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

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的所有挑战，它将独特的基因组见解和著名的急性淋巴细胞白血病（ALL）临床专业知识与两种新的，强大而多功能的靶向纳米颗粒递送系统-原始细胞（纳米多孔纳米颗粒支持脂质双层）和病毒样颗粒-每一个都由高度复杂的病毒样颗粒（VLP）亲和选择技术鉴定的肽定向。它有望开发通用纳米载体平台，使治疗药物、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领域，我们提出的研究有三个独特的特点：1)由联合pi Cheryl Willman博士领导的新墨西哥大学癌症研究和治疗中心的儿科白血病项目率先使用基因组技术分析白血病表型基础的分子机制。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，这些蛋白质在高风险ALL患者的细胞上有差异表达。我们将利用这一新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化疗具有抗性的细胞群。2) David Peabody博士利用噬菌体MS2的病毒样颗粒（virus like particle, VLPs）构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衣壳的载货能力整合到一个单一的平台中。这种展示和亲和选择技术有潜力创建和评估比迄今为止使用的复杂数量级的文库，因此有潜力鉴定具有前所未有的靶向性和对任意细胞类型的递送选择性的肽。3)靶向肽将在原细胞和VLPs中实现。在美国国立卫生研究院纳米医学计划的支持下，最近在联合负责人Jeff Brinker博士的实验室里开发出来。正如肝癌细胞所证明的那样，这两类纳米载体通过在纳米尺度上设计的多价效应实现了异常高的选择性，但它们在表面迁移性、装载和释放策略方面是互补的。相关性（见说明）：这项研究的相关性在于它对成功治疗约20%的ALL儿童的贡献，这些儿童要么治疗失败，要么在进入初始缓解期后复发，生存率几乎为零。我们提出的研究的进一步价值将是开发通用的、通用的纳米颗粒平台，专门针对、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.