D-SP5 Peptide-Modified Highly Branched Polyethylenimine for Gene Therapy of Gastric Adenocarcinoma

Abstract

Peptide-mediated targeting of tumors has become an effective strategy for cancer therapy. Retro-inverso peptides resist protease degradation and maintain their bioactivity. We used the retro-inverso peptide D(PRPSPKMGVSVS) (D-SP5) as a targeting ligand to develop gene therapy for gastric adenocarcinoma. D-SP5 has a higher affinity for human gastric adenocarcinoma (SGC7901) cells compared with that of its parental peptide, L(SVSVGMKPSPRP) (L-SP5). Polyethylenimine (PEI)/pDNA, polyethylene glycol (mPEG)-PEI/pDNA and D-SP5-PEG-PEI/pDNA were prepared for further study. Quantitative luciferase assays showed the transfection efficiency of D-SP5-PEG-PEI/pGL(4.2) was larger compared with that of mPEG-PEI/pGL(4.2). Flow cytometry assays revealed that the apoptosis rates of SGC7901 cells treated with D-SP5-PEG-PEI/pTRAIL were larger than mPEG-PEI/pTRAIL. Western blot assays indicated that the expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) protein in SGC7901 cells treated with D-SP5-PEG-PEI/pTRAIL was higher compared with that in cells treated with mPEG-PEI/pTRAIL. In vivo pharmacodynamics study revealed that D-SP5-PEG-PEI/pTRAIL could inhibit the growth of gastric adenocarcinoma SGC7901 xenografts in nude mice. Our results demonstrate that D-SP5-PEG-PEI is a safe and efficient gene delivery vector with potential applications in antitumor gene therapy.

Retro-inverso follicle-stimulating hormone peptide-mediated polyethylenimine complexes for targeted ovarian cancer gene therapy

“…Accordingly, the antibody or peptide selected is the key to successful treatment of ovarian tumors (Schiffelers, 2004 ). Currently, the choice of target sites in ovarian cancer focuses on tumor cell surface molecules such as anti-angiogenesis receptor (Koneru et al., 2015 ) (vascular endothelial growth factor [VEGF], epidermal growth factor receptor [EGFR/ErbB]), blood markers of ovarian cancer (Li et al., 2015 ) (mucin 16 [MUC16], human epididymis protein 4 [HE4]), and glycosylated proteases related to suppressing ovarian tumor cell invasion and metastasis (BCL2 interacting killer [BIK]) (Kanhaiya et al., 2017 ). However, most of them do not move forward to clinical trials because of unsatisfactory treatment effects due to the lack of specificity.…”

D‐Peptides as Recognition Molecules and Therapeutic Agents

“…Additionally, Li et al . prepared RI‐SP5‐modified PEG‐PEI as a gene carrier, and both the in vitro and in vivo pharmacodynamics confirmed that RI‐SP5 had a greater therapeutic effect in gastric adenocarcinoma 100…”

Polyamide Backbone Modified Cell Targeting and Penetrating Peptides in Cancer Detection and Treatment

“…Retroinverso peptides consisting of D-amino acid residues in reversed sequence adopt side chain topologies similar to the parent peptide but with inverted amide bonds. These modifications have served to improve peptide metabolic stability but with limited capabilities of adopting bio-active peptide α-helical structures necessary for protein binding interactions and downstream biological signaling such as silencing gene expression in certain cancer types (Li et al, 2010(Li et al, , 2015. Main chain replacement with peptide amide bond isosteres (Williams et al, 1994;Hart and Etzkorn, 1999;Chen et al, 2017) have also resulted in important contributions in varying peptide conformation and stereoelectronic effects which impacts peptide bioactivity against receptor targets in cancer (Crombez et al, 2009).…”

“…Representative examples of polyamide backbone modified cell-targeting peptides described in this study. (A) c(RGDfV) (Kessler, 1997) (Dechantsreiter et al, 1999;Marinelli et al, 2003), (C) Pep42-(Val-Cit) 2 -PABO-Dox (Yoneda et al, 2008), (D) D-SP5 (Li et al, 2015).…”

“…The retro-inverso D-peptide (prpspkmgvsvs) (D-SP5) is an analog of the parental peptide, SP5-52, which was used as a targeting ligand for gastric adenocarcinoma (SGC7901) cells (Li et al, 2015). The D-SP5 was functionalized with a PEG spacer containing a reactive maleimide group for conjugation with polyethyleneimine (PEI) to generate the D-SP5-PEG-PEI formulation which effectively condensed plasmid DNA (pGL) according to DLS and gel retardation assays.…”