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Peptide-directed protocells and virus-like particles-new nanoparticle platforms f

肽导向的原始细胞和病毒样颗粒——新的纳米颗粒平台

基本信息

批准号：
8320745
负责人：
C Jeffrey Brinker
金额：
$ 35.31万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320745
关键词：
Acute Lymphocytic Leukemia Address Adverse effects Affinity Amino Acid Sequence Animal Model Antibody Formation Apoptosis Binding Biochemical Biodistribution Biological Biological Assay CCNE1 gene Cancer Center Capsid Capsid Proteins Carrying Capacities Cell Culture Techniques Cell Line Cell Surface Receptors Cell Survival Cells Characteristics Chemistry Child Childhood Childhood Acute Lymphocytic Leukemia Clinical Collaborations Complex Confocal Microscopy Contrast Media Coupled Couples Development Disease remission Dissociation Doctor of Philosophy Doxorubicin Drug Carriers Drug Delivery Systems Drug Kinetics Encapsulated Engineering Engraftment Enterobacteria phage MS2 Enzyme-Linked Immunosorbent Assay Epitopes Evaluation Family Feedback Flow Cytometry Fluorescence Generic Drugs Genetic Transcription Genomics Goals HIV Hour Image Immune response Immunoglobulin G In Vitro Instruction Laboratories Libraries Ligands Lipid Bilayers Lipids Malignant Neoplasms Measures Methods Modeling Modification Molecular Analysis Mus Nanotechnology Nucleosome Core Particle Organelles Oxidative Stress Participant Patients Pattern Peptide Library Peptides Phage Display Pharmaceutical Preparations Phase Phenotype Physical condensation Physiological Population Postdoctoral Fellow Principal Investigator Production Property Proteins RNA Sequences Relapse Research Resistance Resources SCID Mice Sampling Scheme Schools Serum Proteins Silicon Dioxide Sodium Chloride Students Surface Survival Rate System Techniques Technology Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Training Transgenes Translations Virus-like particle Xenograft Model anticancer research base cancer cell cancer therapy cell type cellular engineering chemotherapeutic agent chemotherapy cytotoxicity density design extracellular fluidity high risk in vivo innovation insight interest leukemia member nanocarrier nanomedicine nanoparticle nanoscale nanotoxicity nanotoxicology novel particle prevent programs protein aminoacid sequence receptor research study sensor targeted delivery trafficking treatment center uptake

项目摘要

Our proposed research addresses the full spectrum of challenges underlying nanocarriers as targeted delivery platforms for cancer therapy, it couples unique genomic insight and renowned clinical expertise on Acute Lymphoblastic Leukemia (ALL) with two new, powerful and versatile targeted nanoparticle delivery systems - protocells (nanoporous nanoparticle supported lipid bilayers) and virus-like particles - each directed with peptides identified by a high complexity virus-like particle (VLP) affinity selection technology. It promises the development of universal nanocarrier platforms enabling the delivery of therapeutics, imaging and contrast agents, sensors, etc. to arbitrary cancer cells with unprecedented selectivity and minimal side effects. Within the highly populated field of targeted drug delivery using nanocarriers, our proposed research is distinguished by three unique attributes: 1) The Pediatric Leukemia Program in the UNM Cancer Research and Treatment Center led by co-PI Cheryl Willman, MD, has pioneered the use of genomic technology in the analysis of the molecular mechanisms that underlie the leukemic phenotype. As part of this effort, her team has identified a number of proteins with extracellular epitopes that are differentially expressed on cells from high risk ALL patients. We will use this novel genomic information as the basis of the development of nanoparticles that specifically target a population of cells generally found to be resistant to standard intense chemotherapies. 2) Using virus like particles (VLPs) of bacteriophage MS2, David Peabody, PhD, created a new peptide display system, which integrates into a single platform the affinity selection capability of conventional filamentous phage display and the cargo carrying capacity of the hollow MS2 capsid. This display and affinity selection technology has the potential to create and evaluate libraries with complexities orders of magnitude greater than those used to date and therefore the potential to identify peptides with unprecedented targeting and delivery selectivities to arbitrary cell types. 3) Targeting peptides will be Implemented In protocells and VLPs. recently developed within the laboratory of co-PI, Jeff Brinker, PhD, through support by the NIIH Nanomedicine initiative. As demonstrated for hepatocarcinoma cells, both classes of nanocarriers achieve exceptionally high selectivity through multivalency effects engineered at the nanoscale, but they are complementary with respect to surface mobility, loading and release strategies.

我们提出的研究解决了纳米载体作为癌症治疗靶向递送平台的全部挑战，它将独特的基因组见解和着名的急性淋巴细胞白血病（ALL）临床专业知识与两个新的，强大的和通用的靶向纳米粒子输送系统-原始细胞（纳米多孔纳米颗粒支撑的脂质双层）和病毒样颗粒-各自用由高复杂性病毒样颗粒（VLP）鉴定的肽引导亲和选择技术它承诺开发通用纳米载体平台，使治疗剂、成像和造影剂、传感器等能够以前所未有的选择性和最小的副作用递送到任意癌细胞。在使用纳米载体的靶向药物递送的高度流行的领域内，我们提出的研究具有三个独特的属性：1）UNM癌症研究和治疗中心的儿科白血病项目由共同PI Cheryl Willman领导，医学博士开创了使用基因组技术分析白血病表型的分子机制。作为这项工作的一部分，她的团队已经确定了一些具有细胞外表位的蛋白质，这些蛋白质在高危ALL患者的细胞上差异表达。我们将使用这种新的基因组信息作为开发纳米颗粒的基础，这些纳米颗粒特异性靶向通常被发现对标准强化疗有抗性的细胞群体。2)利用噬菌体MS 2的病毒样颗粒（VLP），大卫皮博迪博士创建了一种新的肽展示系统，其将常规丝状噬菌体展示的亲和选择能力和中空MS 2衣壳的货物携带能力整合到单个平台中。这种展示和亲和选择技术具有创建和评估文库的潜力，其复杂性比迄今为止使用的文库大几个数量级，因此具有鉴定对任意细胞类型具有前所未有的靶向和递送选择性的肽的潜力。3)靶向肽将在原始细胞和VLP中实施。最近在共同PI实验室内开发，Jeff Brinker博士，通过NIIH纳米医学倡议的支持。如肝癌细胞所示，这两类纳米载体通过在纳米级设计的多价效应实现了极高的选择性，但它们在表面流动性、装载和释放策略方面是互补的。