纳米级载药微泡的制备及其超声介导下的抑瘤研究

Preparation of Drug-loaded Nanobubbles and Their Ultrasound-mediated Antitumor Effect

具有超声造影剂和药物载体双重功能的聚乳酸(PLA)微泡存在着载药率较低以及不能有效地透过肿瘤组织等缺点.对此,以PLA和卵磷脂为药物载体,采用改良的超声复乳法制备载紫杉醇的PLA-卵磷脂纳米级微泡.考察了卵磷脂对载药微泡理化特性(包括:形态、粒径、载药量、包封率和体外释药特性)的影响,利用X-射线衍射分析(XRD)考察了药物在微泡中的状态,最后在超声介导下对荷瘤小鼠的抑瘤率进行了研究.结果表明,卵磷脂与PLA质量比为50∶250时可制备得到平均粒径615 nm、内部空心的纳米级微泡,药物包封率达(90.90±5.79)%,载药率为(8.26±0.53)%,紫杉醇以无定型状态分布在微泡的壳中.微泡的体外药物释放具有缓释、零级释放以及超声介导加快药物释放的特性,而通过对H22肝癌荷瘤小鼠的实验研究表明,相对于紫杉醇针剂而言,超声介导下载药PLA-卵磷脂纳米级微泡注射剂能减小对小鼠的毒副作用,提高抑瘤率.

Drug loaded PLA microbubbles that combine properties of ultrasound imaging contrast agents and drug carriers suffer from low encapsulation efficiency and do not allow effective extravasation into tumor tissue.In this paper,paclitaxel-loaded PLA-lecithin nanobubbles were developed with the method of modified ultrasonic double emulsion-solvent evaporation technology.The impact of lecithin content on physical and chemical properties of drug-loaded bubbles including morphology,particle size,drug loading,encapsulation efficiency and in vitro drug release characteristics were investigated,encapsulated drug state in the bubbles was detected,and drug-loaded bubbles combining ultrasound treatment of H22 tumor-beared mice was carried out.The results showed that the nanobubbles prepared with the mass ratio of PLA and lecithin at 250∶50 were characterized to be inner hollow,the size was around 615 nm,and the drug loading and encapsulation efficiency reached（8.26±0.53）% and（90.90±5.79）% respectively.X-ray diffraction analysis（XRD） showed paclitaxel was amorphously dispersed within the shell of the nanobubble.The in vitro drug release showed retained,zero-order release and ultrasound triggered properties.Paclitaxel-loaded nanobubbles combining ultrasound treatment of H22 tumor-beared mice presented enhanced antitumor rate and reduced side effects compared with the paclitaxel-injection.The results illustrated that the PLA-lecithin nanobubbles have great potential in targeted delivery to tumor tissue and ultrasound mediated anticancer therapy.