肿瘤相关巨噬细胞靶向纳米药物在非小细胞肺癌治疗中的研究

项目名称： 肿瘤相关巨噬细胞靶向纳米药物在非小细胞肺癌治疗中的研究

项目编号： No.81460454

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 崔正荣

作者单位： 内蒙古医科大学

项目金额： 48万元

中文摘要： 中国每年新增癌症患者占全球新增的20%以上，其中肺癌最常见、死亡人数最多。非小细胞肺癌（包括腺癌、鳞癌、大细胞癌）占肺癌总数的80%以上。化疗是非小细胞肺癌治疗的主要方法之一，但一方面由于缺乏特异性，另一方面致密结缔组织增生形成的肿瘤基质包围着肿瘤细胞，形成生理屏障阻止抗癌药物到达肿瘤细胞，药物往往只能产生边际效应。研究发现，巨噬细胞是最常见的肿瘤浸润炎性细胞，与肿瘤血管生成，肿瘤的生长，迁移，侵袭，转移和免疫抑制机制相关联。本项目旨在以肿瘤相关巨噬细胞（TAMs）为靶点，设计携带肿瘤化疗药物吉西他滨（Gemcitabine）的新型纳米颗粒以提高该抗肿瘤药物在肿瘤内的浓度进而增强其抗肿瘤效果并减少药物副作用，开展非小细胞肺癌靶向治疗新策略的研究。该项目的顺利实施有望为推动以TAMs为药物输送系统靶点的肿瘤治疗新方法研究进展以及提高肺癌化疗效果提供良好的科学研究基础，具有巨大的潜在应用价值。

中文关键词： 非小细胞肺癌；肿瘤相关巨噬细胞；吉西他滨；纳米颗粒；靶向治疗

英文摘要： Lung cancer is the leading cause of cancer death in China. In the past three decades, the registered death rate from lung cancer has increased by 465%. There are two major types of lung cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for about 85% of lung cancers. The lungs are large, and tumors can grow in them for a long period of time before they are detected. Therefore, early-stage lung cancer (stages I and II) is difficult to detect and most people with lung cancer are diagnosed at stages III and IV. For stages III and IV lung cancers, chemotherapy is a critical treatment modality, but often produces only limited benefits due to the lack of specificity to tumor cells. For decades, researchers have sought to increase the specific killing of tumor cells by targeting chemotherapeutic agents to tumors. Historically, tumor targeting is largely aimed at the tumor cells per se, but it has proven difficult to translate this strategy from lab to clinics, partially due to the heterogeneity of tumor cells in patients. Tumor cells in solid tumors are often surrounded by tumor stroma. Inflammatory cells are a critical component of tumor stroma. Macrophages are the most popular immune cells that infiltrate tumor stroma, and tumor-associated macrophages (TAMs) may represent up to 50% of tumor mass. Importantly, substantial evidence exists correlating TAMs, especially the M2 type antitumoral TAMs, with poor prognosis in human lung cancer. In this application, we hypothesize that M2 TAMs are a viable target to increase the delivery of a chemotherapeutic agent into tumor tissues and to improve it antitumor activity. Recently, we developed an acid-sensitive PEG-sheddable, mannose-modified polymeric nanoparticle system that can target TAMs. We choose to use this nanoparticle system to deliver gemcitabine into NSCLC to test our hypothesis, because lung cancer is the most deadly cancer in China, and gemcitabine is commonly used in NSCLC therapy. We propose three specific aims in this application: 1) to develop and characterize TAM-targeting gemcitabine nanoparticles; 2) to establish the extent to which the TAM-targeting nanoparticles will increase the delivery of gemcitabine in lung tumor tissues in a mouse model; and 3) To identify the extent to which the TAM-targeting gemcitabine will increase the antitumor activity of gemcitabine in a mouse model of NSCLC, relative to free gemcitabine. Our project is innovative because we expect to establish TAMs as a viable target to increase the delivery of an anticancer drug to tumor tissues to improve NSCLC chemotherapy. This highly significant work will lay a solid foundation for future translation of the TAM-targeting gemcitabine into clinics to improve the outcomes of lung cancer chemotherapy. Similar strategies may be adopted for the therapy of other solid tumors that contain a high density of TAMs.

英文关键词： Non-small cell lung cancer;Tumor-associated macrophages;Gemcitabine;Nanoparticle;Targeted treatment