EDAPT: Enzyme-Directed Assembly of Particle Theranostics

EDAPT：酶引导的粒子治疗诊断组装

• 批准号: 8324572
• 负责人: David J Hall
• 金额: $ 32.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324572
• 关键词: Adverse effects; Affect; Antineoplastic Agents; Behavior; Benign; Biochemical; Biological; Biological Availability; Biological Process; Blood; Blood Circulation; Cells; Characteristics; Chemistry; Clinical; Complement; Complex; Constitution; Contrast Media; Dependence; Detection; Development; Device or Instrument Development; Diagnosis; Diagnostic; Disease; Disease Vectors; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Enzymes; Fluorescence; Fluorescence Microscopy; Fluorescence Resonance Energy Transfer; Goals; Histocompatibility Testing; Histologic; Home environment; Human; Image; Imagery; Imaging Techniques; In Situ; In Vitro; Investigation; Lead; Life; Lung nodule; Magnetic Resonance Imaging; Magnetism; Malignant - descriptor; Measurement; Medicine; Metabolic; Metabolic Clearance Rate; Modeling; Molecular; Molecular Profiling; Molecular Weight; Monitor; Morphology; Mus; Nanostructures; Noise; Normal tissue morphology; Organism; Outcome; Patients; Pharmaceutical Preparations; Polymers; Positron-Emission Tomography; Process; Property; Research; Reticuloendothelial System; Shapes; Signal Transduction; Site; Specificity; Stimulus; Stream; Structure; Surface; System; Therapeutic; Therapeutic Agents; Tissues; Translations; Tumor Tissue; Tumor-Associated Process; Virus; antiangiogenesis therapy; base; cancer therapy; clinical application; clinical practice; design; human disease; improved; in vivo; interest; knowledge base; lymph nodes; molecular imaging; nanomaterials; nanoparticle; nanoscale; novel; novel strategies; particle; prognostic; programs; response; small molecule; targeted delivery; theranostics; therapeutic angiogenesis; tumor; uptake; vector

DESCRIPTION (provided by applicant): There is an ever-increasing knowledgebase concerning the molecular signatures of specific diseases and their potential in personalized medicine, however, the translation of this information into clinical applications lags significantly behind. To bridge this gap, so-called "theranostic" materials are sought after to combine diagnostic and therapeutic agents within single systems. Nanomaterials provide a powerful platform for combining such functions. Indeed, the intense interest in nanoscale vehicles designed for targeted delivery and detection in vivo is predicated on the idea that such materials may infer their pharmacokinetic, bioavailability and targeting properties on small molecules and other cargo. Therefore, nanoscale packaging strategies aim to alleviate dose-limiting side effects associated with many otherwise clinically effective chemotherapeutic drugs presenting a major hurdle in the treatment of cancer. In addition, targeting diagnostics efficiently and selectively to given tissues while avoiding non-specific accumulation greatly enhances signal to noise in vivo imaging applications leading to more effective and accurate diagnoses. The naturally efficient targeting and infectious properties of biological disease vectors, in particular viruses, has made them models in efforts to design and develop synthetic and semi synthetic nanoscale vectors for targeted drug delivery. Therefore, research has focused on the development of appropriately decorated spherical particles of various sizes, degradability profiles, surface chemistry and material constitution. More recently, an increasing ability to synthesize complex nanoscale structures has inspired investigations into how shape can affect synthetic nanoscale particle interactions with cells and their behavior in vivo. The intriguing shape and size dependence of these key properties of delivery vectors inspires our proposal to develop polymeric materials capable of assembling into nanoscale objects in response to specific disease associated biochemical stimuli. These materials seek to combine the blood circulation and rapid clearance profiles of relatively low molecular weight polymers from normal tissues, with rapid accumulation and slow clearance rates of nanomaterials in tumor tissue. This approach utilizing switchable, transformable morphologies of smart polymeric materials is proposed as a new design paradigm in targeted diagnostic and therapeutic delivery. Therefore, we propose the development of a novel class of materials capable of switchable, programmed pharmacokinetic and targeting profiles in vivo. We aim to study differential uptake into particular tissue types via MRI-based imaging together with fluorescence-based imaging for materials optimization and in vivo analysis. Our long-term goal is to develop programmable stimuli-responsive nanomaterials for detecting and treating disease. The objective herein is to develop an approach for the selective in vivo assembly of nanoscale objects with detectable properties unique to the assemblies; we term this approach Enzyme- directed Assembly of Particle Theranostics - EDAPT.

描述（由申请人提供）：关于特定疾病的分子特征及其在个性化医疗中的潜力的知识库不断增加，然而，将这些信息转化为临床应用却明显滞后。为了弥补这一差距，人们寻求所谓的“治疗诊断”材料，将诊断剂和治疗剂结合在单个系统中。纳米材料为结合这些功能提供了一个强大的平台。事实上，人们对设计用于体内靶向递送和检测的纳米级载体的浓厚兴趣是基于这样的想法：此类材料可以推断其药代动力学、生物利用度以及对小分子和其他货物的靶向特性。因此，纳米级包装策略旨在减轻与许多其他临床有效化疗药物相关的剂量限制副作用，这是癌症治疗的主要障碍。此外，有效、选择性地针对给定组织进行诊断，同时避免非特异性积累，大大增强了体内成像应用的信噪比，从而实现更有效、更准确的诊断。 生物疾病载体（特别是病毒）的自然有效靶向和感染特性，使其成为设计和开发用于靶向药物递送的合成和半合成纳米级载体的模型。因此，研究重点是开发各种尺寸、可降解性、表面化学和材料构成的适当装饰的球形颗粒。最近，合成复杂纳米级结构的能力不断增强，激发了人们对形状如何影响合成纳米级颗粒与细胞的相互作用及其体内行为的研究。递送载体的这些关键特性的有趣的形状和尺寸依赖性激发了我们的提议，即开发能够组装成纳米级物体以响应特定疾病相关生化刺激的聚合物材料。这些材料试图将正常组织中相对低分子量聚合物的血液循环和快速清除特性与肿瘤组织中纳米材料的快速积累和缓慢清除率结合起来。这种利用智能聚合物材料的可切换、可变形形态的方法被提议作为靶向诊断和治疗递送的新设计范例。因此，我们建议开发一类新型材料，能够在体内切换、编程药代动力学和靶向特性。我们的目标是通过基于 MRI 的成像和基于荧光的成像来研究特定组织类型的差异吸收，以进行材料优化和体内分析。我们的长期目标是开发用于检测和治疗疾病的可编程刺激响应纳米材料。本文的目的是开发一种选择性体内组装纳米级物体的方法，该物体具有组装体独有的可检测特性；我们将这种方法称为酶引导的粒子治疗组装方法 - EDAPT。