Metformin-conjugated micellar system with intratumoral pH responsive de-shielding for co-delivery of doxorubicin and nucleic acid.
Metformin-conjugated micellar system with intratumoral pH responsive de-shielding for co-delivery of doxorubicin and nucleic acid.
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DOI：
10.1016/j.bcp.2021.114453
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发表时间：
2021-07
影响因子：
5.8
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Liu Y;Sun J;Huang Y;Chen Y;Li J;Liang L;Xu J;Wan Z;Zhang B;Li Z;Li S
开发了一种新型PMet-P（cdmPEG 2K）聚合物胶束载体，用于DOX和核酸（NA）的肿瘤靶向共递送，该载体基于聚二甲双胍和设计为响应于酸性细胞外肿瘤环境而失去PEG壳的结构。NA/DOX共负载的胶束复合物表现出增强的细胞增殖抑制相比，DOX负载的胶束，并显示出较高水平的细胞毒性在酸性pH值（6.8），模拟肿瘤微环境。PMet-P（cdmPEG 2K）胶束实现了报告质粒或Cy 3-siRNA的转染显著改善，并增强了4T1.2细胞在pH 6.8下的DOX细胞内摄取。重要的是，PMet-P（cdmPEG 2K）胶束在侵袭性鼠乳腺癌（4T1.2）模型中显示出优异的pEGFP（EGFP表达质粒）转染。利用编码IL-12的质粒（pIL-12），我们研究了化疗和基因治疗的联合作用。与单独负载DOX或pIL-12的胶束相比，共负载DOX和pIL-12的PMet-P（cdmPEG 2K）胶束在抑制肿瘤生长方面更有效。此外，该胶束系统可有效地将siRNA和DOX共递送到肿瘤细胞中。我们的研究结果表明，PMet-P（cdmPEG 2K）具有潜在的化疗和核酸联合治疗癌症。
A novel PMet-P(cdmPEG2K) polymeric micellar carrier was developed for tumor-targeted co-delivery of DOX and nucleic acids (NA), based on polymetformin and a structure designed to lose the PEG shell in response to the acidic extracellular tumor environment. NA/DOX co-loaded micelleplexes exhibited enhanced inhibition of cell proliferation compared to DOX-loaded micelles, and displayed a higher level of cytotoxicity at an acidic pH (6.8) which mimicks the tumor microenvironment. The PMet-P(cdmPEG2K) micelles achieved significantly improved transfection with either a reporter plasmid or Cy3-siRNA, and enhanced DOX intracellular uptake in 4T1.2 cells at pH 6.8. Importantly, PMet-P(cdmPEG2K) micelles showed excellent pEGFP (EGFP expression plasmid) transfection in an aggressive murine breast cancer (4T1.2) model. By using a plasmid encoding IL-12 (pIL-12), we investigated the combined effect of chemotherapy and gene therapy. PMet-P(cdmPEG2K) micelles co-loaded with DOX and pIL-12 were more effective at inhibiting tumor growth compared to micelles loaded with DOX or pIL-12 alone. In addition, this micellar system was effective in co-delivery of siRNA and DOX into tumor cells. Our results suggest that PMet-P(cdmPEG2K) has the potential for chemo and nucleic acid combined cancer therapy.
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发表时间：
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期刊：
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影响因子：
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期刊：
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