pH-Responsive Poly(d,l-lactic-co-glycolic acid) Nanoparticles with Rapid Antigen Release Behavior Promote Immune Response

Abstract

In the quest to treat intracellular infectious diseases and virus infection, nanoparticles (NPs) have been considered to be efficient tools for inducing potent immune responses, specifically cellular immunity. Antigen processing and presenting by antigen presenting cells (APCs) could influence immune response, especially the priming of T-cell-mediated cellular immunity. Here, we fabricated pH-responsive poly(D,L-lactic-co-glycolic acid) (PLGA) NPs with rapid antigen intracellular release behavior in APCs. The NPs, which had thin shells and large inner space, contain ammonium bicarbonate (NH4HCO3), which could regulate release in endosomes and lysosomes, acting as an antigen release promoter in dendritic cells (DCs), and were coencapsulated with antigen (ovalbumin, OVA). Hydrogen ions (H(+)) in DC endosomes and lysosomes (pH ∼5.0 and 6.5) could react with NH4HCO3 to generate NH3 and CO2, which broke NPs and released antigens. After uptake by DCs, antigens encapsulated in pH-responsive PLGA NPs could escape from lysosomes into the cytoplasm and be cross-presented. Moreover, the NPs induced up-regulation of co-stimulatory molecules and stimulated cytokine production. Mouse immunization with pH-responsive PLGA NPs induced greater lymphocyte activation, more antigen-specific CD8(+) T cells, stronger cytotoxic capacity (IFN-γ and granzyme B), enhanced antigen-specific IgG antibodies, and higher serum IgG2a/IgG1, indicating cellular immunity. The NPs also improved generation of memory T cells to protect against reinfection. Thus, pH-responsive PLGA NPs, which induced strong cellular immune responses and offered antibody protection, could be potentially useful as effective vaccine delivery and adjuvant systems for the therapy of intracellular infectious diseases and virus infection.

NIR‐Activated Polydopamine‐Coated Carrier‐Free “Nanobomb” for In Situ On‐Demand Drug Release

“…Upon exposure to lower pH environment (pH = 5.0), the DNPs/N@PDA showed a relatively fast release of DOX molecules, with about 56.4% of the releasing over the same period (Figure S3, Supporting Information). The enhanced drug‐releasing rate at lower pH should be mainly ascribed to the pH sensitivity of PDA coating and NH 4 HCO 3 37, 38, 39, 40. More attractively, when exposed to a momentary NIR irradiation (808 nm, 5 W cm −2 , 5 min), the drug release rate was significantly enhanced and showed a similar release profile as DNPs.…”

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

“…575 In this study, PLGA NPs were loaded with ammonium bicarbonate (NH 4 HCO 3 ), which led to increased release of the coencapsulated antigen (ovalbumin, OVA) (Figure 38). The hypothesis in this study was that protons within the endosomes and lysosomes of dendritic cells react with the ammonium bicarbonate to release NH 3 and CO 2 , which destabilized the NPs.…”

“…(E) Illustration of pH-responsive PLGA NPs and the release mechanism. Reprinted with permission from ref 575. Copyright 2015 American Chemical Society.…”

The Horizon of the Emulsion Particulate Strategy: Engineering Hollow Particles for Biomedical Applications

“…[110] The particles promoted antigen uptake and the activation of the recruited antigen presenting cells. Liu and co-workers loaded NH 4 HCO 3 and antigens via PLGA nanoparticles.…”