Enzymatically synthesized poly(amino-co-ester) polyplexes for systemic delivery of pcDNA-miRNA-214 to suppress colorectal cancer liver metastasis. Issue 40 (24th September 2018)

• Record Type: Journal Article
• Authors: Luo, Hui-yan; Yang, Zhe; Wei, Wei; Li, Ying-qin; Pu, Hengying; Chen, Ya; Sheng, Hui; Liu, Jie; Xu, Rui-hua
• Is Part Of: Journal of materials chemistry. Volume 6:Issue 40(2018)
• Page Start: 6365
• Page End: 6376
• Publication Date: 2018-09-24
• Subjects: Materials -- Periodicals; Chemistry, Analytic -- Periodicals; Biomedical materials -- Research -- Periodicals; 543.0284
• DOI: 10.1039/c8tb01932k
• Languages: English
• ISSNs: 2050-750X

Abstract

Abstract : Upregulation of miRNA-214 expression level by PPMS polyplexes can efficiently inhibit colorectal cancer liver metastasis. Abstract : Liver metastases from colorectal cancer (CRC) are the major cause of cancer-related deaths in CRC patients. In our previous study, microRNA-214 (miR-214) was identified in CRC patients as a novel regulator of CRC liver metastasis, which could serve as a therapeutic target to inhibit CRC proliferation and metastasis. In this study, we aim to develop a new CRC treatment strategy based on miR-214 gene therapy using biodegradable non-viral gene vectors. We developed multifunctional quaternary polyplexes that consist of cationic poly(ω-pentadecalactone- co-N -methyldiethyleneamine- co -sebacate) (PPMS) for DNA condensation to form a nano-sized polyplex core, hyaluronic acids (HA) grafted with a poly(ethylene glycol) (PEG) (HA- g -mPEG) shell for polyplex stabilization and targeted delivery, and nuclear localization signal (NLS) peptides for enhanced intracellular transport of pDNA to the nucleus. The results showed that the DNA/NLS/PPMS/HA- g -mPEG quaternary polyplexes could enhance DNA condensation, increase cellular uptake efficiency and decrease cytotoxicity. Most importantly, the quaternary polyplexes showed favorable transfection efficiency both in vitro and in vivo . The colony formation and migration ability were significantly inhibited in HCT116 cells transfected with pcDNA-miR-214 quaternary polyplexes. The up-regulation of miR-214 in HCT116 cells by pre-transfection of polyplexes-miR-214 could remarkably inhibit tumor growth and liver metastases in a xenograft mouse model. Furthermore, systemic administration of miR-214 using this multifunctional vector resulted in dramatic inhibition of liver metastasis without obvious toxicity in CRC xenografted mice. Collectively, systemic delivery of pcDNA-miR-214 by this multifunctional vector could be a powerful and highly specific therapeutic approach in the treatment of CRC liver metastasis.