>>1892572
"cancer immunotherapy"
J Am Chem Soc. 2009 Aug 5;131(30):10360-1. doi: 10.1021/ja903984s.
Chemoselective ligation in the functionalization of polysaccharide-based particles.
Beaudette TT1, Cohen JA, Bachelder EM, Broaders KE, Cohen JL, Engleman EG, Fréchet JM.
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Abstract
Despite the promise of precisely targeted or otherwise functionalized polymeric particulate drug delivery vehicles, typical biocompatible particles are generally not amenable to facile and selective surface modification. Herein, we report the development of a simple, mild, and chemoselective strategy for the conjugation of biologically active molecules to the surface of dextran-based microparticles. Alkoxyamine-bearing reagents were used to form stable oxime conjugates with latent aldehyde functionality present in reducing carbohydrate chain ends. We demonstrate the functionalization of dextran-based microparticles with a fluorophore as well as a cell-penetrating peptide sequence, which facilitated the delivery of cargo to nonphagocytic cells leading to a 60-fold increase in the expression of a reporter gene when plasmid DNA-loaded particles were used.
PMID: 19591467 PMCID: PMC2759380 DOI: 10.1021/ja903984s
Mol Pharm. 2009 Jul-Aug;6(4):1160-9. doi: 10.1021/mp900038e.
In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines.
Beaudette TT1, Bachelder EM, Cohen JA, Obermeyer AC, Broaders KE, Fréchet JM, Kang ES, Mende I, Tseng WW, Davidson MG, Engleman EG.
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Abstract
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.
PMID: 19415922 PMCID: PMC2731711 DOI: 10.1021/mp900038e