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Development of a gold nanoparticles based targeted delivery system

基于金纳米粒子的靶向递送系统的开发

基本信息

批准号：
8714936
负责人：
Priyabrata Mukherjee
金额：
$ 23.3万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714936
关键词：
Address Adenocarcinoma Adverse effects Antibodies Antineoplastic Agents Area Binding Biochemical Biodistribution Biological Biological Assay Biological Availability Biology Bioluminescence Bladder Breast CA-19-9 Antigen Cancer Etiology Cancer cell line Carcinoembryonic Antigen Cell Line Cells Cessation of life Chemicals Chemistry Color Cytotoxic agent Data Development Diagnostic Discipline Disease Dose Drug Kinetics Drug or chemical Tissue Distribution Drug usage Engineering Epidermal Growth Factor Receptor Equilibrium Exhibits Exocrine pancreas Experimental Designs Goals Gold Growth Human Immunohistochemistry In Vitro Lead Luciferases Magnetism Malignant Neoplasms Malignant neoplasm of pancreas Measures Medical Medicine Metabolism Metals Modeling Monitor Monoclonal Antibody C225 Mus Nanoconjugate Nanotechnology Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Optics Organ Ovarian Patients Pattern Pharmaceutical Preparations Plasma Play Process Property Radioisotopes Research Design Role Science Semiconductors Shapes Solubility Solutions Staging Surface System Techniques Technology Testing Therapeutic Toxic effect Treatment Efficacy Tumor Volume Tumor Weights United States Validation Viola Whole Blood Withdrawal Xenograft Model advanced disease aqueous base biomaterial compatibility cancer cell design drug efficacy effective therapy gemcitabine improved in vitro testing in vivo mouse model multidisciplinary nanofabrication nanoparticle nanoscale neoplastic cell overexpression pancreatic cancer cells pancreatic neoplasm pre-clinical quantum red wine research study targeted delivery tumor tumor growth tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Targeted delivery of a drug should result in enhanced therapeutic efficacy with low to minimal side effects. This is a widely accepted concept, but limited in application due to lack of available technologies and process of validation. Biomedical nanotechnology can play an important role in this aspect. Biomedical nanotechnology is a burgeoning field and brings with it a myriad of opportunities and possibilities for advancing medical science and disease treatment. It is a multidisciplinary field cutting across the disciplines of biology, chemistry, materials science, engineering and medicine. At the nano scale, the physico-chemical, and biological properties of materials (metals, semiconductors, etc) differ fundamentally from their corresponding bulk counter part because of the quantum size effect e.g. gold nanoparticles (AuNPs) have wine red color whereas metallic gold is golden yellow and this wine red color can be tuned to either pink, or violet or blue by simply controlling the size and shape of AuNPs. Furthermore, nanoparticles also have large surface area to load multiple diagnostic (such as optical, radioisotope, magnetic) and therapeutic (such as drugs). In this application we want to exploit the unique properties of nanoparticles to create a targeted delivery system that will show better therapeutic efficacy with minimal to no side effects. The long-term goal of this project is to develop a nanoparticle-based delivery system for targeted delivery of cytotoxic drug with enhanced efficacy and reduced systemic toxicity. Our preliminary studies demonstrated that targeted delivery of a low dose of gemcitabine (Gem) as a gold nanoconjugate using anti-EGFR antibody (C225) as a targeting agent resulted in enhanced efficacy of the drug to inhibit the tumor growth in an orthotopic human xenograft model of pancreatic cancer. These results encouraged us to study, in depth, the nanofabrication process to improve the efficacy further and delineate the mechanism of enhanced drug activity. Therefore, our proposed studies center on gold nanoparticles (AuNPs) as a delivery vehicle, Gem as a cytotoxic drug and C225 as a targeting agent bound to the same gold core in a "2 in 1" fashion. The efficacy of nanofabrication will be tested in vitro first by determining the activity of the nanoconjugates against primary (PANC-1, MiaPaca2) and metastatic (AsPC-1) human pancreatic cancer cell lines. Therefore, studying efficacy in these models will allow us to determine the application of these systems in a wide range of disease condition (e.g. primary vs. metastatic disease, early stage vs. late stage of the disease). These cells also differ by EGFR expression pattern, cells with higher expression (PANC-1 and AsPC-1) will uptake more of the nanoconjugates than MiaPaca2 (with low EGFR expression). In vivo efficacy will then be tested in a preclinical mouse model of pancreatic cancer. The aims proposed in this study are designed to (i) optimize the nanofabrication process for targeted delivery in vitro and in vivo, (ii) to determine the pharmacokinetics, biodistribution and toxicity of the nanoconjugates in targeted vs. non-targeted delivery and (ii) to determine the therapeutic efficacy of the nanoconjugates to inhibit tumor growth, metastasis and increasing survival in targeted vs. non-targeted delivery. Pancreatic cancer is the 4th leading cause of cancer deaths in United States. Currently, surgery is the only option, however, due to late presentation only 10-15 % of the patients are amenable to surgery. The significance of this application is that it will study both targeted and non-targeted delivery of anti-cancer drugs using a nanodelivery system against pancreatic cancer where no effective therapy is currently available. Such a delivery in targeted fashion will enhance the efficacy of the drug with minimal side effects. According to our hypothesis, gemcitabine will have reduced systemic toxicity with better efficacy when delivered in a targeted fashion as a gold nanoconjugates. This application will also address a number of issues to obtain an optimized delivery vehicle such as loading of targeting agent and drug to a nanoparticle, bioavailability of the drug, biocompatibility and toxicity of gold nanoparticles and nanoconjugates. For those patients where the antibody is unsuccessful in targeting all the pancreatic tumor cells or patients that do not express EGFR, we may use other targets such as carcinoembryonic antigen (CEM) or carbohydrate antigen 19-9 (CA-19-9) or need to further identify other targeting molecules and expand our "proof of concept" experiments. Importantly, as we have already discussed that EGFR is overexpressed in a number of other cancers such as CRC, NHSC, NSCLC and gemcitabine is also used in other malignancies such as NSCLC, bladder, breast, therefore, this strategy could be used not only for the treatment of pancreatic cancers but also as a generalized approach in the treatment of a number of other malignancies such as CRC, NHLC, NSCLC, breast, ovarian, etc.

