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

描述(申请人提供)：我们拟议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，它将独特的基因组学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型、强大和多功能的靶向纳米颗粒递送系统相结合--原细胞(纳米多孔纳米颗粒支撑的脂质双层)和病毒样颗粒--每个系统都直接与由高复杂性病毒样颗粒(VLP)亲和选择技术鉴定的多肽相结合。它承诺开发通用的纳米载体平台，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输送到任意的癌细胞。在人口稠密的纳米载体靶向药物输送领域，我们建议的研究有三个独特的特点：1)由医学博士谢丽尔·威尔曼共同领导的新墨西哥州大学癌症研究和治疗中心的儿科白血病计划率先使用基因组技术分析白血病表型背后的分子机制。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患者的细胞上有差异表达。我们将利用这一新的基因组信息作为开发纳米颗粒的基础，该纳米颗粒专门针对通常发现对标准强度化疗具有耐药性的细胞群体。2)利用MS2噬菌体的病毒样颗粒(VLP)，David Peabody博士创建了一种新的多肽展示系统，该系统将传统丝状噬菌体展示的亲和力选择能力和MS2中空衣壳的载货能力结合在一起。这种展示和亲和选择技术有可能创建和评估比目前使用的复杂程度更大的文库，因此有可能识别具有前所未有的靶向性和递送到任意细胞类型的选择性的多肽。3)靶向多肽将在原细胞和VLP中实现。最近在NIIH纳米医学倡议的支持下，由合作者Jeff Brinker博士的实验室开发。正如对肝癌细胞所展示的那样，这两类纳米载体都通过在纳米尺度上设计的多价效应实现了非常高的选择性，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(见说明)：这项研究的相关性在于它对治疗失败或进入初始缓解后复发且存活率几乎为零的所有儿童的成功治疗做出了贡献。我们提议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，该平台专为靶向、识别和治疗任意的、选择的、通常是微小的疾病细胞群体而定制。

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.