Luminscent Dendrimer-Lanthanide Nanotechnology for Multiplex Detection

用于多重检测的发光树枝状大分子-镧系元素纳米技术

• 批准号: 7454837
• 负责人: STEPHANE PETOUD
• 金额: $ 18.28万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454837
• 关键词: Address; Affect; Animals; Behavior; Binding; Binding Sites; Biological; Biological Assay; Biological Models; Cancer Detection; Cations; Chemicals; Chemistry; Clinical Medicine; Color; Complex; Condition; Coupled; Data; Dendrimers; Detection; Development; Drops; Dyes; Energy Transfer; Environment; Exhibits; Fluorescence; Fluorescent Dyes; Freezing; Frozen Sections; Generations; Goals; Home environment; Image; In Vitro; Kinetics; Lanthanoid Series Elements; Life; Ligands; Light; Link; Literature; Location; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Measurement; Microscopy; Monitor; Mus; Nanotechnology; Nature; Noise; Numbers; Peptide Synthesis; Peptides; Personal Satisfaction; Photons; Property; Proteins; Protocols documentation; Public Health; RGD (sequence); Reaction; Reporter; Scheme; Serum; Signal Transduction; Site; Solid Neoplasm; Squamous cell carcinoma; Structure; System; Technology; Testing; Time; Tissue Sample; Tissues; Tumor Biology; Tumor Tissue; Whole Blood; absorption; base; cancer diagnosis; concept; design; improved; in vivo; innovation; instrumentation; interest; luminescence; mouse model; multiplex detection; nanoscale; novel; peptide P; quantum; research study; scaffold; size; small molecule; targeted delivery; technology development; tissue culture; tumor

DESCRIPTION (provided by applicant): The overarching goal is to merge lanthanide detection-based nanotechnology for multiplex detection with tumor-targeting peptides to innovate in the field of cancer detection and to facilitate targeted delivery to solid tumors. The development of this technology requires the merging of an understanding of tumor biology with nanotechnology chemistry, and is aligned with the focused nanotechnology initiative of the NCI. Such emphasis by the NCI acknowledges the positive impact on cancer diagnosis and treatment that can be gained through collaborative approaches and the merging of technologies. This proposal will result in 1) the development of novel luminescent dendrimer-lanthanide nanotechnology on the principle that the nanoscale size of a dendrimer scaffold can address and improve upon the limitations of current luminescent lanthanide reporters and 2) a proof of concept demonstration of the utility of such nanoscale molecules for multiplex detection in a mouse model of cancer. The multiplex detection will be realized through synthesizing lanthanide-coordinating PAMAM (polyamidoamine) dendrimer scaffolds with an outer ring of tumor vasculature-targeting peptides; resulting in peptide-dendrimer molecules carrying lanthanide cations (Ln-PD). This proposal will exploit the unique luminescent properties of Ln-PD (long life, unique signatures, and sharp emission bands) to allow sensitive and discriminating detection against the background of natural biologic autofluorescence. The strong emission signal of lanthanide-nanomolecules is possible through the innovative use of sensitizers attached to the branch termini of the PAMAM; an approach which overcomes low quantum yield by increasing the absorption of excitation light energy and transferring it to several internally located lanthanides. In turn, the lanthanides emit a strong and spectroscopically unique signal. After characterizing in vitro and verifying with ex vivo studies, the Ln-PD (targeted to the tumor vasculature by peptides RGD and RRL) will be quantified in a multiplex application in the SCC SF/VII mouse model of squamous cell cancer. Successful completion of the proposal will demonstrate the functional nature of lanthanide-based detection systems which may by realized through improved applications in luminescence microscopy and bioassays. Subsequently, any improvement in the sensitivity of detection of tumors and their microenvironments will positively impact the ability of scientific discovery and improvements in clinical medicine. PUBLIC HEALTH RELEVANCE This project aims to use nanotechnology of dendrimers to improve the detection of and delivery to cancers through the innovative use of chemistry to modify the dendrimers. Additionally, small proteins will be attached to the dendrimers to allow assay of ability of the dendrimers to home to tumor model systems.

描述（由申请人提供）：总体目标是将用于多重检测的基于镧系元素检测的纳米技术与肿瘤靶向肽合并，以在癌症检测领域进行创新并促进靶向递送至实体瘤。这项技术的发展需要将对肿瘤生物学的理解与纳米技术化学相结合，并与NCI的重点纳米技术倡议保持一致。NCI的这种强调承认了通过合作方法和技术融合可以对癌症诊断和治疗产生的积极影响。该提议将导致1）基于树枝状聚合物支架的纳米级尺寸可以解决和改善当前发光镧系元素报告物的局限性的原理开发新型发光树枝状聚合物-镧系元素纳米技术，以及2）证明这种纳米级分子用于小鼠癌症模型中的多重检测的实用性的概念证明。多重检测将通过合成镧系元素配位的PAMAM（聚酰胺胺）树状聚合物支架与肿瘤血管靶向肽的外环来实现;产生携带镧系元素阳离子（Ln-PD）的肽树状聚合物分子。该提案将利用Ln-PD的独特发光特性（长寿命，独特的签名和尖锐的发射带），以允许对天然生物自体荧光背景进行灵敏和有区别的检测。镧系元素纳米分子的强发射信号是可能的，通过创新性地使用敏化剂连接到PAMAM的分支末端;通过增加激发光能的吸收并将其转移到几个内部定位的镧系元素来克服低量子产率的方法。反过来，镧系元素发出强烈的光谱独特的信号。在体外表征并用离体研究验证后，将在鳞状细胞癌的SCC SF/VII小鼠模型中的多重应用中定量Ln-PD（通过肽RGD和RRL靶向肿瘤脉管系统）。该提案的成功完成将证明镧系元素为基础的检测系统的功能性质，这可能通过改进发光显微镜和生物测定中的应用实现。因此，肿瘤及其微环境检测灵敏度的任何提高都将对科学发现和临床医学改进的能力产生积极影响。 公共卫生相关性该项目旨在使用树枝状聚合物的纳米技术，通过创新使用化学修饰树枝状聚合物来改善癌症的检测和递送。此外，将小蛋白质连接到树枝状聚合物上，以允许测定树枝状聚合物归巢到肿瘤模型系统的能力。