传递体纳米粒复合体的透皮性及抗乳腺癌作用

Breast cancer is one of the most common malignant tumors which are harmful to women health. Its high incidence and difficulty in cure become the largest challenge in medical and pharmacy. Transdermal administration is utilized to improve the uptake of drug by lymphatic and blood circulation, and establish a high efficient therapy to breast cancer upon local and lymphatic level simultaneously. Transfersome is prepared as efficient transdermal carrier with phospholipid and edge activator, assembled with HA-GMS on the surface, and loaded with O-CSNP modified by L-histidine, giving rise to a transfersome/nanoparticle complex for local and lymphatic therapy. Upon its own super-flexcibility, the complex is able to penetrate across the skin easily and act as a reservoir carrier for hydrophilic and lipophilic drugs, improving their direct uptake by blood and lymphatic system especially. HA-GMS could increase surface hydrophilicity of the carrier, offering receptor mediated cancer targeting ligand and promote endocytosis by cancer cells. Lipophilic drugs could be loaded in O-CSNP and retain transfersome's flexibility thereby. This entity is also be able to benefit for endocytosis. L-Histidine plays a critical role in increasing endosome escape rate of O-CSNP, through which the drug release in cytoplasm could be highly improved.

乳腺癌是危害女性健康最常见的恶性肿瘤之一，其难以治愈和高发病率是药学和医学面临的重要难题。本项目采用经皮给药方式，提高淋巴和血液的吸收效率，实现安全高效且兼顾局部与淋巴系统治疗乳腺癌。拟采用磷脂与表面活性剂，制备传递体作为高效透皮载体，表面装配HA-GMS，内部包载组氨酸修饰的O-CSNP，构建高效安全，兼顾局部与淋巴系统治疗的传递体纳米粒复合体系。该复合体系可凭借传递体超柔性结构，实现高效透皮，可携带亲水及疏水药物，促进药物被血液特别是淋巴直接吸收；HA-GMS可增强载体表面亲水性，提供受体介导癌细胞靶向基团，并促进载体被癌细胞内吞；O-CSNP可携带疏水药物，保持传递体柔性结构，并有利于细胞吞噬；组氨酸修饰的O-CSNP可增加了纳米粒内体逃逸性能，提高药物胞浆释放效率，形成安全高效的，整合局部与淋巴系统治疗乳腺癌的给药策略。

乳腺癌是危害女性健康最常见的恶性肿瘤之一，转移复发率高，而淋巴是癌细胞转移的重要途径。本项目利用传递体（Transfersome，T）为药物载体，通过经皮给药方式，提高淋巴和血液对药物的吸收效率。以卵磷脂（L）与脱氧胆酸钠（DOC）为膜材，采用薄膜分散法制备纳米载体，表面装配透明质酸-单硬脂酸甘油酯复合物（HA-GMS），构建安全、靶向、高效的经皮给药载体（HA-T）。最佳制备条件为：L/DOC用量为70/25（m/m），三氯甲烷/乙醇（1:1，v/v）作溶剂，HA-GMS浓度为1mg/ml（pH 7.4），55℃水浴搅拌，超声4次（20%，3s开，2s关,20 s）制得。制备的HA-T平均粒径为91.74±3.07 nm，透光度T%=92.0±1.89，体系澄清透明，PdI=0.32±0.01，粒径分布较为均一，具有明显的多层微结构。HA-T对盐酸阿霉素（DOX）的包封率为60.86%，包载率为4.63%；具有良好的细胞相容性和血液相容性。离体皮肤渗透实验表明，HA-T可实现DOX透皮吸收量提高3倍，与同类透皮剂型微乳相比，能够渗透至皮肤的更深层组织，并促进药物的深层渗透和吸收。细胞摄取实验验证了HA-T能够被癌细胞（MCF-7）有效吞噬，并显著提高DOX的细胞摄取率；活体动物实验表明，HA-T实现了药物在大鼠淋巴结部位的显著分布，并避免了肝脏首过效应。以上结果证实，以HA-T为载体，通过对药物的有效携载，可实现抗癌药物的经皮给药，具有高效渗透效率、低毒副作用、高癌细胞吸收率和促淋巴吸收作用，为兼顾淋巴与局部治疗乳腺癌提供了新理论、新技术和新策略。