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2015 ; 17
(2
): 358-69
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Enhancement of MHC-I antigen presentation via architectural control of
pH-responsive, endosomolytic polymer nanoparticles
#MMPMID25501498
Wilson JT
; Postma A
; Keller S
; Convertine AJ
; Moad G
; Rizzardo E
; Meagher L
; Chiefari J
; Stayton PS
AAPS J
2015[Mar]; 17
(2
): 358-69
PMID25501498
show ga
Protein-based vaccines offer a number of important advantages over organism-based
vaccines but generally elicit poor CD8(+) T cell responses. We have previously
demonstrated that pH-responsive, endosomolytic polymers can enhance protein
antigen delivery to major histocompatibility complex class I (MHC-I) antigen
presentation pathways thereby augmenting CD8(+) T cell responses following
immunization. Here, we describe a new family of nanocarriers for protein antigen
delivery assembled using architecturally distinct pH-responsive polymers.
Reversible addition-fragmentation chain transfer (RAFT) polymerization was used
to synthesize linear, hyperbranched, and core-crosslinked copolymers of
2-(N,N-diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that
were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA)
segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In
aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and
enabled efficient and reducible conjugation of a thiolated protein antigen,
ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in
an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer
architectures exhibiting significantly higher hemolysis at pH???7.0 than the
linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer
architecture enhanced in vitro MHC-I antigen presentation relative to free
antigen, whereas the linear construct did not have a discernible effect. The
hyperbranched system elicited a four- to fivefold increase in MHC-I presentation
relative to the cross-linked architecture, demonstrating the superior capacity of
the hyperbranched architecture in enhancing MHC-I presentation. This work
demonstrates that the architecture of pH-responsive, endosomolytic polymers can
have dramatic effects on intracellular antigen delivery, and offers a promising
strategy for enhancing CD8(+) T cell responses to protein-based vaccines.
|*Nanoparticles
[MESH]
|Acrylamides/chemistry
[MESH]
|Animals
[MESH]
|Antigen Presentation/immunology
[MESH]
|CD8-Positive T-Lymphocytes/immunology
[MESH]
|Cross-Linking Reagents/chemistry
[MESH]
|Endosomes/metabolism
[MESH]
|Hemolysis/drug effects
[MESH]
|Histocompatibility Antigens Class I/*immunology
[MESH]