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阿霉素共轭负载Beclin1小干扰RNA的三甲基壳聚糖聚合物胶束用于耐药性膀胱癌治疗的合成、抗肿瘤活性及分子机制

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

作者信息

Zhong Zhou, Cheng Zhong, Su Dongyuan, Xu Ting, Li Xiang, Wu Fengbo

机构信息

Department of Urology and Department of Orthopaedic Surgery, West China Hospital, Sichuan University Chengdu 610041 China

Department of Pharmacy, West China Hospital, Sichuan University Chengdu 610041 China.

出版信息

RSC Adv. 2018 Oct 16;8(62):35395-35402. doi: 10.1039/c8ra06548a. eCollection 2018 Oct 15.

DOI:10.1039/c8ra06548a
PMID:35547901
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9087860/
Abstract

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 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, 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.

摘要

在此，我们描述了一种便捷的方法，用于制备一种聚合物胶束，该胶束使用与Beclin-1小干扰RNA（Si-Beclin1）偶联的阿霉素（DOX）共轭三甲基壳聚糖（TMC）（Si-Beclin1/DOX-TMC）。这种胶束在BIU-87/ADR细胞系中显示出强大的自噬抑制能力，并逆转了对阿霉素的耐药性。Si-Beclin1/DOX-TMC胶束对药物敏感的BIU-87细胞和耐药的BIU-87/ADR细胞均具有高度细胞毒性。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。阿霉素通过pH敏感的席夫碱与TMC偶联，该席夫碱对酸性溶酶体微环境有反应，导致阿霉素在细胞质中释放。通过核磁共振（NMR）、凝胶渗透色谱（GPC）、透射电子显微镜（TEM）和动态光散射（DLS）对阿霉素与TMC聚合物胶束的偶联结构进行了表征。通过高效液相色谱（HPLC）测定了不同pH环境下阿霉素的释放曲线。使用荧光显微镜观察细胞摄取、细胞核形态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给予Si-Beclin1/DOX-TMC胶束的抗肿瘤活性，结果显示Si-Beclin1/DOX-TMC胶束显著抑制了肿瘤生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/0c688aaa4370/c8ra06548a-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/7b89421f95b6/c8ra06548a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/0c688aaa4370/c8ra06548a-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/8e0b50d7b05a/c8ra06548a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/870be13e8f6e/c8ra06548a-f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/db0e6dbf575b/c8ra06548a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/d6aebb602c10/c8ra06548a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/7b89421f95b6/c8ra06548a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba8c/9087860/0c688aaa4370/c8ra06548a-f8.jpg

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