Engineering Dual-Targeted Nanoplatforms to Effectively Treat NSCLC.

工程双靶点纳米平台可有效治疗非小细胞肺癌。

• 批准号: 10705589
• 负责人: Raghuraman Kannan
• 金额: $ 66.1万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705589
• 关键词: A549; Abate; Animal Model; Antibodies; Biodistribution; Bypass; Cancer Patient; Cell Line; Cells; Characteristics; Charge; Clinical; Clinical Trials; Compensation; Data; Development; Dose; Drug Kinetics; Drug resistance; Engineering; Epidermal Growth Factor Receptor; Evaluation; Exhibits; Future; Gelatin; Genes; Immunohistochemistry; In Vitro; Institution; Lead; Libraries; Literature; Malignant neoplasm of lung; Medical; Methodology; Modeling; Molecular Target; Mus; Mutate; NF-kappa B; Non-Small-Cell Lung Carcinoma; Organoids; Pathway interactions; Patients; Penetration; Pharmacotherapy; Phenotype; Play; Proteins; Receptor Protein-Tyrosine Kinases; Resistance; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Survival Rate; Tissues; Treatment Efficacy; Tyrosine Kinase Inhibitor; Work; Xenograft procedure; cancer therapy; clinical development; clinically relevant; combat; crosslink; design; drug sensitivity; functional group; improved; in vivo; inhibitor therapy; knock-down; lead candidate; lung cancer cell; mouse model; mutant; nanomedicine; nanoparticle; nanotechnology platform; nanotherapeutic; novel; novel strategies; patient derived xenograft model; side effect; small molecule inhibitor; success; therapeutic evaluation; therapeutic nanoparticles; therapy outcome; transcriptome sequencing; treatment response; tumor; tumor growth; uptake

ABSTRACT Nanomedicine provides new opportunities to solve medical problems that were previously perceived as unsolvable by clinicians. One such problem is drug resistance in Non-Small Cell Lung Cancer (NSCLC). Attempts to overcome the resistance using small molecule inhibitors have failed to restore the drug sensitivity. Alternative compensation survival pathways emerge to allow the regrowth of the tumor. To abate the tumor growth, we need to suppress more than one survival pathway with minimal or no side effects. Nanoparticles possess the ability to selectively and simultaneously arrest multiple survival pathways to control the growth of the tumor. However, nanoparticles to co-knockdown multiple cross-linked survival pathways have not been explored yet. We recently identified two targets AXL and FN14 and demonstrated that the cross-talk between these markers is responsible for resistance in EGFR mutant NSCLC. Subsequently, we designed nanoparticles to simultaneously co-knockdown both AXL and FN14 in the tumor, disrupted the cross-talk, and successfully overcame drug resistance in murine models. The logical next step is to validate the findings in clinically relevant animal models and patient samples. It is equally important to optimize the size of nanoparticles further to maximize deep tumor delivery with favorable in vivo characteristics. Therefore, in this proposal, we will synthesize different sizes of NP, understand their ability to penetrate deep inside the tumor to fully restore drug sensitivity for a long-lasting therapeutic response. We will use patient tissues, patient-derived organoids, drug- resistant cell lines, orthotopic animal models, and patient-derived xenografts to establish the efficacy of the nanoplatform. The data will validate our new nanoparticle platform, as a promising strategy to combat drug resistance in NSCLC and catalyze clinical trials in the future.

摘要 纳米医学提供了新的机会，以解决医疗问题，以前被认为是 临床医生无法解决。其中一个问题是非小细胞肺癌（NSCLC）的耐药性。 使用小分子抑制剂克服耐药性的尝试未能恢复药物敏感性。 替代补偿生存途径的出现，使肿瘤的再生长。为了消除肿瘤 生长，我们需要抑制一个以上的生存途径，最小或没有副作用。纳米颗粒 具有选择性地同时抑制多种存活途径以控制 肿瘤然而，纳米颗粒共敲低多个交联的生存途径还没有被发现。 探索至今。我们最近确定了两个目标AXL和FN 14，并证明了它们之间的串扰。 这些标志物是EGFR突变型NSCLC耐药的原因。随后，我们设计了纳米颗粒 同时共敲低肿瘤中的AXL和FN 14，破坏了交叉作用， 在小鼠模型中克服了耐药性。合乎逻辑的下一步是验证临床相关的发现 动物模型和患者样品。同样重要的是进一步优化纳米颗粒的尺寸， 最大化具有有利的体内特性的深部肿瘤递送。因此，在本提案中，我们将 合成不同大小的NP，了解它们穿透肿瘤深处以完全恢复药物的能力 长期治疗反应的敏感性。我们将使用病人组织，病人衍生的类器官，药物- 耐药细胞系、原位动物模型和患者来源的异种移植物，以确定 纳米平台。这些数据将验证我们的新纳米颗粒平台，作为一种有前途的对抗药物的策略。 在NSCLC中的耐药性，并催化未来的临床试验。