Enzymatically synthesized poly(amino-co-ester) polyplexes for systemic delivery of pcDNA-miRNA-214 to suppress 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.