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Cancer Immunology, Immunotherapy

, Volume 59, Issue 5, pp 759–767 | Cite as

EphA2-derived peptide vaccine with amphiphilic poly(γ-glutamic acid) nanoparticles elicits an anti-tumor effect against mouse liver tumor

  • Shinjiro Yamaguchi
  • Tomohide TatsumiEmail author
  • Tetsuo Takehara
  • Akira Sasakawa
  • Masashi Yamamoto
  • Keisuke Kohga
  • Takuya Miyagi
  • Tatsuya Kanto
  • Naoki Hiramastu
  • Takami Akagi
  • Mitsuru Akashi
  • Norio Hayashi
Original Article

Abstract

The prognosis of liver cancer remains poor, but recent advances in nanotechnology offer promising possibilities for cancer treatment. Novel adjuvant, amphiphilic nanoparticles (NPs) composed of l-phenylalanine (Phe)-conjugated poly(γ-glutamic acid) (γ-PGA-Phe NPs) having excellent capacity for carrying peptides, were found to have the potential for use as a peptide vaccine against tumor models overexpressing artificial antigens, such as ovalbumin (OVA). However, the anti-tumor potential of γ-PGA-Phe NPs vaccines using much less immunogenic tumor-associated antigen (TAA)-derived peptide needs to be clarified. In this study, we evaluated the effectiveness of immunization with EphA2, recently identified TAA, derived peptide-immobilized γ-PGA-Phe NPs (Eph-NPs) against mouse liver tumor of MC38 cells (EphA2-positive colon cancer cells). Immunization of normal mice with Eph-NPs resulted in generation of EphA2-specific type-1 CD8+ T cells. Immunization with Eph-NPs tended to provide a degree of anti-MC38 liver tumor protection more than that observed for immunization with the mixture of EphA2-derived peptide and complete Freund’s adjuvant (Eph + CFA). Neither Eph-NPs nor Eph + CFA vaccines inhibited tumor growth of BL6, EphA2-negative melanoma cells. Splenocytes isolated from MC38-bearing mice treated with Eph-NPs showed strong and specific cytotoxic activity against MC38 cells. Immunization with Eph + CFA induced liver damage as evidenced by elevation of serum alanine aminotransferase, while Eph-NPs vaccination did not exhibit any toxic damage to the liver. These results demonstrated that immunization with Eph-NPs displayed anti-tumor effects against liver tumor by generating acquired immunity equivalent to the toxic adjuvant CFA, suggesting that safe γ-PGA-Phe NPs could be applied clinically for the vaccine treatment of liver cancer.

Keywords

Peptide vaccine EphA2-derived peptide Acquired immunity Liver tumor 

Abbreviations

IFA

Incomplete Freund’s adjuvant

NPs

Nanoparticles

γ-PGA

Poly(γ-glutamic acid)

Phe

l-Phenylalanine

CFA

Complete Freund’s adjuvant

PBS

Phosphate buffered saline

i.p.

Intraperitoneal

ALT

Alanine aminotransferase

DCs

Dendritic cells

Notes

Acknowledgments

This work was supported by a Grant-in-Aid from Core Research for Evolutional Science and Technology (CREST) from Japan Science and Technology Agency (JST).

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Shinjiro Yamaguchi
    • 1
    • 3
  • Tomohide Tatsumi
    • 1
    • 3
    Email author
  • Tetsuo Takehara
    • 1
    • 3
  • Akira Sasakawa
    • 1
    • 3
  • Masashi Yamamoto
    • 1
    • 3
  • Keisuke Kohga
    • 1
  • Takuya Miyagi
    • 1
  • Tatsuya Kanto
    • 1
  • Naoki Hiramastu
    • 1
  • Takami Akagi
    • 2
    • 3
  • Mitsuru Akashi
    • 2
    • 3
  • Norio Hayashi
    • 1
    • 3
  1. 1.Department of Gastroenterology and HepatologyOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Department of Applied Chemistry, Graduate School of EngineeringOsaka UniversitySuitaJapan
  3. 3.Core Research for Evolutional Science and Technology (CREST)Japan Science and Technology Agency (JST)TokyoJapan

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