An Integrated Nano-Cell Delivery Platform of Theranostics for Lung Cancers

肺癌治疗诊断的集成纳米细胞递送平台

基本信息

批准号：
8250460
负责人：
SUBHRA MOHAPATRA
金额：
$ 29.59万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250460
关键词：
Accounting Adenocarcinoma Cell Affect Alveolar Animals Antibodies Atrial Natriuretic Factor Atrial Natriuretic Factor Receptors Attenuated Biocompatible Blood Circulation Blood capillaries Breeding Bronchi Cancer Cell Growth Cancer Patient Cancer Remission Carcinoma Cell Line Cell surface Cells Cessation of life Chemistry Chitosan Clara cell Clinical Trials Collaborations Colon Carcinoma Complex Curcumin DNA Death Rate Detection Diagnosis Diagnostic Disease Dose Doxycycline Drug Delivery Systems Dyes Early Diagnosis Endothelial Cells Engineering Epithelial Cells Feasibility Studies Gene Delivery Gene Expression Genes Goals Growth H-Cadherin Humanities Image Immigrant Immune Inflammation Lead Liquid substance Lung Lung Adenocarcinoma Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Methods Modeling Mus Mutant Strains Mice Neoplasm Metastasis Nodule Non-Invasive Cancer Detection Patients Peptide antibodies Peptides Pharmaceutical Preparations Plasmids Polymers Property RNA Interference Radiosurgery Reagent Reporter Reporting Research Personnel Research Proposals Role Safety Series Small Interfering RNA Specificity Staging System Technology Testing Tetanus Helper Peptide Therapeutic Time Toxic effect Trachea Travel Treatment Efficacy Tumor Burden Vitamins atrial natriuretic factor receptor A base cancer cell capillary capillary bed chemotherapy chitosan sulfate enhanced green fluorescent protein gene therapy in vivo inhibitor/antagonist interest interstitial iron oxide killings malignant breast neoplasm mouse model nano nanoparticle neoplastic cell novel novel strategies oncology outcome forecast overexpression particle prevent promoter protein expression receptor response sertoli cell targeted delivery theranostics therapeutic target thioredoxin reductase 1 tumor vector

项目摘要

DESCRIPTION (provided by applicant): The primary goal of this research proposal is to develop a novel approach to detect and treat lung cancers that utilizes specially engineered chitosan theranostic nanoparticles (CTNs) and uses lung-targeting Sertoli cells (SCs) to deliver nanoparticles carrying a cancer cell detecting moiety and a gene or drug to effectively treat lung cancers. Worldwide, lung cancer affects an estimated 1.3 million cases of which close to a million will die the same year. This staggering death rate exceeds the combined number of deaths from the leading types of carcinoma (breast, prostate and colon cancer), and accounts for 6% of all deaths within the US. Lung cancer patients often present with locally advanced or disseminated disease. About 6 out of 10 people with lung cancer die within 1 year of diagnosis. The major limitations have been our inability to detect cancers or remission of cancers early and the lack of drugs, which specifically treat cancer cells and not normal healthy cells. The drug delivery to the lung has been investigated using targeted nanoparticle technology that uses natural, biocompatible and biodegradable chitosan nanoparticles and short interference RNA targeting the atrialnatriuretic receptor A, a novel anti-cancer target that was designated a 'lead discovery' in oncology in 2008 for cancers. However, chitosan nanoparticles have not been used for theranostic studies. Recently, we have found that extra-testicular SCs, when loaded with nanoparticles (i.e., SNAPs) and injected intravenously into mice, travel via the circulation directly to the capillary bed of the lung where they release their nanoparticle cargo. The SNAP method increases delivery of therapeutics to the lung from the current standard of about 20% up to 90%. Together these findings have led to the hypothesize that SCs packaged with cancer cell-targeting theranostic nanoparticles comprising a near-infrared dye and siNPRA can be delivered specifically to the lung, which may provide both detection and treatment of lung cancers. To test these hypotheses, the following specific aims are proposed. Aim #1 Develop a polymer theranostics for lung cancers. In this aim, it is planned to develop strategy to develop well-defined specially engineered spherical polymeric nanoparticles (100-300nm) and deliver into lung via cell carriers for diagnostic (by in vivo imaging and MRI) and therapeutic purposes. Aim #2. Optimize and further develop a robust lung-specific delivery of Theranostic SNAPs. In this aim it is planned to optimize the delivery system by regulating intracellular expression of the enhanced green fluorescent protein (EGFP) as a reporter. The delivery efficiency, time course, dose response and persistence of gene expression in the mouse lung will be evaluated. In addition, it is proposed to evaluate the short- and long-term safety of the SNAP method by assessing the expression of SC secretory products in the lung following their delivery with or without nanoparticles. Aim #3. Test cell-targeted SNAP method in LLC1 model of lung metastasis and validate therapeutic role of siNPRA. In this study, it is proposed to evaluate the efficacy of the SNAP delivery system using cancer cell-targeted multifunctional theranostics packaged with siNPRA or psiNPRA in preventing LLC1 lung metastasis. Aim #4. Evaluate the efficacy of SNAP-iNPRA in a CC10 Cre- K-Ras-G12D model of spontaneous lung cancer. In this aim, it is planned to establish a model of spontaneous lung cancer by breeding LSL-K-ras- G12D mice with CC10- Cretg mice to generate CC10-Cre-LSL-K-ras G12D mice and to evaluate the efficacy of theranostics complexed with the inducible siNPRA or psiNPRA in suppressing spontaneous lung cancer induced by overexpression of K-ras in a mouse model. The investigators have access to all reagents and methods and have already developed necessary collaborations and feasibility studies. The results of the proposed studies are expected to validate NPRA as a therapeutic target for lung cancer and the utility of the SNAP method of gene delivery as a safe and effective approach to treat lung cancers, and set the stage for clinical trials for utilizing SNAPs to treat metastatic lung cancers.

