Xiong Qingqing, Cui Mangmang, Yu Ge, Wang Jian, Song Tianqiang
Department of Hepatobiliary Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Hebei province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China.
Front Pharmacol. 2018 Feb 6;9:61. doi: 10.3389/fphar.2018.00061. eCollection 2018.
Combination of doxorubicin with sorafenib (SF) was reported to be a promising strategy for treating hepatocellular carcinoma (HCC). In this study, we designed a reduction-responsive supramolecular nanosystem based on poly (ethylene glycol)-β-cyclodextrin (PEG-CD) and a disulfide-containing adamantine-terminated doxorubicin prodrug (AD) for efficient co-delivery of doxorubicin and sorafenib. PEG-CD/AD supramolecular amphiphiles were formed through host-guest interaction between cyclodextrin and adamantine moieties, and then self-assembled into regular spherical nanoparticles with a uniform size of 166.4 nm. Flow cytometry analysis and confocal laser scanning microscopy images showed that PEG-CD/AD nanoparticles could be successfully taken up by HepG2 cells and then released doxorubicin into the cell nuclei. Moreover, sorafenib could be facilely encapsulated into the hydrophobic cores to form PEG-CD/AD/SF nanoparticles with a slightly larger size of 186.2 nm. PEG-CD/AD/SF nanoparticles sequentially released sorafenib and doxorubicin in a reduction-response manner. cytotoxicity assay showed that PEG-CD/AD/SF nanoparticles had an approximately 4.7-fold decrease in the IC value compared to that of PEG-CD/AD and SF physical mixtures, indicating stronger inhibitory effect against HepG2 cells by co-loading these two drugs. In summary, this novel supramolecular nanosystem provided a simple strategy to co-deliver doxorubicin and sorafenib toward hepatoma cells, which showed promising potential for treatment of HCC.
据报道，阿霉素与索拉非尼（SF）联合使用是治疗肝细胞癌（HCC）的一种有前景的策略。在本研究中，我们设计了一种基于聚乙二醇-β-环糊精（PEG-CD）和含二硫键的金刚烷末端阿霉素前药（AD）的还原响应超分子纳米系统，用于高效共递送阿霉素和索拉非尼。PEG-CD/AD超分子两亲物通过环糊精与金刚烷部分之间的主客体相互作用形成，然后自组装成尺寸均匀为166.4 nm的规则球形纳米颗粒。流式细胞术分析和共聚焦激光扫描显微镜图像显示，PEG-CD/AD纳米颗粒可被HepG2细胞成功摄取，然后将阿霉素释放到细胞核中。此外，索拉非尼可轻松封装到疏水核中，形成尺寸稍大、为186.2 nm的PEG-CD/AD/SF纳米颗粒。PEG-CD/AD/SF纳米颗粒以还原响应方式依次释放索拉非尼和阿霉素。细胞毒性试验表明，与PEG-CD/AD和SF物理混合物相比，PEG-CD/AD/SF纳米颗粒的IC值降低了约4.7倍，表明通过共负载这两种药物对HepG2细胞具有更强的抑制作用。总之，这种新型超分子纳米系统为向肝癌细胞共递送阿霉素和索拉非尼提供了一种简单策略，显示出治疗HCC的潜在前景。
