In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines.
Protein-based vaccines have been explored as a safer alternative to traditional weakened or killed whole organism based vaccination strategies and have been investigated for their ability to activate the immune system against certain cancers. For optimal stimulation of T lymphocytes, protein-based vaccines should deliver protein antigens to antigen presenting cells in the context of appropriate immunostimulatory signals, thus mimicking actual pathogens. In this report, we describe the synthesis, characterization, and biological evaluation of immunostimulatory acid-degradable microparticles, which are suitable delivery vehicles for use in protein-based vaccines and cancer immunotherapy. Using a 3' conjugation strategy, we optimized the attachment of immunostimulatory CpG DNA to our vaccine carriers and demonstrated that under acidic conditions similar to those found in endosomal compartments, these new particles were capable of simultaneously releasing a model protein antigen and a CpG DNA adjuvant. We found in an in vivo cytotoxicity assay that the co-encapsulation of ovalbumin, a model antigen, and immunostimulatory agent in the same particle led to superior cytotoxic T lymphocyte activity compared to particles coadministered with adjuvant in an unbound form. In addition, we investigated the ability of these acid-degradable particles to induce protective immunity in the MO5 murine melanoma model and found that they were effective until tumor escape, which appeared to result from a loss of antigen expression by the cancer cells due to in vivo selection pressure.
College of Chemistry, University of California, Berkeley, California 94720-1460, USA.
Tristan T
TT
Beaudette
Eric M
EM
Bachelder
Joel A
JA
Cohen
Allie C
AC
Obermeyer
Kyle E
KE
Broaders
Jean M J
JM
Fréchet
Eun-Suk
ES
Kang
Ines
I
Mende
William W
WW
Tseng
Matthew G
MG
Davidson
Edgar G
EG
Engleman
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D015996:Survival Rate; D014018:Tissue Distribution
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D010047:Ovalbumin