描述（由申请人提供）：该研究建议的主要目的是开发一种新型方法来检测和治疗肺癌，该肺癌使用了特殊设计的壳聚糖Theranostic纳米颗粒（CTN），并使用肺靶向sertoli细胞（SCS）来提供携带癌细胞检测癌细胞或药物或药物的纳米颗粒，从而有效地处理癌细胞。肺癌在全球范围内影响约130万病例，其中近一百万将在同年死亡。这种惊人的死亡率超过了主要类型的癌（乳腺癌，前列腺和结肠癌）的死亡人数总数，占美国所有死亡人数的6％。肺癌患者经常出现局部晚期或传播疾病。在诊断后的1年内，大约有10人中有10人死亡。主要的局限性是我们无法尽早检测癌症或癌症的缓解，并且缺乏药物，这些药物专门治疗癌细胞而不是正常的健康细胞。已经使用针对性的纳米颗粒技术研究了向肺部的药物，该技术使用天然，生物相容性和可生物降解的壳聚糖纳米粒子和靶向靶向心natriaretic受体A的短干扰RNA，这是一种新型的抗癌靶标，在2008年为Cancers cancers in Cancersology in Concologic in Cancersology in Cancersology in Cancersology in cancers inccersologe of cancers cancers cancers inccersology。但是，壳聚糖纳米颗粒尚未用于治疗研究。最近，我们发现，当装有纳米颗粒（即捕捉）并静脉注射到小鼠中时，我们发现了新的内科生SC，直接通过循环传播到肺的毛细管床上，在那里它们释放了纳米颗粒货物。 SNAP方法将治疗剂的递送从当前标准的大约20％升至90％。这些发现一起导致了一个假设，即用癌细胞靶向的肉毒细胞肉体纳米颗粒包装，其中包括近红外染料和SINPRA，可以专门传递到肺部，这可能同时提供肺癌的检测和治疗。为了检验这些假设，提出了以下特定目标。 AIM＃1为肺癌开发一种聚合物疗法。为此，计划制定策略，以开发定义明确的球形聚合物纳米颗粒（100-300nm），并通过细胞载体运送到肺部以进行诊断（通过体内成像和MRI）和治疗目的。目标＃2。优化并进一步开发出强大的肺静脉快照递送。在此目标中，计划通过调节增强的绿色荧光蛋白（EGFP）作为记者的细胞内表达来优化递送系统。将评估小鼠肺中基因表达的递送效率，时间过程，剂量反应和持久性。此外，建议通过评估使用或没有纳米颗粒后的肺中SC分泌产物的表达来评估SNAP方法的短期和长期安全性。目标＃3。肺转移的LLC1模型中的测试细胞靶向SNAP方法并验证Sinpra的治疗作用。在这项研究中，建议使用以Sinpra或Psinpra包装的癌细胞靶向多功能疗法来评估SNAP递送系统的功效，以防止LLC1肺转移。目标＃4。评估SNAP-INPRA在自发肺癌的CC10 cre-k-ras-g12d模型中的功效。 In this aim, it is planned to establish a model of spontaneous lung cancer by breeding LSL-K-ras- G12D mice with CC10- Cretg mice to generate CC10-Cre-LSL-K-ras G12D mice and to evaluate the efficacy of theranostics complexed with the inducible siNPRA or psiNPRA in suppressing spontaneous lung cancer induced by overexpression of K-ras in鼠标模型。研究人员可以使用所有试剂和方法，并且已经开发了必要的协作和可行性研究。拟议的研究的结果预计将验证NPRA作为肺癌的治疗靶标，以及基因递送方法的实用性，作为治疗肺癌的安全有效方法，并为利用快照治疗转移性肺癌的临床试验奠定了基础。