Journal
BIOMATERIALS
Volume 79, Issue -, Pages 88-100Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.11.040
Keywords
pH-sensitive; Lysosomal rupture; ROS; Proteasome activity; MHC I antigen presentation
Funding
- National Natural Science Foundation of China [81171446, 81371679]
- Shenzhen Overseas Outstanding Professional Talent [KQCX201405201541150]
- Shenzhen Science and Technology Program [GJHS20140610151856702, CXZZ20130506140505859]
- Guangdong leading talents program (Antibody/Protein Drugs for Major Diseases)
- Shenzhen Peacock Next-generation Monoclonal Antibody Drug research and development program [KQTD201210]
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MHC class I (MHC I) antigen presentation of exogenous antigens (so called cross presentation) is a central mechanism of CD8(+) cytotoxic T lymphocyte (CTL) responses essential for successful vaccine based cancer immunotherapy. The present study constructed amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) nanogels for cancer vaccine delivery, in which dextran was conjugated with all trans retinal (a metabolite of vitamin A) through a pH-sensitive hydrazone bond, followed by galactosylation to acquire dendritic cell (DC)-targeting ability. Our results showed that pH-sensitive GDR nanogel was a self-adjuvanted vaccine carrier that not only promoted DC maturation through activating retinoic acid receptor (RAR) signaling, but also facilitated antigen uptake and cytosolic antigen release in DCs. Furthermore, pH-sensitive GDR nanogel effectively augmented MHC I antigen presentation and evoked potent anti-cancer immune responses in vivo. More importantly, we first reported that nanoparticle-triggered lysosome rupture could directly induce ROS production in DCs, which was found to be essential for augmenting proteasome activity and downstream MHC I antigen presentation. Hence, DC-targeted pH-sensitive GDR nanogels could be a potent delivery system for cancer vaccine development. Triggering lyososomal rupture in DCs with pH-sensitive nanoparticles might be a plausible strategy to elevate intracellular ROS production for promoting antigen cross presentation, thereby improving cancer vaccine efficacy. (C) 2015 Elsevier Ltd. All rights reserved.
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