描述（由申报人提供）：靶向给药应提高治疗效果，副作用低至最小。这是一个被广泛接受的概念，但由于缺乏可用的技术和验证过程，在应用中受到限制。生物医学纳米技术可以在这方面发挥重要作用。生物医学纳米技术是一个新兴的领域，它为推进医学科学和疾病治疗带来了无数的机会和可能性。它是一个多学科领域，横跨生物学、化学、材料科学、工程学和医学等学科。在纳米尺度上，由于量子尺寸效应，材料（金属、半导体等）的物理化学和生物特性与它们相应的体积对应部分有根本的不同，例如，金纳米粒子（AuNPs）具有酒红色，而金属金是金黄色的，这种酒红色可以通过简单地控制AuNPs的大小和形状来调整为粉红色、紫色或蓝色。此外，纳米粒子还具有较大的表面积，可以装载多种诊断（如光学、放射性同位素、磁性）和治疗（如药物）。在这个应用中，我们希望利用纳米颗粒的独特特性来创建一个靶向递送系统，该系统将显示出更好的治疗效果，并且几乎没有副作用。该项目的长期目标是开发一种基于纳米颗粒的细胞毒性药物靶向递送系统，提高疗效并降低全身毒性。我们的初步研究表明，靶向递送低剂量吉西他滨（Gem）作为金纳米偶联物，使用抗egfr抗体（C225）作为靶向剂，可增强药物抑制胰腺癌原位人异种移植模型肿瘤生长的功效。这些结果鼓励我们深入研究纳米加工工艺以进一步提高药效，并描述增强药物活性的机制。因此，我们提出的研究重点是金纳米颗粒（AuNPs）作为递送载体，Gem作为细胞毒性药物，C225作为靶向剂以“二合一”的方式结合到同一个金核上。纳米合成的有效性将首先通过测定纳米偶联物对原发（PANC-1, MiaPaca2）和转移（AsPC-1）人胰腺癌细胞系的活性来进行体外测试。因此，研究这些模型的疗效将使我们能够确定这些系统在广泛疾病状况中的应用（例如原发性疾病与转移性疾病，疾病早期与晚期）。这些细胞也因EGFR表达模式而不同，表达较高的细胞（PANC-1和AsPC-1）比低EGFR表达的MiaPaca2摄取更多的纳米偶联物。体内疗效将在胰腺癌的临床前小鼠模型中进行测试。本研究的目的是：(1)优化体外和体内靶向递送的纳米制造工艺，(2)确定纳米偶联物在靶向递送和非靶向递送中的药代动力学、生物分布和毒性，(2)确定纳米偶联物在靶向递送和非靶向递送中抑制肿瘤生长、转移和提高生存率的治疗效果。胰腺癌是美国癌症死亡的第四大原因。目前，手术是唯一的选择，然而，由于出现较晚，只有10- 15%的患者适合手术。这项应用的意义在于，它将研究靶向和非靶向抗癌药物的递送，使用纳米递送系统来治疗胰腺癌，目前没有有效的治疗方法。这种有针对性的递送方式将以最小的副作用提高药物的疗效。根据我们的假设，吉西他滨作为金纳米缀合物以靶向方式递送时，将降低全身毒性并具有更好的疗效。该应用程序还将解决许多问题，以获得优化的递送载体，如靶向剂和药物装载到纳米颗粒上，药物的生物利用度，金纳米颗粒和纳米缀合物的生物相容性和毒性。对于那些抗体不能靶向所有胰腺肿瘤细胞或不表达EGFR的患者，我们可能会使用其他靶点，如癌胚抗原（CEM）或碳水化合物抗原19-9 (CA-19-9)，或者需要进一步确定其他靶向分子，扩大我们的“概念验证”实验。重要的是，正如我们已经讨论过的，EGFR在许多其他癌症中过表达，如CRC、NHSC、NSCLC和吉西他滨也用于其他恶性肿瘤，如NSCLC、膀胱癌、乳腺癌，因此，该策略不仅可用于治疗胰腺癌，还可作为治疗许多其他恶性肿瘤的通用方法，如CRC、NHLC、NSCLC、乳腺癌、卵巢癌等。