Abstract
MiR-34a, an important tumor suppressor, has been demonstrated to possess great potential in tumor gene therapy. To achieve the upregulation of miR-34a expression level, an oligoethyleneimine (OEI) derivative was constructed and employed as the carrier through the modification with lipoic acid (LA), namely LA-OEI. In contrast to OEI, the derivative LA-OEI exhibited superior transfection efficiency measured by confocal laser scanning microscopy and flow cytometry, owing to rapid cargo release in the disulfide bond-based reduction sensitive pattern. The anti-proliferation and anti-migration effects were tested after the miR-34a transfection to evaluate the anti-tumor response, using human cervical carcinoma cell line HeLa as a model. The delivery of LA-OEI/miR-34a nanoparticles could achieve obvious anti-proliferative effect caused by the induction of cell apoptosis and cell cycle arrest at G1 phase. In addition, it could inhibit the migration of tumor cells via the downregulation of MMP-9 and Notch-1 level. Overall, the LA-OEI-mediated miR-34a delivery was potential to be used as an effective way in the tumor gene therapy.
Highlights
Cancer has been accepted as a leading cause of death in humans [1], and conventional therapeutic strategies based on radiotherapy, chemotherapy and surgery still remain a formidable challenge for the recurrence of cancer [2,3]
Since miRNAs are susceptible to pH or enzymes in vivo, the protective effect of lipoic acid (LA)-OEI was conducted through the incubation of LA-OEI/miR-34a nanoparticles with RNase A and 50% fetal bovine serum (FBS), respectively, which were treated with heparin and analyzed through agarose gel electrophoresis (Figure S2)
Free miR-34a could be degraded by the treatment with 50% FBS or RNase A, while clear bands of miR-34a were found for LA-OEI/miR-34a groups after the treatment with 50% FBS or RNase A, indicating that the derivative LA-OEI could protect miR-34a against the degradation of RNase A and 50% FBS
Summary
Cancer has been accepted as a leading cause of death in humans [1], and conventional therapeutic strategies based on radiotherapy, chemotherapy and surgery still remain a formidable challenge for the recurrence of cancer [2,3]. Except for these routes, gene therapy has been widely investigated in which exogenous nucleic acids were used as therapeutics to suppress the oncogenes and trigger the anti-proliferation and anti-migration effects of tumors [4,5]. MiR-34a has been confirmed to be a well-defined tumor suppressor which could persuade the cell apoptosis, the cell cycle arrest at G1 phase and restrain the migration of tumor cells by decreasing the expression of Bc1-2, Notch-1, survivin, CD44 and the cyclin family [9,10,11,12,13]
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