Zhu Dunwan, Wu Shengjie, Hu Chunyan, Chen Zhuo, Wang Hai, Fan Fan, Qin Yu, Wang Chun, Sun Hongfan, Leng Xigang, Kong Deling, Zhang Linhua
Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.
Department of Biomedical Engineering, University of Minnesota, 7-116 Hasselmo Hall, 312 Church Street S.E, Minneapolis, MN 55455, USA.
Acta Biomater. 2017 Aug;58:399-412. doi: 10.1016/j.actbio.2017.06.017. Epub 2017 Jun 13.
Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In this study, folate (FA) receptor-targeted polymersomes with apparent bilayered lamellar structure were successfully developed to co-encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (PTX and DOX) in a single vesicle for enhancing the combination chemotherapeutic effect. Hydrophobic PTX was loaded into the thick hydrophobic lamellar membrane by the self-assembly of triblock copolymer PCL-PEG-PCL, while hydrophilic DOX was encapsulated into the hydrophilic reservoir using a trans-membrane ammonium sulfate gradient method. In vitro release study indicated that the drugs were released from the polymersomes in a controlled and sustained manner. Cellular uptake study indicated that FA-targeted Co-PS had higher internalization efficiency in FA receptor-overexpressing BEL-7404 cells than non-targeted Co-PS. In vitro cytotoxicity assay demonstrated that FA-targeted Co-PS exhibited less cytotoxic effect than free drug cocktail, but suppressed the growth of tumor cells more efficiently than non-targeted Co-PS. Ex vivo imaging biodistribution studies revealed that FA-targeted Co-PS led to highly efficient targeting and accumulation in the BEL-7404 xenograft tumor. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of polymersomes to BEL-7404 tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy.
Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In our study, novel folate-targeted co-delivery polymersomes (Co-PS) were successfully developed to encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (paclitaxel and doxorubicin) into the different compartments of the vesicle. In vivo studies revealed that the combination chemotherapy of polymersomes to BEL-7404 xenograft tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy.
联合化疗是一种很有前景的改善癌症治疗的方法，但联合药物独特的药代动力学和非特异性药物分布减缓了其临床开发进程。在本研究中，成功制备了具有明显双层片状结构的叶酸（FA）受体靶向聚合物囊泡，以在单个囊泡中共包封一对疏水 - 亲水化疗药物（紫杉醇和阿霉素），从而增强联合化疗效果。疏水性紫杉醇通过三嵌段共聚物PCL - PEG - PCL的自组装被载入厚疏水层状膜中，而亲水性阿霉素则采用跨膜硫酸铵梯度法被包封在亲水储库中。体外释放研究表明，药物从聚合物囊泡中以可控且持续的方式释放。细胞摄取研究表明，FA靶向的共聚物囊泡（Co - PS）在FA受体过表达的BEL - 7404细胞中的内化效率高于非靶向的Co - PS。体外细胞毒性试验表明，FA靶向的Co - PS比游离药物混合物表现出更低的细胞毒性作用，但比非靶向的Co - PS更有效地抑制肿瘤细胞生长。离体成像生物分布研究表明，FA靶向的Co - PS导致在BEL - 7404异种移植肿瘤中高效靶向和积累。此外，体内抗肿瘤研究表明，通过静脉注射聚合物囊泡对BEL - 7404肿瘤进行联合化疗优于游离药物混合物治疗，并且FA靶向的Co - PS比非靶向的Co - PS组表现出显著更高的肿瘤生长抑制率。因此，新开发的FA靶向共递送聚合物囊泡在同时递送多种化疗药物方面具有很大潜力，并且在肿瘤靶向和联合化疗中具有巨大潜力。
联合化疗是一种很有前景的改善癌症治疗的方法，但联合药物独特的药代动力学和非特异性药物分布减缓了其临床开发进程。在我们的研究中，成功开发了新型叶酸靶向共递送聚合物囊泡（Co - PS），以将一对疏水 - 亲水化疗药物（紫杉醇和阿霉素）包封到囊泡的不同隔室中。体内研究表明，通过静脉注射聚合物囊泡对BEL - 7404异种移植肿瘤进行联合化疗优于游离药物混合物治疗，并且FA靶向的Co - PS比非靶向的Co - PS组表现出显著更高的肿瘤生长抑制率。因此，新开发的FA靶向共递送聚合物囊泡在同时递送多种化疗药物方面具有很大潜力，并且在肿瘤靶向和联合化疗中具有巨大潜力。
