MSKCC -Cornell Center for Translation of Cancer Nanomedicines.

 描述(由申请人提供)：新的诊断和治疗工具能够实现更早和更具体的检测，以及提高疗效，是改善患者预后的关键，特别是在本中心研究的黑色素瘤和恶性脑瘤中。例如，这样的工具应该使手术医生能够直接可视化肿瘤边缘和转移到淋巴结的疾病，同时识别邻近的重要神经血管结构。这样的结构可能难以想象，从而使它们面临受伤的风险。不幸的是，尽管纳米粒子具有许多理想的特征，允许添加新的功能来创建更有效的、肿瘤导向的成像和/或治疗平台，但这种分子靶向的多模式粒子可以提高诊断准确性和/或将患者分流到适当的治疗臂，进展缓慢，进入临床试验阶段。MSKCC-康奈尔癌症纳米药物翻译中心(MC2TCN)的愿景是开发、翻译和传播一套尺寸、亮度和几何形状可调的超小(10 Nm)多模(PET/光学)二氧化硅-有机杂化纳米颗粒，由于它们在人类患者中已被证明具有良好的药代动力学、清除性和肿瘤背景比，因此有可能克服这些限制，显著影响我们诊断和治疗癌症患者的方式。这包括开发和实施术中光学检测工具，以改进癌症的定位、分期和治疗，以及开发优化的治疗平台，以增强相对于现有技术的输送和治疗指数。拟议的中心侧重于诊断粒子探测器、称为康奈尔点或C点的荧光核壳二氧化硅纳米颗粒的初步开发工作， 它们已经获得了FDA的新药研究(IND)批准，可以进行首次人体临床试验。这项成功的工作首次在人类患者身上验证了该中心所追求的10纳米纳米粒子的“Tret or Clear”方法，为变革性研究和开发新的具有临床前景的纳米粒子类别及其在癌症诊断和治疗中的应用打开了大门。这里提出的过渡到水基合成方法将使具有成本效益的新的诊断和治疗颗粒平台的创建成为可能，其尺寸为&lt；10纳米。这些超小颗粒平台将通过改变颗粒核心成分显示出高亮度，以实现最高的检测灵敏度，导致颗粒几何形状(环状与球状)具有更大的表面积，从而最大限度地提高药物载药量，并解决颗粒尺寸和表面化学异质性对PK、清晰度分布和靶本底比的影响，这些都是纳米材料在纳米医学中使用的关键问题。第一代多模式C点人类临床试验的令人鼓舞的结果，建立在拟议的多机构、多学科团队的研究人员之间多年的合作研究基础上，我们预见，由该中心的框架定义的拟议工作以及通过使用展示改进和显著增强的能力的相同尺寸的颗粒平台，将有现实的机会改变这里所追求的癌症护理应用的范式。

 DESCRIPTION (provided by applicant):: Novel diagnostic and therapeutic tools that can enable earlier and more specific detection, as well as enhance efficacy are critically needed to improve patient outcomes, in particular in melanoma and malignant brain tumors studied in this Center. For example, such tools should enable the operating surgeon to directly visualize tumor margins and metastatic disease spread to lymph nodes, while identifying adjacent vital neurovascular structures. Such structures may be difficult to visualize, thus putting them at risk for injury. Unfortunately, while nanoparticles have a number of desirable features permitting the addition of new functionalities to create a more potent, tumor-directed imaging and/or therapeutic platform, such molecularly targeted, multimodality particles that can improve diagnostic accuracy and/or triage patients to appropriate treatment arms, have been slow to advance to the clinical trial stage. The vision of the MSKCC-Cornell Center for Translation of Cancer Nanomedicines (MC2TCN) is to advance, translate, and disseminate a suite of ultrasmall (<10 nm) multimodality (PET/optical) silica-organic hybrid nanoparticles with tunable size, brightness, and geometry that, as a result of their proven favorable pharmacokinetics, clearance profiles and tumor-to-background ratios in human patients, have the potential to overcome these limitations and dramatically impact the way we diagnose and treat cancer patients. This includes the development and implementation of intraoperative optical detection tools to improve cancer localization, staging, and treatment, as well as the development of optimized therapeutic platforms that enhance delivery and therapeutic index relative to existing technologies. The proposed Center is focused on initial development efforts of diagnostic particle probes, fluorescent core-shell silica nanoparticles referred to as Cornell dots or C dots, which have already received FDA investigational new drug (IND) approvals for first in-human clinical trials. This successful work, for the first time in human patients, has validated the "taret or clear" approach of <10 nm nanoparticles pursued in this Center, opening the door to transformative research and development of new clinically promising classes of nanoparticles and their applications in cancer diagnostics and therapeutics. Transitioning to water-based synthetic approaches proposed here will enable cost-effective creation of novel diagnostic and therapeutic particle platforms with sizes <10 nm. These ultrasmall particle platforms will exhibit high brightness for maximum detection sensitivity by altering particle core composition, lead to particle geometries (rings vs. spheres) with increased surface area for maximizing drug loading capacity, and address the effects of particle size and surface chemistry heterogeneity on PK, clearance profiles and target-to-background ratios - key issues in the use of nanomaterials in nanomedicine. Informed by the encouraging results of the first-in-human clinical trials with first generation multimodal C dots, built on many years of collaborative research between investigators of the proposed multi-institutional, multi-disciplinary team, we envision that the proposed work defined by the framework of this Center and by the use of same-sized particle platforms exhibiting improved and significantly enhanced capabilities has a realistic chance to change the paradigm of cancer care applications pursued herein.