EDAPT: Enzyme-Directed Assembly of Particle Theranostics

EDAPT：酶引导的粒子治疗诊断组装

• 批准号: 8188308
• 负责人: David J Hall
• 金额: $ 30.9万
• 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/8188308
• 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. PUBLIC HEALTH RELEVANCE: The ability to accurately target diseased tissue to diagnose and treat patients remains a key challenge. This proposal aims to develop agents that use enzymes generated in diseased tissues to assemble within the tissue, to serve as nanoscale indicators for imaging and for targeting toxic anticancer drugs. This is a novel approach with broad implications for programmed; "smart" theranostics for tackling as yet unsolved problems in the treatment of human disease.

描述（由申请人提供）：但是，关于特定疾病的分子特征及其在个性化医学中的潜力的知识库不断增加，但是，将此信息转化为临床应用的转换很大程度上落后了。为了弥合这一差距，寻求所谓的“疗法”材料，以将诊断和治疗剂结合在单个系统中。纳米材料为结合此类功能提供了强大的平台。实际上，针对在体内靶向输送和检测的纳米级车辆的强烈兴趣是基于这样的想法，即这种材料可以推断出其在小分子和其他货物上的药代动力学，生物利用度和靶向性能。因此，纳米级包装策略旨在减轻与许多其他临床上有效的化学治疗药物相关的剂量限制副作用，这些药物呈现出癌症治疗的主要障碍。此外，在避免非特异性积累的同时将诊断有效地靶向诊断，从而大大提高了体内成像应用中噪声的信号，从而导致更有效和准确的诊断。 生物学疾病载体的自然有效靶向和感染性能，特别是病毒，使它们成为设计和开发靶向药物递送的合成和半合成纳米级向量的努力。因此，研究集中在开发各种大小，降解性曲线，表面化学和材料构成的适当装饰的球形颗粒。最近，越来越多地合成复杂的纳米级结构的能力激发了对形状如何影响合成纳米级粒子与细胞及其在体内行为的相互作用的研究。这些递送载体的这些关键特性的有趣形状和大小依赖性激发了我们开发能够组装成纳米级物体的聚合物材料的建议，以响应特定疾病相关的生化刺激。这些材料试图结合正常组织中相对较低的分子量聚合物的血液循环和快速清除曲线，并在肿瘤组织中迅速积累和纳米材料的清除速率缓慢。这种方法利用智能聚合物材料的可切换，可转换的形态是针对目标诊断和治疗递送的新设计范式。因此，我们提出了一种能够在体内切换，编程的药代动力学和靶向剖面的新型材料的开发。我们旨在通过基于MRI的成像以及基于荧光的成像来研究对特定组织类型的差异吸收，以优化材料和体内分析。我们的长期目标是开发可编程刺激响应性的纳米材料来检测和治疗疾病。本文的目的是为纳米级对象的体内组装中的选择性属性开发一种具有可检测属性的方法。我们称这种方法为酶疗法的酶的组装-Edapt。 公共卫生相关性：准确靶向患病组织诊断和治疗患者的能力仍然是一个关键挑战。该提案旨在开发使用患病组织中产生的酶在组织内组装的剂，以作为成像和靶向有毒抗癌药物的纳米级指标。这是一种新颖的方法，对编程具有广泛的影响； “智能”治疗方法是解决人类疾病的尚未解决的问题。