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

描述（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-各自用通过高复杂性病毒样颗粒（VLP）亲和选择技术鉴定的肽指导。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。相关性（参见说明）：这项研究的相关性是它对成功治疗约20%的ALL儿童的贡献，这些儿童在进入初始缓解后治疗失败或复发，并且生存率几乎为零。我们提出的研究的另一个价值将是开发通用的通用纳米颗粒平台，用于靶向，识别和治疗任意的，选择的，通常是微小的患病细胞群体。

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.