Bionanotechnology approach for treatment of lung cancer

生物纳米技术治疗肺癌的方法

基本信息

批准号：
10553243
负责人：
Tamara Minko
金额：
$ 58.12万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-04 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553243
关键词：
Accounting Antineoplastic Agents Biotechnology Buffers Cancer Etiology Cell Death Induction Cell Line Cell Proliferation Cell Separation 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 Expression Generations Gonadotropin-Releasing Hormone Receptor Histology Human Immune response Immunodeficient Mouse In Vitro Induction of Apoptosis Inhalation Intravenous Invaded Longevity Lung 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 Persons Pharmaceutical Preparations Postoperative Period Primary Neoplasm Proteins 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 cancer cell cancer type chemotherapy clinically relevant combination gene therapy combinatorial cytotoxicity established cell line gene therapy 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 side effect small molecule structured lipid systemic toxicity targeted delivery targeted treatment treatment response tumor

项目摘要

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：治疗肺癌的生物纳米技术方法项目概要肺癌是全球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。化疗是NSCLC术前和术后的主要治疗方法。然而，效率大多数患者的化疗率仍然相对较低，并且受到特异性不足、药物浓度低的限制积聚并滞留在肺部，造成严重的治疗副作用。最近，小分子酪氨酸激酶（TK）抑制剂作用于表皮生长因子受体（EGFR）引入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并且无法有效预防非经典 EGFR 信号传导。结果，仅大约 10% 的 NSCLC 患者从这种疗法中受益。为了克服这些限制，提出了新颖的多层生物技术治疗方法，包括：（1）抑制所有四种类型由小干扰 RNA (siRNA) 库组成的 EGFR-TK； (2)抗癌药物诱导细胞死亡，(3) 通过将治疗剂局部吸入输送至肺部来提高治疗效率（被动靶向），(4) 主动受体介导的靶向疗法，专门针对癌细胞，以及 (5) 使用纳米结构脂质提高 siRNA 和药物的稳定性、溶解度和细胞渗透性运营商 (NLC)。我们假设这种基于纳米技术的肿瘤靶向应用，多功能方法将大大提高非小细胞肺癌的治疗效率减少化疗的不良副作用。当前研究的主要目的是测试提出的假设并开发一种新颖的基于纳米级的技术来进行概念验证提出的策略。拟议研究的具体目标是：（1）设计、综合和表征包含 NLC（一组 siRNA）的多功能、多组分递送系统 (DS) 靶向 EGFR-TK、作为抗癌药物的紫杉醇 (TAX) 和促黄体激素释放药物激素 (LHRH) 肽作为肺癌细胞中过度表达的受体的特异性靶向部分； (2) 至检查主动（LHRH 受体介导）和被动（局部吸入递送）双肿瘤的效率基于 NLC 的 DS 的定位； (3) 表征组合基因和化疗的效率 EGFR-TK 信号通路沉默和细胞死亡诱导； (4) 体内抗肿瘤活性评价基于 NLC 的靶向和非靶向 DS 对临床相关原位小鼠的不良副作用原发性人类非小细胞肺癌异种移植模型。预计所提出的方法和使用开发的基于NLC的多功能DS将大大提高NSCLC的治疗效率限制治疗的不良副作用。获得的实验数据将提供概念验证提出的方法，可能会对药物输送领域产生相当大的影响并改善肺癌和其他类型癌症的治疗效率。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plant-derived single domain COVID-19 antibodies.

植物源性单域 COVID-19 抗体。

DOI：
发表时间：
2023-07
期刊：
影响因子：
0
作者：
Shen, Andrew M;Malekshah, Obeid M;Pogrebnyak, Natalia;Minko, Tamara
通讯作者：
Minko, Tamara

Nanotechnology-Based Nucleic Acid Vaccines for Treatment of Ovarian Cancer.

基于纳米技术的核酸疫苗用于治疗卵巢癌。

DOI：
发表时间：
2023-01
期刊：
影响因子：
3.7
作者：
Gildiz, Simav;Minko, Tamara
通讯作者：
Minko, Tamara

Anti-Tumor Effects of a Penetratin Peptide Targeting Transcription of E2F-1, 2 and 3a Is Enhanced When Used in Combination with Pemetrexed or Cisplatin.

与培美曲塞或顺铂联合使用时，靶向 E2F-1、2 和 3a 转录的穿透素肽的抗肿瘤作用会增强。

DOI：
发表时间：
2021-02-26
期刊：
影响因子：
5.2
作者：
Rather, Gulam Mohmad;Anyanwu, Michael;Minko, Tamara;Garbuzenko, Olga;Szekely, Zoltan;Bertino, Joseph R
通讯作者：
Bertino, Joseph R

Multifunctional Lipid-Based Nanoparticles for Codelivery of Anticancer Drugs and siRNA for Treatment of Non-Small Cell Lung Cancer with Different Level of Resistance and EGFR Mutations.

用于共同递送抗癌药物和 siRNA 的多功能脂质纳米颗粒，用于治疗具有不同耐药水平和 EGFR 突变的非小细胞肺癌。