近红外光响应的榄香烯智能门控肝靶向纳米载体的研究

Liver cancer is one of the common malignant tumor in our country. The chemotherapy is still an important means of tumor therapy, but accompanied by low efficacy or side effects. As a good security and multispectral anti-cancer active ingredient, Elemene (ELE) is extracted from the natural herbal Wenyujin, which belonged to Zingiberaceae plants. Elemen has less adverse reaction in clinical, but still has some problems such as poor stability, volatile and water-insoluble. In recent years, targeted drug delivery system combined with Near-infrared heat treatment has opened up a new treatment method for malignant tumor. Nanometer oxide grapheme (NGO) is a new type of thermal coupling agent, and it has showed great application potential in the field of tumor treatment, but NGO itself couldn’t adjust the temperature and control the drug release in tumor target.　In order to enhance the antitumor effect and reduce the systemic toxicity of　ELE, an active tumor targeting nano-drug delivery system (nDDS) was designed.　ELE and　NGO　were　co-loaded　into the temperature-sensitive liposomes，and the tumor targeted molecular glycyrrhetinic acid (GA) was modified on it’s surface.　By　the mediation　of GA and the EPR effect of tumor tissue for nanometer，the nDDS could targeted distribute　to the liver tumor tissues，and rapidly release the　drug under　the illumination of 808 nm near-infrared light which could make NGO produce　heat and reactive oxygen. This study could provide some certain theoretical basis for clinical liver tumors treatment with combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT).

肝癌是我国常见的恶性肿瘤之一。目前药物疗法仍是肝癌综合治疗的重要手段，但通常药效较低或副作用较大。榄香烯是从天然中草药姜科植物温郁金中提取获得的萜烯类化合物，是安全性好的多谱抗癌活性成分，但存在稳定性差、非水溶性等问题。近年来，靶向纳米递药载体联合近红外光进行光热治疗为临床恶性肿瘤开辟了新的治疗策略。纳米氧化石墨烯是一种新型的光热偶联剂，已在肿瘤光热治疗中表现出巨大的应用潜力，但其本身很难通过调节温度控制药物在肿瘤靶部位释放。本课题将榄香烯和纳米氧化石墨烯同时包裹于温敏脂质体当中，并采用肝肿瘤靶向分子甘草次酸进行修饰，从而构建一种具有肿瘤主动靶向特征的纳米递药载体。通过靶向分子的介导和肿瘤组织EPR效应使纳米载体集中分布于肝组织，利用近红外光照射使纳米氧化石墨烯产热并产生活性氧，触发温敏载体快速释药，从而实现肿瘤的光-热-化联合治疗。本研究可为临床肝肿瘤的多机制治疗提供一定的理论依据。

本课题以纳米氧化石墨烯（NGO）为光敏剂，肝肿瘤靶向分子甘草次酸（GA）为靶头，β-榄香烯（ELE）为模型药物，构建一种具有肿瘤主动靶向特征的脂质体温敏水凝胶（GA-NGO-ELE-Lip-gel）。课题先通过化学修饰合成GA-NGO，并对其结构鉴定、形态观察、粒径和电位、稳定性及光热转换特性等进行研究，同时GA-NGO水分散液粒径大小较为均匀，稳定性良好。结合808 nm激光照射时GA-NGO的光热转换性能良好，具有浓度和时间依赖性特征。分别采用逆相蒸发法制备脂质体、冷溶法制备空白温敏凝胶，然后将两者按照一定比例混合制得GA-NGO-ELE-Lip-gel，并从粒径、形态、包封率、载药量、稳定性等方面进行考察。分别以SMMC-7721肝癌细胞和4T1荷瘤BALB/c小鼠为模型，结合808 nm激光进行体内外抗肿瘤活性和组织分布研究。GA-NGO-ELE-Lip-gel的粒径和Zeta电位分别为(171.0±0.248) nm和(8.06±4.982) mV，大小均匀、胶凝特性和稳定性良好，与808 nm激光照射下光热转换特性良好。GA-NGO-ELE-Lip-gel能够有效抑制SMMC-7721细胞的增殖，并具有良好的缓释效果。近红外光照射条件下，100 μg/mL浓度下GA-NGO-ELE-Lip-gel的抑制率由75.31 %升至82.14 %，表明光热治疗效果显著。本研究可为临床恶性肿瘤的多机制治疗提供一定的理论依据。.目前该项目已在SCI期刊Journal of Nanoparticle Research发表论文1篇，在中文核心期刊中国中药杂志、医药导报等发表论文4篇，发表会议论文2篇，培养本科毕业生3名，硕士毕业生5名，申请国家发明专利1项（No:201811081294.X）