Bionanotechnology approach for treatment of lung cancer

生物纳米技术治疗肺癌的方法

• 批准号: 10094206
• 负责人: Tamara Minko
• 金额: $ 58.56万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-04 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094206
• 关键词: Accounting; Antineoplastic Agents; Biotechnology; Buffers; Cancer Etiology; Cell Death Induction; Cell Line; Cell Proliferation; Cessation of life; Charge; Colon Carcinoma; Data; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug resistance; Drug usage; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Excision; GNRH1 gene; Gene Combinations; Gene Expression; Gene Proteins; Generations; Genes; Gonadotropin-Releasing Hormone Receptor; Histology; Human; Immune response; Immunodeficient Mouse; In Vitro; Induction of Apoptosis; Inhalation; Intravenous; Lipids; Longevity; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mus; Mutation; Nanostructures; Nanotechnology; Nebulizer; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Organ; Paclitaxel; Patients; Penetration; Pharmaceutical Preparations; Postoperative Period; Primary Carcinoma; Primary Neoplasm; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Resistance; Serum; Shapes; Signal Induction; Signal Pathway; Signal Transduction; Small Interfering RNA; Solubility; Specificity; System; Technology; Testing; Therapeutic; Therapeutic Agents; Treatment Effectiveness; Treatment Efficacy; Treatment Side Effects; Tumor Tissue; Tyrosine Kinase Inhibitor; United States; Xenograft procedure; base; cancer cell; cancer type; chemotherapy; clinically relevant; combinatorial; cytotoxicity; established cell line; genotoxicity; human model; improved; in vivo; innovation; lung Carcinoma; lung cancer cell; malignant breast neoplasm; molecular mass; mouse model; nanobiotechnology; nanoparticle; nanoscale; neoplastic cell; new therapeutic target; novel; overexpression; particle; peptide hormone; prevent; receptor; response; side effect; small molecule; systemic toxicity; targeted delivery; targeted treatment; tumor

Project Title: Bio-nanotechnology approach for treatment of lung cancer Project Summary Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small Cell Lung Carcinoma (NSCLC) is the most common type of lung cancer, accounting for more than 80% of all lung cancer cases. Chemotherapy is the primary pre-operative and post-operative treatment of NSCLC. However, the efficiency of chemotherapy remains relatively low in most patients and is limited by insufficient specificity, low drug accumulation, and retention in the lungs with severe adverse side effects of treatment. Recently, small molecule Tyrosine Kinase (TK) inhibitors which act on the Epidermal Growth Factor Receptors (EGFRs) were introduced for treatment of NSCLC. However, even the latest generation of EGFR inhibitors cause severe systemic toxicities and are ineffective in preventing non-canonical EGFR signaling. As a result, only approximately 10% of patients with NSCLC benefit from this therapy. In order to overcome these limitations, a novel multi-tier biotechnology treatment approach is proposed that includes: (1) suppression of all four types of EGFR-TKs by a pool of small interfering RNAs (siRNAs); (2) induction of cell death by an anticancer drug, (3) enhancing the efficiency of the treatment by the local inhalatory delivery of therapeutic agents to the lungs (passive targeting), (4) active receptor-mediated targeting of the therapy specifically to cancer cells and (5) increasing the stability, solubility, and cellular penetration of siRNA and drug by using Nanostructured Lipid Carriers (NLC). We hypothesize that the application of this nanotechnology-based tumor-targeted, multifunctional approach will substantially enhance the efficiency of the treatment of NSCLC and reduce adverse side effects of chemotherapy. The main objective of the current research is to test the stated hypothesis and develop a novel nanoscale-based technology to carry out proof-of-concept of the proposed strategy. The specific aims of the proposed research are: (1) to engineer, synthesize, and characterize a multifunctional, multicomponent Delivery System (DS) containing NLC, a pool of siRNAs targeted to EGFR-TKs, paclitaxel (TAX) as an anticancer drug, and a Luteinizing Hormone-Releasing Hormone (LHRH) peptide as a targeting moiety specific to receptors overexpressed in lung cancer cells; (2) to examine efficiency of active (LHRH receptor-mediated) and passive (local inhalation delivery) dual tumor targeting of NLC-based DS; (3) to characterize the efficiency of combinatorial gene and chemotherapy for silencing of EGFR-TK signaling pathways and cell death induction; (4) to evaluate in vivo antitumor activity and adverse side effects of targeted and non-targeted NLC-based DS in clinically relevant orthotopic mouse models of primary human NSCLC xenografts. It is expected that the proposed approach and the use of the developed multifunctional NLC-based DS will substantially enhance the efficiency of therapy of NSCLC and limit adverse side effects of the treatment. Experimental data obtained will provide the proof-of-concept of the proposed approach, and can potentially make a considerable impact on the field of drug delivery and improve the efficiency of therapy for lung and other types of cancer.

项目名称：肺癌治疗的生物纳米技术方法 项目摘要 肺癌是全球与癌症相关死亡的主要原因。非小细胞肺癌 （NSCLC）是最常见的肺癌类型，占所有肺癌病例的80％以上。 化学疗法是NSCLC的主要术前和术后治疗。但是，效率 在大多数患者中，化学疗法仍然相对较低，并且受特异性不足，药物较低的限制 积累，并在肺部保留严重的治疗副作用。最近，小 作用于表皮生长因子受体（EGFR）的分子酪氨酸激酶（TK）抑制剂 引入了用于NSCLC的治疗。但是，即使是最新一代的EGFR抑制剂也会引起严重 全身毒性，无效预防非典型的EGFR信号传导。结果，只有 NSCLC患者中约有10％受益于这种疗法。为了克服这些限制， 提出了新型多层生物技术治疗方法，其中包括：（1）抑制所有四种类型的 eGfr-tks在一个小的干扰RNA（sirnas）中； （2）抗癌药物诱导细胞死亡，（3） 通过将治疗剂递送到肺部提高治疗的效率 （被动靶向），（4）该治疗专门针对癌细胞的主动受体介导的靶向和（5） 通过使用纳米结构脂质，提高siRNA和药物的稳定性，溶解度和细胞渗透率 载体（NLC）。我们假设这种基于纳米技术的肿瘤靶向的应用， 多功能方法将大大提高NSCLC治疗的效率和 减少化学疗法的不良副作用。当前研究的主要目的是测试 陈述了假设并开发了一种新型的基于纳米级的技术，以进行概念证明 拟议的策略。拟议的研究的具体目的是：（1）工程师，合成和 表征包含NLC的多功能多功能输送系统（DS） 针对EGFR-TKS，紫杉醇（税）作为抗癌药物和黄体生成激素释放 激素（LHRH）肽是针对肺癌细胞过表达的受体的靶向部分； （2）至 检查活性（LHRH受体介导的）和被动（局部吸入递送）双重肿瘤的效率 靶向基于NLC的DS； （3）表征联合基因和化学疗法的效率 EGFR-TK信号通路和细胞死亡诱导的沉默； （4）评估体内抗肿瘤活性和 临床相关的原位小鼠中靶向和非靶向NLC的DS的不良副作用 原代人NSCLC异种移植的模型。预计拟议的方法和使用 开发的基于NLC的多功能DS将大大提高NSCLC的治疗效率和 限制治疗的不良副作用。获得的实验数据将提供 拟议的方法，并可能对药物输送领域产生重大影响并改善 肺和其他类型癌症治疗的效率。