Bionanotechnology approach for treatment of lung cancer

项目名称：治疗肺癌的生物纳米技术方法 项目摘要 肺癌是全球癌症相关死亡的主要原因。非小细胞肺癌 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。 化疗是非小细胞肺癌手术前、后的主要治疗方法。然而，它的效率 化疗在大多数患者中仍然相对较低，并受到特异性不足、药物含量低的限制 在肺部蓄积、滞留，治疗副作用严重。最近，小米 作用于表皮生长因子受体(EGFR)的分子酪氨酸激酶(TK)抑制剂有 介绍用于治疗非小细胞肺癌。然而，即使是最新一代的EGFR抑制剂也会导致严重的 全身毒性，在防止非规范的EGFR信号转导方面无效。因此，只有 大约10%的非小细胞肺癌患者从这种疗法中受益。为了克服这些限制，一个 提出了新的多层生物技术治疗方法，包括：(1)抑制所有四种类型的 (2)抗癌药物诱导细胞死亡；(3) 通过向肺部局部吸入治疗药物来提高治疗效率 (被动靶向)，(4)主动受体介导的针对癌细胞的主动靶向治疗和(5) 利用纳米结构脂质提高siRNA和药物的稳定性、溶解性和细胞渗透性 运营商(NLC)。我们假设这种以纳米技术为基础的肿瘤靶向的应用， 多功能方法将大大提高非小细胞肺癌的治疗效率和 减少化疗的副作用。目前研究的主要目标是测试 提出假设并开发一种新的基于纳米的技术来进行概念验证 建议的战略。拟议研究的具体目标是：(1)设计、合成和 描述包含NLC的多功能、多组分递送系统(DS)，NLC是一个siRNA池 靶向EGFR-TKS，紫杉醇(TAX)作为抗癌药物，以及黄体激素释放 激素(LHRH)多肽作为肺癌细胞中高表达受体的特异性靶向部分； 检测主动(LHRH受体介导)和被动(局部吸入)双重肿瘤的疗效 以NLC为基础的DS的靶向性；(3)联合基因和化疗的有效性 沉默EGFR-TK信号通路和诱导细胞死亡；(4)评价体内抗肿瘤活性和 靶向和非靶向NLC-DS对临床相关原位小鼠的不良反应 原代人NSCLC异种移植模型的建立。预计拟议的方法和使用 开发多功能非小细胞肺癌DS将大大提高非小细胞肺癌的治疗效率 限制治疗的不良副作用。所获得的实验数据将提供概念验证 建议的方法，并可能对药物输送领域产生相当大的影响和改进 肺癌和其他类型癌症的治疗效率。

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.