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

• 批准号: 8444590
• 负责人: Priyabrata Mukherjee
• 金额: $ 4.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-06-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444590
• 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; Health; 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

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（由申请人提供）：靶向递送药物应提高治疗功效，并低至最小的副作用。这是一个广泛接受的概念，但由于缺乏可用技术和验证过程，因此应用程序的应用有限。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，并带来了无数的机遇和可能性来推进医学和疾病治疗。这是一个多学科的领域，跨越了生物学，化学，材料科学，工程和医学的学科。在纳米尺度上，材料的物理化学和生物学特性（金属，半导体等）与相应的体积计数器部分有所不同，因为量子大小效应，例如金纳米颗粒（Aunps）具有红色，而金属金为金黄色，并且可以通过简单地控制Aunps的尺寸和形状来调节粉红色，紫罗兰色或蓝色。此外，纳米颗粒还具有较大的表面积，可以加载多个诊断（例如光学，放射性同位素，磁性）和治疗性（例如药物）。在此应用程序中，我们希望利用纳米颗粒的独特属性来创建一个目标的输送系统，该系统将显示出更好的治疗功效，而无副作用最小。该项目的长期目标是开发一种基于纳米颗粒的输送系统，用于靶向递送细胞毒性药物，具有增强的疗效和降低的全身毒性。我们的初步研究表明，使用抗EGFR抗体（C225）作为靶向剂作为靶向剂，将低剂量的吉西他滨（GEM）作为金纳米偶联物作为靶向剂，从而增强了药物抑制肿瘤生长在正素人Xenerograft模型中的肿瘤生长胰腺癌。这些结果鼓励我们深入研究进一步提高疗效并描述增强药物活性机制的纳米制作过程。因此，我们提出的研究中心以金纳米颗粒（AUNP）为中心，作为递送工具，将GEM作为细胞毒性药物，C225作为靶向剂，以“ 2中的2中”方式结合到同一金芯。纳米化的功效将在体外首先通过确定纳米偶联物对原代（PANC-1，MIAPACA2）和转移性（ASPC-1）人胰腺癌细胞系的活性进行测试。因此，在这些模型中研究疗效将使我们能够确定这些系统在多种疾病状况中的应用（例如，原发性疾病与转移性疾病，早期阶段与疾病的后期）。这些细胞也因EGFR表达模式而有所不同，具有较高表达（PANC-1和ASPC-1）的细胞将与MIAPACA2（EGFR表达较低）相比，吸收更多的纳米缀合物。然后将在胰腺癌的临床前小鼠模型中测试体内功效。本研究中提出的目的旨在（i）优化靶向递送体外和体内的纳米化过程，（ii）确定靶向纳米偶联物的药代动力学，生物分布和毒性和靶向非目标递送和II（ii） ）确定纳米偶联物的治疗功效以抑制肿瘤生长，转移和靶向非靶向递送的生存率增加。胰腺癌是美国癌症死亡的第四个主要原因。目前，手术是唯一的选择，但是，由于迟到的出现，只有10-15％的患者可以接受手术。该应用的重要性在于，它将使用针对胰腺癌的纳米传递系统研究靶向和非目标的抗癌药物，目前尚无有效的治疗。这种以有针对性的方式递送将增强药物的功效，并具有最小的副作用。根据我们的假设，吉西他滨将以目标方式作为金纳米偶联物降低系统毒性，以更好的效力。该应用还将解决许多问题，以获取优化的输送工具，例如将靶向剂和药物加载到纳米颗粒上，药物的生物利用度，金纳米颗粒和纳米轭物的生物相容性和毒性。对于那些抗体在靶向所有胰腺肿瘤细胞或未表达EGFR的患者方面不成功的患者，我们可能会使用其他靶标，例如癌细胞胚抗原（CEM）或碳水化合物抗原19-9（CA-19-9），或者需要进一步识别其他靶向分子并扩大我们的“概念证明”实验。重要的是，正如我们已经讨论过的那样，EGFR在其他许多癌症（例如CRC，NHSC，NSCLC和Gemcitabine）中过表达胰腺癌的治疗，但也是一种在治疗许多其他恶性肿瘤（例如CRC，NHLC，NSCLC，NSCLC，乳房，卵巢）方面的普遍方法。