在几个胶质瘤动物模型中进行测试。拟议的研究是由一个现有的合作研究小组设计和实施的，其中包括应用物理学、生物纳米技术、化学、神经外科、神经病理学、神经毒理学、光学和核磁共振成像以及光动力疗法方面的专家。

DESCRIPTION (provided by applicant): Improvements in the treatment of brain tumors have produced little impact on outcomes over the past three decades. We propose the development of targeted, multifunctional nanoparticles designed to improve the survival of brain tumor patients by increasing surgical efficiency and mediating adjuvant photodynamic therapy. By optically imaging tumor margins, targeted multifunctional nanoparticles will enable maximal surgical resection, while minimizing adjacent tissue damage. In addition, the same nanoparticles will be used intraoperatively to mediate photodynamic therapy, thereby eradicating occult or un-resectable tumor. This combination presents a unique approach towards a highly significant practical outcome, a large quantitative improvement in the survival statistics of patients with malignant brain cancers. For instance, increases in survival on the order of up to 100% are expected for pediatric low/high grade glioma. Specifically we propose the synthesis of dye-labeled nanoparticles that can be administered intravenously and selectively targeted to brain tumors to optimize the ability of neurosurgeons to delineate neoplasm and healthy nervous tissue. Furthermore, it is proposed that photodynamic components inside the same targeted nanoparticles will enable the eradication of residual tumor following surgical resection. The surgical exposure, performed for resection, will provide a corridor for the efficient delivery of visible laser light to unresectable or occult tumor, for photodynamic therapy. The multifunctional nanoparticles will consist of a biodegradable polyacrylamide core containing blue delineation dye and photosensitizer. The nanoparticle size (30-70 nm) has been designed to allow extravasation across areas of blood brain barrier breakdown, characteristic of tumors, while minimizing passage across an intact blood-brain barrier. The localization of nanoparticles at tumor sites will be optimized by coating nanoparticles with tumor-homing F3 peptide. We demonstrated previously the high therapeutic index, non-toxicity and bio-elimination of similar nanoparticles. The ability of targeted multifunctional nanoparticles to enable intraoperative optical delineation and photodynamic therapy (PDT) will be tested in several animal models of glioma. The proposed research was designed and will be carried out by an existing collaborative team of investigators, including experts in applied physics, bio-nanotechnology, chemistry, neurosurgery, neuropathology, neurotoxicology, optical and MRI imaging, and photodynamic therapy.