Degradable Cationic Polycarbamates Designed for Robust IL-12 Gene Therapy against Metastatic Lung Cancer

Abstract

Polyethylenimine (PEI)-based gene carriers hold a massive promise for nonviral gene delivery against cancers. However, their poor degradability regularly results in rather high cytotoxicity, thus seriously hampering further clinical translations. Herein, a group of degradable cationic polycarbamates (CPCs) were finely designed to possess similar chemical structures with the PEIs for nonviral gene transfection. These CPCs containing multiple primary (or secondary) plus tertiary amino groups were synthesized by the polycondensation reaction of tertiary amino-containing primary diamines and the biscarbonates with butoxycarbonyl-protected primary (or secondary) amino groups, followed by the removal of the protecting group. These CPCs displayed degradation profiles under physiological conditions and degraded more rapidly when comprising the secondary amino groups compared with the primary amino residues. Moreover, these CPCs had favorable gene delivery properties including strong gene condensation ability and high buffering capacity as well as less cytotoxicity in comparison with nondegradable PEI controls, giving rise to efficient in vitro gene transfection in varied cells. Particularly, the secondary amino-containing CPCs based on the Nmethyl-2, 2′-diaminodiethylamine (denoted as BHE-MDE) caused excellent in vitro transfection activity selectively in type-II alveolar epithelial cells compared to other cells. The transfection efficiency of the BHE-MDE in the epithelial cells was comparable to that of 25 kDa linear PEI (LPEI) as a positive control. In the C57BL/6 mouse model, similar to this positive control, the BHE-MDE induced a high level of transgene expression in the lung and marked IL-12 expression in the mouse peripheral blood. As such, the BHE-MDE-mediated IL-12 expression afforded highly robust gene therapy against metastatic LLC cells in the lung of mice, thereby prolonging their survival time. The results indicate great potential of degradable LPEI-mimetic CPCs for nonviral gene therapy against metastatic lung cancer.