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Reducible chimeric polypeptide consisting of octa-D-arginine and tetra-L-histidine peptides as an efficient gene delivery vector.

ABSTRACT: Cationic oligopeptide as a nonviral gene delivery vector has aroused much research interest recently, but its further application is limited by its low transfection efficiency. In the present study, we have created a high-efficiency gene vector by using octa-D-arginine and tetra-L-histidine to form a disulfide cross-linked chimeric polypeptide and used this vector to deliver the therapeutic gene tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) to see whether the gene could be transferred and could exert antitumor effects in vitro and in vivo. The result showed that the newly designed vector was able to condense DNA into nanosized polyplexes effectively, thus facilitating its transmembrane transport, promoting its endosomal escape, and finally enabling degradation within the cell. Our study has demonstrated that this chimeric polypeptide is an effective gene carrier in cancer therapy.

SUBMITTER: Wang X

PROVIDER: S-EPMC4516254 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Reducible chimeric polypeptide consisting of octa-D-arginine and tetra-L-histidine peptides as an efficient gene delivery vector.

Wang Xiaoyu X Tai Zongguang Z Tian Jing J Zhang Wei W Yao Chong C Zhang Lijuan L Gao Yuan Y Zhu Quangang Q Gao Jing J Gao Shen S

International journal of nanomedicine 20150722

Cationic oligopeptide as a nonviral gene delivery vector has aroused much research interest recently, but its further application is limited by its low transfection efficiency. In the present study, we have created a high-efficiency gene vector by using octa-D-arginine and tetra-L-histidine to form a disulfide cross-linked chimeric polypeptide and used this vector to deliver the therapeutic gene tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) to see whether the gene could be tran ...[more]

PMID: 26229469

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Project description:Linear (HR)n and cyclic [HR]n peptides (n = 4,5) containing alternate arginine and histidine residues were synthesized. The peptides showed 0⁻15% cytotoxicity at 5⁻100 µM in human ovarian adenocarcinoma (SK-OV-3) cells while they exhibited 0⁻12% toxicity in human leukemia cancer cell line (CCRF-CEM). Among all peptides, cyclic [HR]₄ peptide was able to improve the delivery of a cell impermeable fluorescence-labeled phosphopeptide by two-fold. Fatty acids of different alkyl chain length were attached at the N-terminal of the linear peptide (HR)₄ to improve the molecular transporter property. Addition of fatty acyl chains was expected to help with the permeation of the peptides through the cell membrane. Thus, we synthesized seven fatty acyl derivatives of the linear (HR)₄ peptide. The peptides were synthesized using Fmoc/tBu solid phase peptide chemistry, purified by reverse-phase high-performance liquid chromatography (RP-HPLC) and characterized by matrix-assisted laser desorption/ionization (MALDI) spectrometry. The fatty acyl peptides containing C₈, C12, C14, and C18 alkyl chain did not show cytotoxicity on SK-OV-3 or CCRF-CEM cell lines up to 50 µM concentration; however, at higher concentration (100 µM), they showed mild cytotoxicity. For example, C16-(HR)₄ was also found to reduce the proliferation of SK-OV-3 cells by 11% at 50 µM and C20-(HR)₄ showed mild toxicity at 10 µM, reducing the proliferation of SK-OV-3 cells by 21%. Increase in the length of alkyl chain showed cytotoxicity to the cell lines. C20-(HR)₄ peptide showed better efficiency in translocation of F′-GpYEEI to SK-OV-3 than the phosphopeptide alone. Further investigation of C20-(HR)₄ peptide efficacy showed that the peptide could deliver doxorubicin and epirubicin into SK-OV-3 and also improved the drug antiproliferative ability. These studies provided insights into understanding the structural requirements for optimal cellular delivery of the fatty acyl-(HR)₄ peptide conjugates.

Dataset Information

Reducible chimeric polypeptide consisting of octa-D-arginine and tetra-L-histidine peptides as an efficient gene delivery vector.

Publications

Reducible chimeric polypeptide consisting of octa-D-arginine and tetra-L-histidine peptides as an efficient gene delivery vector.

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