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：
8138640
负责人：
C Jeffrey Brinker
金额：
$ 37.17万
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/8138640
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 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 Production Property Proteins RNA Sequences Relapse Research Resistance Resources SCID Mice Sampling Schools Serum Proteins Silicon Dioxide Sodium Chloride Specificity 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 biomaterial compatibility cancer cell cancer therapy cell type cellular engineering chemotherapeutic agent chemotherapy cytotoxicity density design extracellular fluidity high risk in vivo innovation insight interest killings leukemia malignant lymphocyte member nanocarrier nanomedicine nanoparticle nanoscale nanotoxicity nanotoxicology novel particle prevent programs protein aminoacid sequence receptor research study sensor targeted delivery treatment center uptake

项目摘要

DESCRIPTION (provided by applicant): 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. RELEVANCE (See instructions): The relevance of this research is its contribution to the successful treatment of the ~20% of ALL children who either fail therapy or relapse after entering an Initial remission and who have nearly a zero rate of survival. A further value of our proposed research will be the development of generic, universal nanoparticle platforms tailored to target, identify, and treat arbitrary, select, and often minute populations of diseased cells.

描述（由申请人提供）：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所面临的全方位挑战，它将独特的基因组见解和急性淋巴细胞白血病（ALL）的著名临床专业知识与两种新的、强大的、多功能的靶向药物结合起来纳米颗粒递送系统 - 原始细胞（纳米孔纳米颗粒支持的脂质双层）和病毒样颗粒 - 每个系统都以通过高复杂性病毒样颗粒 (VLP) 亲和选择技术鉴定的肽为导向。它有望开发通用纳米载体平台，能够以前所未有的选择性和最小的副作用向任意癌细胞输送治疗剂、成像剂和造影剂、传感器等。在使用纳米载体的靶向药物输送这一人口密集的领域中，我们提出的研究具有三个独特的属性：1) 由联合 PI Cheryl Willman 医学博士领导的新墨西哥大学癌症研究和治疗中心的儿童白血病项目率先使用了纳米载体基因组技术在分析白血病表型的分子机制中的应用。作为这项工作的一部分，她的团队已经鉴定出许多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。我们将利用这种新颖的基因组信息作为纳米颗粒开发的基础，这些纳米颗粒专门针对通常被发现对标准强效化疗有抵抗力的细胞群。 2）利用噬菌体MS2的病毒样颗粒（VLP），David Peabody博士创建了一种新的肽展示系统，该系统将传统丝状噬菌体展示的亲和选择能力和中空MS2衣壳的货物承载能力集成到单个平台中。这种展示和亲和选择技术有可能创建和评估其复杂性比迄今为止使用的文库高出几个数量级的潜力，因此有可能识别对任意细胞类型具有前所未有的靶向和递送选择性的肽。 3) 靶向肽将在原始细胞和VLP中实现。最近在 NIIH 纳米医学计划的支持下，由联合 PI Jeff Brinker 博士的实验室开发。正如肝癌细胞所证明的那样，这两类纳米载体通过纳米级设计的多价效应实现了极高的选择性，但它们在表面迁移率、负载和释放策略方面是互补的。相关性（参见说明）：这项研究的相关性在于它对约 20% 的 ALL 儿童的成功治疗做出了贡献，这些儿童要么治疗失败，要么在进入初始缓解后复发，且生存率几乎为零。我们提出的研究的另一个价值将是开发通用的、通用的纳米颗粒平台，用于靶向、识别和治疗任意的、选择性的、通常是微小的患病细胞群。