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Reactive Oxygen Species-Biodegradable Gene Carrier for the Targeting Therapy of Breast Cancer

Ruan, Chunhui, Liu, Lisha, Wang, Qingbing, Chen, Xinli, Chen, Qinjun, Lu, Yifei, Zhang, Yu, He, Xi, Zhang, Yujie, Guo, Qin, Sun, Tao, Jiang, Chen
ACS applied materials & interfaces 2018 v.10 no.12 pp. 10398-10408
biocompatibility, boric acid, breast neoplasms, crosslinking, dissociation, gene silencing, genes, ligands, molecular weight, nanoparticles, neoplasm cells, oxygen, plasmids, polyethylene glycol, polyethyleneimine, reactive oxygen species, small interfering RNA, substance P, therapeutics, toxicity, transfection
An ideal gene-carrying vector is supposed to exhibit outstanding gene-condensing capability with positively charged macromolecules to protect the carried gene during in vivo circulation and a rapid dissociation upon microenvironmental stimuli at the aimed sites to release the escorted gene. Currently, it still remains a challenge to develop an ideal gene carrier with efficient transfection ability and low toxicity for clinical applications. Herein, we have innovatively introduced a reactive oxygen species (ROS)-biodegradable boric acid ester linkage in elaborating the design of a gene carrier. In virtue of the featured intracellular characteristics such as the high level of ROS in tumor cells, an ROS-biodegradable electropositive polymer derived from branched polyethylenimine (BPEI) with a low molecular weight (1.2k) through a cross-linking reaction by the boric acid ester bond was developed in this study to achieve condensation and escorting of carried genes. Furthermore, the polymer was modified with substance P (SP) peptide as the targeting ligand through polyethylene glycol. The final fabricated SP-cross-linked BPEI/plasmid DNA nanoparticles exhibit favorable biocompatibility, ROS-cleavability, and fine targeting ability as well as high transfection efficiency compared with parental BPEI₁.₂ₖ both in vitro and in vivo. SP-cross-linked BPEI/small interfering RNA (pololike kinase 1) polyplex possesses favorable gene-silencing effects in vitro and satisfactory antitumor ability in vivo. Hopefully, this novel cross-linked electropositive polymer may serve well as a safe and efficient gene-delivery vehicle in the clinic.