Tat-TOS,磷脂酶D抑制剂和阿霉素的多组分脂质体递送系统的制备及体内外评价（英文）

Preparation, characterization and evaluation of multi-component-loaded liposomes containing Tat-TOS, phospholipase D inhibitor and doxorubicinPreparation, characterization and evaluation of multi-component-loaded liposomes containing Tat-TOS, phospholipase

本研究的目的是将α-维生素E琥珀酸酯的偶联物Tat-TOS与磷脂酶D抑制剂FIPI以及抗肿瘤药阿霉素共同包载于脂质体递送系统中,用于抗肿瘤转移。首先采用固相合成法合成了Tat-TOS,并对其进行结构确证,用诱导凋亡法考察了游离Tat-TOS和Tat-脂质体的体外诱导细胞凋亡的能力,并评价了表面修饰了Tat-TOS脂质体的肺部靶向特性,采用薄膜分散法结合pH梯度法与后插入法制备了修饰有Tat-TOS的载FIPI和阿霉素的多组分脂质体,并进行理化性质测定,最后评价了细胞对该制剂的体外摄取能力。研究结果表明,所制备脂质体具备粒径分布均一,粒径小的特点,FIPI和DOX的包封率均超过85%,无论是游离还是脂质体包载的Tat-TOS均能显著提高诱导肿瘤细胞凋亡的能力,表面修饰了Tat-TOS的脂质体具有明显聚集于健康肺组织和肿瘤转移肺组织,多组分脂质体具有最强的细胞摄取能力,预示该脂质体制剂具有更强的体外抗转移功效。

In the present study, we aimed to co-load the α-TOS conjugate Tat-TOS with the phospholipase D inhibitor FIPI and the antitumor drug doxorubicin（DOX） in a liposome delivery system for antitumor metastasis. Firstly, Tat-TOS was synthesized by solid-phase synthesis, and its structure was confirmed. The ability of free and liposomal Tat-TOS to induce apoptosis in vitro was evaluated by flow cytometry. Biodistribution of Tat-TOS-loaded liposomes was investigated by a molecular imaging system. Multi-component-loaded liposomes modified with Tat-TOS containing FIPI and DOX was prepared by thin film dispersion method in combination with p H gradient method and post-insertion method. Physicochemical properties were determined, and the in vitro uptake ability of the formulations was evaluated. The results showed that the prepared liposomes were characterized by a uniform particle size distribution and small particle size. The encapsulation efficiency of FIPI and DOX exceeded 85%. Both free and liposomal Tat-TOS significantly improved the activity of inducing apoptosis of tumor cells. The liposomes modified with Tat-TOS were apparently accumulated in normal lung tissue and tumor metastasized lung. Multi-component-loaded liposomes exhibited the strongest cell uptake capacity, suggesting a stronger anti-metastatic effect and anti-tumor activity in vivo.