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J Control Release. 2014 Oct 10;191:24-33. doi: 10.1016/j.jconrel.2014.03.041. Epub 2014 Mar 31.

Neutral polymer micelle carriers with pH-responsive, endosome-releasing activity modulate antigen trafficking to enhance CD8(+) T cell responses.

Author information

  • 1Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-1721, USA. Electronic address: salka@uw.edu.
  • 2Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-1721, USA. Electronic address: wilsonjt@uw.edu.
  • 3Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-1721, USA. Electronic address: patilg@uw.edu.
  • 4Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-1721, USA. Electronic address: kernh@uw.edu.
  • 5Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-1721, USA. Electronic address: aconv@uw.edu.
  • 6Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-1721, USA. Electronic address: stayton@uw.edu.

Abstract

Synthetic subunit vaccines need to induce CD8(+) cytotoxic T cell (CTL) responses for effective vaccination against intracellular pathogens. Most subunit vaccines primarily generate humoral immune responses, with a weaker than desired CD8(+) cytotoxic T cell response. Here, a neutral, pH-responsive polymer micelle carrier that alters intracellular antigen trafficking was shown to enhance CD8(+) T cell responses with a correlated increase in cytosolic delivery and a decrease in exocytosis. Polymer diblock carriers consisted of a N-(2-hydroxypropyl) methacrylamide corona block with pendent pyridyl disulfide groups for reversible conjugation of thiolated ovalbumin, and a tercopolymer ampholytic core-forming block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The diblock copolymers self-assembled into 25-30nm diameter micellar nanoparticles. Conjugation of ovalbumin to the micelles significantly enhanced antigen cross-presentation in vitro relative to free ovalbumin, an unconjugated physical mixture of ovalbumin and polymer, and a non-pH-responsive micelle-ovalbumin control. Mechanistic studies in a murine dendritic cell line (DC 2.4) demonstrated micelle-mediated enhancements in intracellular antigen retention and cytosolic antigen accumulation. Approximately 90% of initially internalized ovalbumin-conjugated micelles were retained in cells after 1.5h, compared to only ~40% for controls. Furthermore, cells dosed with conjugates displayed 67-fold higher cytosolic antigen levels relative to soluble ovalbumin 4h post uptake. Subcutaneous immunization of mice with ovalbumin-polymer conjugates significantly enhanced antigen-specific CD8(+) T cell responses (0.4% IFN-γ(+) of CD8(+)) compared to immunization with soluble protein, ovalbumin and polymer mixture, and the control micelle without endosome-releasing activity. Additionally, pH-responsive carrier facilitated antigen delivery to antigen presenting cells in the draining lymph nodes. As early as 90min post injection, ova-micelle conjugates were associated with 28% and 55% of dendritic cells and macrophages, respectively. After 24h, conjugates preferentially associated with dendritic cells, affording 30-, 3-, and 3-fold enhancements in uptake relative to free protein, physical mixture, and the non-pH-responsive conjugate controls, respectively. These results demonstrate the potential of pH-responsive polymeric micelles for use in vaccine applications that rely on CD8(+) T cell activation.

Copyright © 2014 Elsevier B.V. All rights reserved.

KEYWORDS:

CD8(+) T cell response; Nanoparticles; Polymer micelles; Subunit vaccine; pH-responsive

PMID:
24698946
[PubMed - indexed for MEDLINE]
PMCID:
PMC4156909
Free PMC Article
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