Luminscent Dendrimer-Lanthanide Nanotechnology for Multiplex Detection

描述（由申请人提供）：总体目标是将基于镧系元素检测的纳米技术与肿瘤靶向肽相结合，用于多重检测，以创新癌症检测领域，并促进对实体肿瘤的靶向递送。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的这种强调承认通过协作方法和技术融合可以对癌症诊断和治疗产生积极影响。该提案将导致1)基于纳米级树突支架可以解决和改进当前发光镧系元素报告器的局限性的原理，开发新型发光树突-镧系元素纳米技术；2)这种纳米级分子在癌症小鼠模型中用于多重检测的概念证明演示。通过合成具有肿瘤血管靶向肽外环的镧系配位PAMAM（聚酰胺胺）树突支架实现多重检测；导致携带镧系离子（Ln-PD）的肽-树突状分子。该方案将利用Ln-PD独特的发光特性（长寿命、独特的特征和尖锐的发射带），在自然生物自身荧光的背景下进行敏感和有区别的检测。通过创新地使用附着在PAMAM分支末端的敏化剂，镧系纳米分子的强发射信号成为可能；一种克服低量子产率的方法，通过增加激发光能的吸收并将其转移到几个位于内部的镧系元素。反过来，镧系元素发出强烈的、光谱上独特的信号。在体外表征和离体研究验证后，Ln-PD（通过肽RGD和RRL靶向肿瘤血管）将在鳞状细胞癌SCC SF/VII小鼠模型中的多重应用中被量化。该提案的成功完成将证明基于镧系元素的检测系统的功能性质，这可能通过改进在发光显微镜和生物分析中的应用来实现。因此，肿瘤及其微环境检测灵敏度的任何提高都会对临床医学的科学发现和改进能力产生积极的影响。

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.