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

用于增强治疗诊断学中近红外能量转移过程的生物分子定向组装

• 批准号: 9090086
• 负责人: Jennifer N Cha
• 金额: $ 17.21万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090086
• 关键词: 4T1; Adverse effects; Area; Biological Assay; Blood Circulation; Cells; Clinic; Complex; Deposition; Drug Delivery Systems; Dyes; Electron Microscopy; Energy Transfer; Energy-Generating Resources; Ensure; Environment; Evaluation; Future; Generations; Goals; Gold; Harvest; Health; Heating; Heterogeneity; Hybrids; Image; Knowledge; Label; Lead; Light; Luminescent Measurements; Malignant Neoplasms; Measurement; Measures; Methods; Morphology; Nanostructures; Output; Patients; Pharmaceutical Preparations; Phase Transition; Physiologic pulse; Polymers; Positioning Attribute; Process; Production; Reaction; Research; Singlet Oxygen; Site; Skin; Solid Neoplasm; Source; Stimulus; Structure; Sulfones; Surface; System; Techniques; Technology; Temperature; Testing; Theoretical Studies; Therapeutic; Tissues; Translations; Treatment Efficacy; Validation; Visible Radiation; absorption; anticancer research; cancer imaging; cancer therapy; cancer type; contrast imaging; depolymerization; design; in vitro Model; irradiation; luminescence; macromolecule; matrigel; nanoparticle; nanorod; nanoscale; particle; poly-N-isopropylacrylamide; response; theranostics; tumor; tumor heterogeneity

 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.

 描述（由申请人提供）：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，以获得用于实体瘤令人兴奋的区域的成像和治疗的理想治疗诊断学。​癌症研究，因为它们允许对肿瘤环境进行无创跟踪治疗，然后释放肿瘤特异性的 650-1000 nm 的“组织透明窗口”光。然而，大多数红外诱导成像和治疗仅需要浅表部位的光通量，因此无法应用于许多其他癌症。纳米级组装和大分子，用于合理设计利用近红外的纳米结构。所提出的治疗诊断将产生可见图像对比度或药物释放，具体取决于辐照强度。所提出的纳米结构将由各向异性金纳米结构组成。为了实现近红外最大吸收，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聚合物涂层，能够在非浅层深度执行这些功能的纳米结构需要对两者有基本的了解。金表面发生的能量转移过程以及收集该能量的机制将通过以下方式完成： 1. 精确 Au-UCNP 纳米结构的合成和表征。最近的理论研究表明，如果粒子被正确组装，局部场增强可以将上转换发光输出增强几个数量级。生物分子组装技术将用于将 UCNP 定位在各向异性金纳米棒 (AuNR) 和纳米星的尖端。 AuNSs）以最大化能量转移。这些结构将使用单粒子和整体发光测量进行验证。2.热响应和光降解聚合物的合成和评估。红外能量在 Au 纳米结构表面的沉积将用于通过 Au 表面加热或单线态氧的产生来促进表面接枝聚合物的药物输送。分别使用能够构象转换或氧化解聚的聚合物进行。 3. 优化的 Au-UCNP-聚合物治疗诊断的合成和体外模型的验证。将针对在 3D Matrigel 基质中生长的 4T1 细胞来测试优化的治疗诊断的功能，以模拟肿瘤环境的结构和异质性。