In Vivo Studies on the Effect of Co-Encapsulation of CpG DNA and Antigen in Acid-Degradable Microparticle Vaccines

详细信息    查看全文

• 作者：Tristan T. Beaudette ; Eric M. Bachelder ; Joel A. Cohen ; Allie C. Obermeyer ; Kyle E. Broaders ; Jean M. J. Frchet ; Eun-Suk Kang ; Ines Mende ; William W. Tseng ; Matthew G. Davidson ; Edgar G. Engleman
• 刊名：Molecular Pharmaceutics
• 出版年：2009
• 出版时间：August 3, 2009
• 年：2009
• 卷：6
• 期：4
• 页码：1160-1169
• 全文大小：323K
• 年卷期：v.6,no.4(August 3, 2009)
• ISSN：1543-8392

文摘

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.