Biomolecule-Directed Assembly for Enhancing Near IR Energy Transfer Processes in Theranostics

 描述(申请人提供)：拟议研究的目标是控制各向异性金纳米结构、UCNP和响应性聚合物涂层的离散簇的组装和制造，以获得用于实体肿瘤成像和治疗的理想治疗学。治疗学代表了癌症研究的一个令人兴奋的领域，因为它们允许对治疗药物进行非侵入性跟踪，进入肿瘤环境，然后进行肿瘤特异性释放。650-1000纳米的“组织透明窗”中的光可以作为能量源来执行这两种功能。然而，大多数IR诱导的成像和治疗需要仅在表面部位获得的光通量，因此不能应用于许多其他癌症。这项拟议的研究将利用PI在光物理、纳米级组装和大分子方面的知识来合理设计利用近红外的纳米结构。根据照射强度的不同，所提出的治疗方法将产生可见的图像对比度或药物释放。建议的纳米结构将包括用于最大限度地吸收近红外的各向异性金纳米结构，用于转换为可见光的上转换纳米颗粒(UCNP)，以及用于响应辐射释放药物分子的刺激响应型聚合物涂层。一个能够在非表面深度执行这些功能的纳米结构需要对金表面发生的能量传递过程和获取这种能量的机制有一个基本的了解。这将通过：1.精确的Au-UCNP纳米结构的合成和光致发光的表征来实现。最近的理论研究表明，如果粒子正确组装，局域场增强可以使上转换发光输出增强几个数量级。生物分子组装技术将被用来在各向异性Au纳米棒(AuNRs)和纳米星(AuNSS)的尖端专门定位UCNP，以最大限度地实现能量转移。这些结构将使用单粒子和系综发光测量来验证。2.热响应性和光降解聚合物的合成及其对Au-UCNP团簇的近红外响应性能的评价。在金纳米结构表面沉积的红外能量将被用来通过金表面加热或产生单线态氧来促进表面接枝聚合物的药物输送。这些研究将分别使用能够构象转换或氧化解聚的聚合物来进行。3.优化的Au-UCNP聚合物治疗药物的合成及体外模型验证。优化的治疗药物的成像和治疗能力将在3D Matrigel基质中生长的4T1细胞上进行测试，以模拟肿瘤环境的结构和异质性。

 DESCRIPTION (provided by applicant): The goal of the proposed research is to control the assembly and fabrication of discrete clusters of anisotropic gold nanostructures, UCNPs, and responsive polymer coatings to obtain ideal theranostics for the imaging and treatment of solid tumors. Theranostics represent an exciting area of cancer research because they allow noninvasive tracking of therapeutics into the tumor environment followed by tumor-specific release. Light in the "tissue transparency window" of 650-1000 nm can serve as an energy source to perform both of these functions. However, most IR-induced imaging and therapy requires light flux only available at superficial sites and thus cannot be applied to many other cancers. The proposed research will utilize the PIs' knowledge of photophysics, nanoscale assembly, and macromolecules for the rational design of NIR-utilizing nanostructures. The proposed theranostic will produce either visible image contrast or drug release, depending on irradiation intensity. The proposed nanostructures will consist of an anisotropic gold nanostructure for NIR maximum absorption, an upconverting nanoparticle (UCNP) for conversion to visible light, and a stimulus-responsive polymer coating to release drug molecules in response to irradiation. A nanostructure able to perform these functions at non-superficial depths requires both a fundamental understanding of the energy transfer processes occurring at the gold surface and the mechanisms by which this energy can be harvested. This will be accomplished through: 1. Synthesis of precise Au-UCNP nanostructures and characterization of photoluminescence. Recent theoretical studies have shown that local field enhancement can enhance upconverted luminescence output by orders of magnitude if the particles are assembled correctly. Biomolecular assembly techniques will be used to specifically position UCNPs at the tips of anisotropic Au nanorods (AuNRs) and nanostars (AuNSs) to maximize energy transfer. These structures will be validated using both single particle and ensemble luminescence measurements. 2. Synthesis of thermally-responsive and photodegradable polymers and evaluation of their responsiveness to NIR irradiation of Au-UCNP clusters. The deposition of IR energy at the surface of the Au nanostructures will be employed to facilitate drug delivery by surface-grafted polymers via either Au surface heating or generation of singlet oxygen. These studies will be performed using polymers capable of conformational switching or oxidative depolymerization, respectively. 3. Synthesis of optimized Au-UCNP-polymer theranostics and validation in in vitro models. The imaging and therapeutic capabilities of the optimized theranostics will be tested against 4T1 cells grown in a 3D Matrigel substrate to mimic both the structure and heterogeneity of the tumor environment.