纳米硫化铜载药红细胞靶向蓄积及提高肿瘤光热治疗效果研究

光热治疗偶联剂纳米硫化铜的临床应用,存在增加浓度、提高光热治疗效果的同时也增加毒副作用的矛盾。利用红细胞作为纳米硫化铜载体,体外激光照射控制其在肿瘤组织释放,增强光热治疗效果。采用改良低渗预膨胀法,将纳米硫化铜包载入红细胞,构建纳米硫化铜载药红细胞(CuS@ER);用小动物活体成像表征其肿瘤靶向效率,评价光热升温效果。40只荷瘤小鼠随机分为4组:对照组、单纯激光照射组、硫化铜+激光照射组和纳米硫化铜载药红细胞+激光照射组,每组10只,比较肿瘤体积变化率、生存率,并评价其安全性。结果表明:已成功构建纳米硫化铜载药红细胞,载药率为17.24 %±0.98%,包载后显著降低纳米硫化铜的细胞毒性。在0.44 W/cm² 的980 nm 激光作用下,光热效率超过53%。荷瘤小鼠给药后,激光作用2 min,肿瘤内硫化铜浓度高达(0.061 ± 0.007) μg/g,显著高于纳米硫化铜组的相应浓度(P<0.01)。纳米硫化铜载药红细胞给药组肿瘤内部温度达到60℃以上,与纳米硫化铜组相比具有显著统计学意义(P<0.01);肿瘤体积变化比为0.91 ± 0.02,与纳米硫化铜组相比具有显著性差异(P<0.01);48 d荷瘤小鼠存活率达90%,显著高于纳米硫化铜组。所构建的纳米硫化铜载药红细胞具有高肿瘤靶向率及优良的光热治疗效果,可为临床光热治疗提供一种新思路。

A Tumor Targeted Controlled-Release Nano-CuS Loaded Erythrocytes for Tumor Photothermal Therapy

The application of photothermal agent copper sulfide nanoparticles (CuS) requires an increase in the drug concentration to achieve desired therapeutic effect. However, the increase of drug concentration would lead to more side effects, which limited clinical applications. In this study, erythrocytes were used as the carriers for CuS, which can rapidly respond to the laser, and tumor targeted release of CuS can increase photothermal effects. In this work, 40 mice bearing tumor were randomly divided into 4 groups, control group, laser treated group, CuS+laser group, CuS@ER+laser group, there were 10 mice in each group. According to the modified expansion method, the nano CuS was packed into erythrocytes, and the laser-responsive release behavior was investigated after lasered. The target behavior was examined with a in vivo imaging detection system for small animals and the photothermal therapy effect was detected by thermal imager. Additional outcome measures included tumor response rate, overall survival, and safety. It was found out that CuS was loaded into erythrocytes and the loading efficiency was 17.24%±0.98%. The biocompatibility of the CuS was improved due to the encapsulation of erythrocytes and the photothermal conversion efficiency was over 53% after 0.44 W/cm² 980 nm laser radiation. The concentration of CuS in the tumor after CuS@ER treatment was(0.061±0.007)μg/g, it was significantly higher than that of the free nano-CuS treatment (P<0.01), because of laser-response release behavior. The inhibitory rate of tumor growth for the CuS@ER group was 0.91 ± 0.02 with less side effects, as the temperature of the photothermal therapy increased. The survival rate of CuS@ER treatment was 90% after 48 days with less side effects. Our study provided a promising strategy to increased photothermal therapy without concede biocompatibility, by using an erythrocyte-inspired and laser-activatable platform.