Nanoparticle Enabled Intraoperative Imaging and Therapy

描述(由申请人提供)：在过去的三十年里，脑瘤治疗的改进对结果几乎没有影响。我们建议开发靶向的、多功能的纳米颗粒，旨在通过提高手术效率和介导辅助光动力疗法来提高脑肿瘤患者的存活率。通过对肿瘤边缘进行光学成像，有针对性的多功能纳米颗粒将实现最大限度的手术切除，同时将邻近组织的损害降至最低。此外，同样的纳米粒子将在术中用于介导光动力疗法，从而根除隐匿性或无法切除的肿瘤。这种结合提供了一种独特的方法，以实现一个非常重要的实际结果，即在恶性脑癌患者的生存统计方面的巨大量化改善。例如，预计儿童低/高级别胶质瘤的存活率将增加100%左右。具体地说，我们建议合成染料标记的纳米颗粒，这种纳米颗粒可以静脉注射并选择性地靶向于脑瘤，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，研究还提出，在相同的靶向纳米颗粒中加入光动力学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提供一条走廊，有效地将可见光输送到无法切除或隐蔽的肿瘤，以便进行光动力治疗。这种多功能纳米粒子将由一个可生物降解的聚丙烯酰胺核组成，其中包含蓝色描绘染料和光敏剂。这种纳米颗粒的尺寸(30-70 nm)被设计成允许通过血脑屏障破坏的区域，这是肿瘤的特征，同时最大限度地减少穿过完整的血脑屏障。纳米粒子在肿瘤部位的定位将通过包裹肿瘤归巢F3多肽来优化。我们以前证明了类似纳米粒的高治疗指数、无毒和生物消除。靶向多功能纳米颗粒使术中光学描绘和光动力疗法(PDT)的能力将在几种胶质瘤动物模型中进行测试。这项拟议的研究是由一个现有的合作研究团队设计并进行的，研究人员包括应用物理、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.