In vivo delivery of peptides and Toll-like receptor ligands by mannose-functionalized polymeric nanoparticles induces prophylactic and therapeutic anti-tumor immune responses in a melanoma model

J Control Release. 2015 Jan 28;198:91-103. doi: 10.1016/j.jconrel.2014.11.033. Epub 2014 Dec 5.

Abstract

We hypothesized that the co-entrapment of melanoma-associated antigens and the Toll-like receptor (TLR) ligands Poly(I:C) and CpG, known to be Th1-immunopotentiators, in mannose-functionalized aliphatic polyester-based nanoparticles (NPs) could be targeted to mannose receptors on antigen-presenting cells and induce anti-tumor immune responses. High entrapment efficiencies of antigens and immunopotentiators in 150nm NPs were obtained. The co-entrapment of the model antigen ovalbumin and the TLR ligands was crucial to induce high IgG2c/IgG1 ratios and high levels of IFN-γ and IL-2. Mannose-functionalization of NPs potentiated the Th1 immune response. The nanoparticulate vaccines decreased the growth rate of murine B16F10 melanoma tumors in therapeutic and prophylatic settings. The combination of mannose-functionalized NPs containing MHC class I- or class II-restricted melanoma antigens and the TLR ligands induced the highest tumor growth delay. Overall, we demonstrate that the multifunctional properties of NPs in terms of targeting and antigen/adjuvant delivery have high cancer immunotherapeutic potential.

Keywords: Antigen presenting cells; Cancer vaccine; Mannose receptor targeting; Melanoma; Nanoparticles; PLGA; TLR.

MeSH terms

  • Animals
  • Cancer Vaccines*
  • Cell Line, Tumor
  • Cytokines / immunology
  • Disease Models, Animal
  • Female
  • Granzymes / metabolism
  • Immunoglobulin G / blood
  • Ligands
  • MART-1 Antigen / administration & dosage*
  • MART-1 Antigen / chemistry
  • MART-1 Antigen / immunology
  • Male
  • Mannose / chemistry
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nanoparticles / administration & dosage
  • Nanoparticles / chemistry
  • Oligodeoxyribonucleotides / administration & dosage*
  • Oligodeoxyribonucleotides / chemistry
  • Ovalbumin / administration & dosage*
  • Ovalbumin / chemistry
  • Ovalbumin / immunology
  • Peptides / administration & dosage
  • Peptides / chemistry
  • Poly I-C / administration & dosage
  • Poly I-C / chemistry
  • Polymers / chemistry
  • Toll-Like Receptors / immunology*
  • Tumor Burden / drug effects
  • gp100 Melanoma Antigen / administration & dosage*
  • gp100 Melanoma Antigen / chemistry
  • gp100 Melanoma Antigen / immunology

Substances

  • Cancer Vaccines
  • CpG ODN 1826
  • Cytokines
  • Immunoglobulin G
  • Ligands
  • MART-1 Antigen
  • Oligodeoxyribonucleotides
  • Peptides
  • Polymers
  • Toll-Like Receptors
  • gp100 Melanoma Antigen
  • Ovalbumin
  • Granzymes
  • Poly I-C
  • Mannose