Yonsei Med J.  2018 Jul;59(5):595-601. 10.3349/ymj.2018.59.5.595.

A Tumor-Specific Tissue-Penetrating Peptide Enhances the Efficacy of Chemotherapy Drugs in Gastric Cancer

• Jin Z
• Wang P
• Chen J
• He L
• Xiao L
• Yong K
• Deng S
• Zhou L

• KMID: 2412650
• DOI: http://doi.org/10.3349/ymj.2018.59.5.595

Abstract

PURPOSE
C-end rule (CendR) peptides are found to enhance the penetration of chemotherapeutic agents into tumor cells, while GX1 is a peptide that homes to gastric cancer (GC) vasculature. This study aimed to synthesize a novel peptide GX1-RPAKPAR (GXC) and to explore the effect of GXC on sensitizing GC cells to chemotherapeutic agents.
MATERIALS AND METHODS
Intracellular Adriamycin concentration analysis was applied to conform whether GXC peptide increases the penetration of chemotherapeutic agents into GC cells in vitro. The effect of GXC peptide on sensitizing GC cells to chemotherapeutics was validated by apoptosis assay and in vitro/vivo drug sensitivity assay. The specificity of GXC to GC tissue was validated by ex vivo fluorescence imaging.
RESULTS
In vitro, administration of GXC significantly increased Adriamycin concentrations inside SGC-7901 cells, and enhanced the efficacy of chemotherapeutic agents by decreasing the IC50 value. In vivo, FITC-GXC specifically accumulated in GC tissue. Moreover, systemic co-injection with GXC peptide and Adriamycin statistically improved the therapeutic efficacy in SGC-7901 xenograft models, surprisingly, without obviously increasing side effects.
CONCLUSION
These results demonstrated that co-administration of the novel peptide GXC with chemotherapeutic agents may be a potential way to enhance the efficacy of anticancer drugs in GC treatment.

Keyword

GXC; GX1; C-end rule peptide; gastric cancer; penetration

MeSH Terms

Apoptosis
Doxorubicin
Drug Therapy*
Heterografts
In Vitro Techniques
Inhibitory Concentration 50
Optical Imaging
Peptides
Sensitivity and Specificity
Stomach Neoplasms*
Doxorubicin
Peptides

Figure

• 

  Fig. 1 GXC peptide enhanced the drug sensitivity of SGC-7901 cells in vitro. (A) Cytotoxicity of RPAKPAR, GX1, and GXC to SGC-7901 cells was acceptable. (B–D) RPAKPAR and GXC peptides sensitize gastric cancer cells to chemotherapeutics in vitro. (B) The effect of co-administration of three kinds of peptides on IC50 values of SGC-7901 cells to ADR, VCR, 5FU, and CDDP. (C) The apoptotic rates of SGC-7901 cells treated with ADR (0.4 µg/mL) or 5FU (10 µg/mL), co-administrated with GX1 (1×10−6 µmol/mL) or RPAKPAR (1×10−6 µmol/mL), respectively, for 24 h, were measured by flow cytometry. (D) The statistical analyses of cell apoptosis of SGC-7901 to ADR and 5FU. *p<0.05. GXC, GX1-RPAKPAR.

• 

  Fig. 2 GXC increased intracellular ADR concentrations in vitro. (A) SGC-7901 cells were treated with ADR (10 µg/mL) combined with GX1, RPAKPAR, and GXC (1×10−6 µmol/mL) respectively for 1 h. Green fluorescence indicates the cytoplasmic membrane stained with DIO, and red fluorescence indicates ADR. (B) The average red fluorescence intensity at different times. GXC, GX1-RPAKPAR.

• 

  Fig. 3 GXC specifically accumulated in gastric cancer in nude mice bearing tumor xenografts derived from SGC-7901 cells. (A) Ex vivo imaging of tumor and normal tissues of FITC-GXC (40 µmol/kg) uptake at 2 h after euthanizing the mice. (B) Fluorescence intensity ratio of tumor and normal tissues were quantified using regions of interest analysis (p<0.01). GXC, GX1-RPAKPAR; GFP, green fluorescent protein.

• 

  Fig. 4 Co-administration with GXC enhanced the anti-tumor effect of free ADR in nude mice bearing tumor xenografts. (A) Fluorescence imaging of GFP-SGC-7901 tumor models every 4 days. (B) Fluorescence intensity ratio of tumors was quantified by region of interest analysis. (C) The statistical analyses of tumor weight collected after treating for 24 days. (D) The statistical analyses of mice body weight shift. *p<0.05; **p<0.01. GXC, GX1-RPAKPAR; GFP, green fluorescent protein.

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