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Bioreducible crosslinked cationic nanopolyplexes from clickable polyethylenimines enabling robust cancer gene therapy.
Nanomedicine: Nanotechnology, Biology and Medicine ( IF 4.2 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.nano.2019.102144 Kangkang An 1 , Huizhi Fengyan 1 , Xinting Xu 2 , Rong Jin 3 , Xiaoxin Hu 2 , Peng Zhao 2 , Chao Lin 4
Nanomedicine: Nanotechnology, Biology and Medicine ( IF 4.2 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.nano.2019.102144 Kangkang An 1 , Huizhi Fengyan 1 , Xinting Xu 2 , Rong Jin 3 , Xiaoxin Hu 2 , Peng Zhao 2 , Chao Lin 4
Affiliation
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Bioreducible crosslinked polyplexes from branched polyethylenimine (BPEI, 10 kDa) were successfully constructed through DNA neutralization by disulfide-linked azidated BPEI (PAZ) and subsequent DNA condensation by azadibenzocyclooctyne-modified BPEI (PDB), following their self-crosslinking via azide-azadibenzocyclooctyne click chemistry. Click-crosslinked cationic polyplexes (c-polyplexes) revealed high extracellular colloidal stability against negative heparin and ions while intracellular bioreducible degradability for efficient gene unpacking. In vitro gene transfection in cancer cells indicated that the c-polyplexes produced markedly higher transfection efficiency than non-crosslinked counterparts in the serum. The c-polyplexes also had prolonged circulation kinetics, elevated gene accumulation level in SKOV-3 tumor xenografted in a mouse model and in turn superior transgene expression in the tumor. By small hairpin RNA for VEGF silencing, the c-polyplexes exerted significant tumor growth inhibition following with low systemic toxicity in the mouse. This study highlights the design of clickable polycations to construct crosslinked cationic nanopolyplexes for intravenous gene delivery against cancer.
中文翻译：
可点击的聚乙烯亚胺的可生物还原的交联阳离子纳米复合物，可实现强大的癌症基因治疗。
支链聚乙烯亚胺（BPEI，10 kDa）的可生物还原的交联多聚体是通过二硫键连接的叠氮化BPEI（PAZ）进行DNA中和并由azadibenzocyclooctyne修饰的BPEI（PDB）随后进行DNA缩合而成功构建的，之后通过叠氮化物-azadibenzocyclooctyne自交联化学。单击交联的阳离子多聚体（c-多聚体）显示出对负肝素和离子具有高的细胞外胶体稳定性，而细胞内生物可降解的降解性可有效地解开基因。癌细胞中的体外基因转染表明，与血清中非交联的对应物相比，c-polyplex产生的转染效率显着更高。c-多聚体还具有延长的循环动力学，在小鼠模型中异种移植的SKOV-3肿瘤中，其基因积累水平升高，进而在肿瘤中表现出更高的转基因表达。通过用于VEGF沉默的小发夹RNA，c-多聚体在小鼠中具有低的全身毒性之后表现出显着的肿瘤生长抑制作用。这项研究强调了可点击的聚阳离子的设计，以构建用于静脉输注抗癌基因的交联阳离子纳米复合物。
更新日期：2019-12-13
中文翻译：
可点击的聚乙烯亚胺的可生物还原的交联阳离子纳米复合物，可实现强大的癌症基因治疗。
支链聚乙烯亚胺（BPEI，10 kDa）的可生物还原的交联多聚体是通过二硫键连接的叠氮化BPEI（PAZ）进行DNA中和并由azadibenzocyclooctyne修饰的BPEI（PDB）随后进行DNA缩合而成功构建的，之后通过叠氮化物-azadibenzocyclooctyne自交联化学。单击交联的阳离子多聚体（c-多聚体）显示出对负肝素和离子具有高的细胞外胶体稳定性，而细胞内生物可降解的降解性可有效地解开基因。癌细胞中的体外基因转染表明，与血清中非交联的对应物相比，c-polyplex产生的转染效率显着更高。c-多聚体还具有延长的循环动力学，在小鼠模型中异种移植的SKOV-3肿瘤中，其基因积累水平升高，进而在肿瘤中表现出更高的转基因表达。通过用于VEGF沉默的小发夹RNA，c-多聚体在小鼠中具有低的全身毒性之后表现出显着的肿瘤生长抑制作用。这项研究强调了可点击的聚阳离子的设计，以构建用于静脉输注抗癌基因的交联阳离子纳米复合物。
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