Abstract
Gene therapy is emerging as a valid method for the treatment of ovarian cancer, including small interfering RNA (siRNA). Although it is so powerful, few targeting efficient gene delivery systems seriously hindered the development of gene therapy. In this study, we synthesized a novel gene vector PEG-GO-PEI-FA by functionalized graphene oxide (GO), in which folic acid (FA) can specifically bind to the folate receptor (FR), which is overexpressed in ovarian cancer. Characterizations of the nanocomplexes were evaluated by dynamic light scattering (DLS), atomic force microscopy (AFM), and Fourier transform infrared spectroscopy (FTIR). The siRNA condensation ability and stability were assessed by agarose gel electrophoresis. Cellular uptake efficiency and lysosomal escape ability in ovarian cancer cells were investigated by confocal laser scanning microscopy. Furthermore, cellular biosafety of the system and inhibitory of the siRNA tolerability were evaluated by CCK-8 assay. The size of the PEG-GO-PEI-FA nanocomplexes was 216.1 ± 2.457 nm, exhibiting mild cytotoxicity in ovarian cancer cells. With high uptake efficiency, PEG-GO-PEI-FA can escape from the lysosome rapidly and release the gene. Moreover, PEG-GO-PEI-FA/siRNA can effectively inhibit the growth of ovarian cancer cells. By and large, the PEG-GO-PEI-FA/siRNA may offer a promising strategy for siRNA delivery in the treatment of FR-positive ovarian carcinoma or similar tumors.
Highlights
Ovarian cancer is the leading gynecological cause of death in the world and is usually associated with poor clinical outcomes due to the difficulties of early diagnosis and therapy [1–3]
Synthesis of Polyethylene glycol (PEG)-graphene oxide (GO)-PEI-folic acid (FA) The expression of folate receptor (FR) was firstly analyzed in different cancer cell lines based on the Cancer Cell Line Encyclopedia (CCLE; http://portals.broadinstitute. org/ccle) database [30] and different tissues of ovary based on the Gene Expression Profiling Interactive Analysis (GEPIA2; http:// gepia2.cancer-pku.cn) database [31]
After PEI and FA reacted with GO, the NH (1590 cm−1), C–N (1420 cm−1) stretching vibration band was observed, indicating PEI and FA had been grafted to GO by esterification
Summary
Ovarian cancer is the leading gynecological cause of death in the world and is usually associated with poor clinical outcomes due to the difficulties of early diagnosis and therapy [1–3]. The lack of a safe, highly efficient, and. GO has been widely used for photothermal cancer therapy, drug and gene delivery, and biosensors [20–22]. PEI shows severe cytotoxicity and poor biocompatibility, thereby limiting its clinical applications. We observed a significant decrease in cytotoxicity when PEI was grafted to the surface of GO. Folate receptor is over-expressing on various cancer cells surface, especially in ovarian cancer cells both before and after chemotherapy [27]. Folic acid molecules were covalently bonded with GO to target folate receptors
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