Follicle-stimulating hormone peptide-conjugated nanoparticles for targeted shRNA delivery lead to effective gro-α silencing and antitumor activity against ovarian cancer

Abstract

The distinct hormone molecules and receptors, such as follicle-stimulating hormone receptor (FSHR) in ovarian cancer, provide opportunities for more precisely targeted therapy. We previously developed FSHR-mediated nanoparticles and found that FSH peptides on the surface of nanoparticles improved the delivery of short interfering RNA (siRNA) into ovarian cancer cells. However, the high toxicity of the nanoparticles and the transient silencing of the siRNA in vivo limited further study. Here, we developed FSH peptide-conjugated nanoparticles with an increased amount of polyethylene glycol (PEG) grafting and encapsulated short hairpin RNA (shRNA) to silence the target gene, growth-regulated oncogene α (gro-α). The nanoparticle complexes exhibited good stability over three weeks. Expression of the target gene, gro-α, was significantly down-regulated by gro-α shRNA-loaded nanoparticles conjugated with FSH peptides (FSH33-G-NP) in FSHR-positive HEY cells. Cell proliferation, migration, and invasion were also inhibited by FSH33-G-NP. Tumor growth was delayed significantly in the mice treated with FSH33-G-NP. No significant loss of body weight or severe toxic effects were observed in any groups. In conclusion, gro-α shRNA-loaded nanoparticles conjugated with FSH peptides overcame the drawbacks of the in vivo application of RNAi therapeutics and polymer-based nanocarriers and showed safe antitumor efficacy. Our study might contribute to the application of FSHR-based targeted therapy and imaging in cancer.

Transcriptional control of the MUC16 promoter facilitates follicle-stimulating hormone peptide-conjugated shRNA nanoparticle-mediated inhibition of ovarian carcinoma in vivo

“…To investigate the silencing effects of the nanoparticle complexes on the target gene, the levels of gro-α secreted in supernatants of the ovarian cancer cells were measured by ELISA. FSHR expression in the ovarian cancer cells that we used has been reported previously (Hong et al., 2013 ; Hong et al., 2018 ). As shown in Figure 3 , HEY cells (which are positive for both FSHR and MUC16) exhibited a decrease in gro-α secretion levels at 24 h and 48 h after treatment with the nanoparticle complexes containing the MUC16.1 promoter.…”

“…The pcDNA3.1 + vector containing gro-α shRNA driven by the MUC16 promoter (MUC16-shGro) was loaded into PEG-PEI copolymers. The nanoparticles modified with or without FSH β 33-53 peptide (YTRDLVYKDPARPKIQKTCTF) were prepared as described in our previous study (Hong et al., 2013 ; Hong et al., 2018 ). Briefly, the mixture of FSH peptides and Maleimide PEG NHS (MW 3,500 Da) (Jenkem Technology, China) was allowed to react for 6 h at room temperature with a molar ratio of 4:1.…”

“…An analysis based on TCGA datasets has shown that FSHR is expressed in multiple histological subtypes of ovarian cancer (Perales-Puchalt et al., 2017 ). We have previously reported a targeted delivery system for paclitaxel and RNA interference (RNAi) drugs of growth-regulated oncogene α (gro-α) using FSHR-binding fragments as targeting moieties, which promoted the uptake of drugs by FSHR-expressing ovarian cancer cells (Zhang et al., 2009 ; Hong et al., 2013 ; Hong et al., 2018 ).…”

Strategies for Delivery of siRNAs to Ovarian Cancer Cells

“…A rather novel approach to particle targeting to OC was developed by Hong et al [119]. The strategy was based on the equipment of PEG–PEI particles with a short peptide mimicking the sequence of the follicle-stimulating hormone (FSH) (Table 6).…”

Correlation of LAMA3 with onset and prognosis of ovarian cancer

“…However, there are few studies on LAMA3 in ovarian cancer. In particular, the characteristics of this gene in the occurrence and development of lung cancer remain unclear (8,9).…”