肺光动力疗法联合肺吸入细胞靶向抗肿瘤药物纳米粒治疗原发性肺癌的研究

Systemic chemotherapy of primary lung cancer leads to low level of drugs in the lung and severe side effect. Pulmonary delivery can transport drugs into the lung tumor tissues directly. In this study, we comprehensively analyze the physiological features of lungs and the pathological features of lung cancer. Photodynamic therapy (PDT) and chemotherapy are combined. Firstly, photosensitizers and chemotherapeutics are entrapped in nanoparticles. And then the microspheres composed of a lot of nanoparticles are prepared with the.coaxially electrospraying technique, which are satisfied for pulmonary delivery. More importantly, their large geometric sizes should prevent uptake of alveolar macrophages. The inhaled microspheres would rapidly disassemble into the original nanoparticles. The iRGD-decorated nanoparticles have high tumor cell targeting effect, which efficiently enter the tumor cells. The internalized photosensitizers produce PDT effect under the lighting of laser light fibers. Moreover, they have the synergistic effect with the internalized chemotherapeutics, resulting in heavy tumor cell death. The locally pulmonary delivery mode makes the drugs accumulating in the lung tumor tissues with the advantages of low doses and low toxicity and side effect. In this study, we will optimize the formulation and preparation process of nanoparticles and microspheres. They are characterized. Drug release, cytotoxicity, and uptake of macrophages are explored. Pharmacodynamic study is performed on the animal primary lung cancer models, and the anticancer mechanisms are revealed. Pharmacokinetics is studied to demonstrate the targeting effect and safety. This study provides a highly efficient, low toxicity, and convenient treatment of primary lung cancer.

原发性肺癌的全身化疗方式使肺内药物分布少，并有严重毒副作用。肺吸入给药可直接将药物递送至肺肿瘤组织。本项目综合分析肺生理和肺肿瘤病理特点，联合应用光动力学治疗和化疗，用纳米粒包裹光敏剂和化疗药物，用同轴静电喷雾技术制备大量纳米粒构成的微球，满足肺吸入颗粒要求，并且大的几何粒径使其避免了肺泡巨噬细胞吞噬。微球吸入肺中后，迅速解离成纳米粒。iRGD改造的纳米粒有肿瘤细胞靶向性，高效进入细胞。光敏剂在插入肺支气管的激光光纤光照下发挥光动力学效应，同时可与进入细胞的化疗药物产生协同作用，高效杀死肿瘤细胞。肺吸入局部给药，药物集中于肺癌组织，剂量小，毒副作用小。优化纳米粒、微球的处方工艺，进行性质表征，考察释药特点，体外考察细胞毒性和巨噬细胞的吞噬，在动物原发性肺癌模型上考察药效学和机理，考察药代动力学特点，证明其靶向性和安全性。本项目为原发性肺癌的治疗提供一种高效、低毒、简捷的治疗方法。

肺癌化疗主要是通过口服或注射的全身给药方式，药物全身分布，而肺组织分布有限，影响了药效和增加副作用。光动力学限于表面肿瘤，光敏剂也是全身给药，易造成副作用。本项目应用肺吸入给药方式，并将化疗药物和光动力学治疗结合，证明治疗肺癌优势，并且拓展研究了多种肺吸入制剂对肺癌和肺纤维化以及声动力学的肺癌治疗。（1）电喷雾多孔纳米粒子聚集微粒。用电喷雾技术制备多纳米粒子聚集微粒，几何粒径较大，可躲避肺泡巨噬细胞吞噬，但空气动力学粒径较小，适合肺吸入。（2）肺吸入吉非替尼纳米粒和5-氨基酮戊酸的化疗-光动力学治疗原发性肺癌。胸部外照射比气管插入光纤对肺组织影响小，更安全。吉非替尼PLGA纳米粒和光敏剂5-氨基酮戊酸协同抑制肺癌细胞。原发性肺癌大鼠两者肺部给药后，明显降低多个肿瘤标志物以及炎症因子，显著减小肿瘤组织。（3）肺吸入吉非替尼和口服吉非替尼治疗原发性肺癌的比较研究。原发性肺癌大鼠气管给吉非替尼脂质体粉雾剂（LGD）、气管给吉非替尼、口服吉非替尼后，发现气管给LGD的血液药时曲线下面积（AUC）最大；气管给药肺组织中药物量较大；口服吉非替尼的肝药量最大；气管给LGD的药效最好。（4）肺吸入羟基喜树碱和5-氨基酮戊酸的化疗-声动力学治疗转移性肺癌研究。羟基喜树碱阳离子脂质体和5-氨基酮戊酸联合肺部给药，同时进行胸部超声，对转移性肺癌效果治疗最佳。（5）肺吸入载紫杉醇脂质体活菌制剂治疗原发性肺癌。用大肠杆菌和干酪乳杆菌载紫杉醇脂质体，吸入后对原发性肺癌效果最好。（6）治疗原发性肺癌的美乐托宁脂质体粉雾剂。原发性肺癌大鼠肺部给药美乐托宁脂质体粉雾剂、美乐托宁、吉西他滨，前者效果最好。（7）肺吸入姜黄素大多孔微粒治疗肺纤维化。姜黄素大多孔微粒肺部给药后，可以避免巨噬细胞吞噬，有效治疗肺纤维化。本项目中新型肺吸入制剂为肺癌治疗提供了新方法和新思路。