A Multi-Purpose Nanovehicle for Targeted Boron Neutron Capture Cancer Therapy & I

描述(由申请者提供)：需要资金来开发一种纳米载体，这种载体可以很容易地进行改装，用于实体组织肿瘤的靶向治疗和成像。我们利用生物素和亲和素之间的强非共价相互作用来设计该平台及其应用。多用途纳米粒子(NP)由一个顺磁核心和一个连接有硫代聚乙二醇-生物素(PEG)的金涂层组装而成，以便于磁共振成像(MRI)。中性亲和素连接到聚乙二醇的生物素末端，为不同组合中的额外生物素化分子提供多价结合位点。纳米平台的靶向是通过针对肿瘤特异性生物标记物的单抗(MAb)实现的。组装的灵活性允许交换各种抗体和/或抗肿瘤治疗药物，而不需要为每种应用从头开始合成纳米载体。纳米载体可以根据肿瘤进展过程中抗体靶标丢失和/或对化疗的耐药性的活组织检查进行调整。该项目的大部分内容将在进入体内系统之前，在体外评估和优化这些生物偶联物。细胞摄取的特异性和水平将得到彻底验证。作为一个概念验证，我们开发了针对胰腺癌的硼中子俘获疗法(BNCT)的NP。我们为这些NPs的最终测试选择的体内模型是携带人肿瘤异种移植瘤的鸟绒毛膜尿囊膜(CAM)。作为这些活体研究的前奏，在韦尔斯利学院的微型核磁共振系统中，已经开发了一种携带我们的NPs的Quail Exovo CAM系统，用于磁共振成像。 与公共卫生相关：需要资金来开发一种多用途纳米载体，用于定向硼中子捕获治疗和癌症成像。当肿瘤变得具有化疗耐药性或靶向减弱时，轻松改变靶向抗体以及抗肿瘤治疗有效载荷的新颖性提供了个性化治疗。

DESCRIPTION (provided by applicant): Funds are requested to develop a nanovehicle that can be easily modified for the targeted treatment and imaging of solid tissue tumors. We have taken advantage of the strong non-covalent interaction between biotin and avidin to design the platform and its applications. The multi-purpose nanoparticles (NP) are assembled with a paramagnetic core to facilitate magnetic resonance imaging (MRI) and a gold coating to which thiolpoly(ethylene glycol)-biotin (PEG) is attached. Neutravidin is linked to the biotin terminus o the PEG to provide multivalent attachment sites for additional biotinylated molecules in different combinations. Targeting of the nanoplatform is achieved by monoclonal antibodies (mAb) directed against tumor-specific biomarkers. The flexibility of assembly allows for various antibodies and/or anti-tumor therapeutics to be exchanged without the need to synthesize the nanovehicle from scratch for each application. The nanovehicle can be adapted based upon biopsy assay for loss of antibody target and/or resistance to chemotherapy during tumor progression. The bulk of the project will be directed towards assessing and optimizing these bioconjugates in vitro before moving to an in vivo system. The specificity and level of cellular uptake will be thoroughly validated. As a proof-of-concept we have developed our NP to target pancreatic adenocarcinoma with boron neutron capture therapy (BNCT). The in vivo model we have selected for the eventual test of these NPs is the bird chorioallantoic membrane (CAM) carrying human tumor xenografts. As a prelude to these in vivo studies, a quail ex ovo CAM system carrying our NPs has been developed for MR imaging in the Wellesley College micro-MRI system. PUBLIC HEALTH RELEVANCE: Funds are requested to develop a multi-purpose nanovehicle for targeted boron neutron capture therapy and imaging of cancers. The novelty to easily change the targeting antibody as well as the anti-tumor therapeutic payload provides for personalized treatment when a tumor becomes chemo-resistant or targeting is diminished.