A Co-Delivery System of Curcumin and p53 for Enhancing the Sensitivity of Drug-Resistant Ovarian Cancer Cells to Cisplatin

Abstract

In order to enhance the sensitivity of drug-resistant ovarian cancer cells to cisplatin (DDP), a co-delivery system was designed for simultaneous delivery of curcumin (CUR) and p53 DNA. Firstly, the bifunctional peptide K14 composed of tumor targeting peptide (tLyP-1) and nuclear localization signal (NLS) was synthesized. A nonviral carrier (PEI-K14) was synthesized by cross-linking low molecular weight polyethyleneimine (PEI) with K14. Then, CUR was coupled to PEI-K14 by matrix metalloproteinase 9 (MMP9)-cleavable peptide to prepare CUR-PEI-K14. A co-delivery system, named CUR-PEI-K14/p53, was obtained by CUR-PEI-K14 and p53 self-assembly. Furthermore, the physicochemical properties and gene transfection efficiency were evaluated. Finally, ovarian cancer cisplatin-resistant (SKOV3-DDP) cells were selected to evaluate the effect of CUR-PEI-K14/p53 on enhancing the sensitivity of drug-resistant cells to DDP. The CUR-PEI-K14/DNA complexes appeared uniformly dispersed and spherical. The particle size was around 20–150 nm and the zeta potential was around 18–37 mV. It had good stability, high transfection efficiency, and low cytotoxicity. CUR-PEI-K14/p53 could significantly increase the sensitivity of SKOV3-DDP cells to DDP, and this effect was better as combined with DDP. The sensitizing effect might be related to the upregulation of p53 messenger RNA (mRNA), the downregulation of P-glycoprotein (P-gp) mRNA, and the upregulation of BCL2-Associated X (bax) mRNA. CUR-PEI-K14/p53 can be used as an effective strategy to enhance the sensitivity of drug-resistant ovarian cancer cells to DDP.