Synthesis, antitumor activity and molecular mechanism of doxorubicin conjugated trimethyl-chitosan polymeric micelle loading Beclin1 siRNA for drug-resisted bladder cancer therapy,RSC Advances

当前位置： X-MOL 学术 › RSC Adv. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Synthesis, antitumor activity and molecular mechanism of doxorubicin conjugated trimethyl-chitosan polymeric micelle loading Beclin1 siRNA for drug-resisted bladder cancer therapy
RSC Advances ( IF 3.9 ) Pub Date : 2018-10-16 00:00:00 , DOI: 10.1039/c8ra06548a
Zhou Zhong _{1,

2} , Zhong Cheng ₃ , Dongyuan Su ₄ , Ting Xu ₂ , Xiang Li ₁ , Fengbo Wu _{1,

2}

Affiliation

Herein, we describe a convenient approach for the preparation of a polymeric micelle using doxorubicin (DOX) conjugated trimethyl-chitosan (TMC) with Beclin-1 siRNA (Si-Beclin1/DOX-TMC). This micelle displayed a potent capacity for autophagy inhibition and reversed drug-resistance to DOX in BIU-87/ADR cell lines. The Si-Beclin1/DOX-TMC micelle was highly cytotoxic to both drug-sensitive BIU-87 and drug-resistant BIU-87/ADR cells. Its capacity to reverse drug-resistance was dependent upon upregulation of autophagy levels in BIU-87/ADR cells. DOX was conjugated to TMC via a pH-sensitive Schiff base, which responded to the acidic lysosome microenvironment and resulted in the cytoplasmic release of DOX. The structure of DOX conjugation to the TMC polymeric micelle was characterized by NMR, GPC, TEM and DLS. DOX release profiles in different pH environment were determined by HPLC. Cellular uptake, changes to nuclei morphology and formation of autophagosomes were observed using a fluorescence microscope. Finally, in vivo antitumor activity of systemic Si-Beclin1/DOX-TMC micelle administration was evaluated in BIU-87/ADR xenograft models and Si-Beclin1/DOX-TMC micelles showed significantly suppressed tumor growth.

中文翻译：

多柔比星偶联三甲基壳聚糖聚合物胶束负载Beclin1 siRNA用于耐药性膀胱癌治疗的合成、抗肿瘤活性及分子机制

在这里，我们描述了一种使用多柔比星 (DOX) 共轭三甲基壳聚糖 (TMC) 与 Beclin-1 siRNA (Si-Beclin1/DOX-TMC) 制备聚合物胶束的便捷方法。这种胶束在 BIU-87/ADR 细胞系中显示出强大的自噬抑制能力和逆转对 DOX 的耐药性。Si-Beclin1/DOX-TMC 胶束对药物敏感的 BIU-87 和耐药的 BIU-87/ADR 细胞具有高度细胞毒性。其逆转耐药性的能力取决于 BIU-87/ADR 细胞中自噬水平的上调。DOX通过以下方式与 TMC 结合一种对 pH 敏感的席夫碱，它对酸性溶酶体微环境作出反应并导致 DOX 的细胞质释放。DOX 与 TMC 聚合物胶束的共轭结构通过 NMR、GPC、TEM 和 DLS 进行了表征。通过 HPLC 测定不同 pH 环境中的 DOX 释放曲线。使用荧光显微镜观察细胞摄取、细胞核形态的变化和自噬体的形成。最后，在 BIU-87/ADR 异种移植模型中评估了全身性 Si-Beclin1/DOX-TMC 胶束给药的体内抗肿瘤活性，并且 Si-Beclin1/DOX-TMC 胶束显示出显着抑制肿瘤生长。

更新日期：2018-10-16

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11