pH-Responsive Nanoparticle Vaccines for Dual-Delivery of Antigens and Immunostimulatory Oligonucleotides

Wilson, John T.; Keller, S.; Manganiello, Matthew J.; Cheng, Chi‐Lien; Lee, Chen-Chang; Opara, Chinonso; Convertine, Anthony J.; Stayton, Patrick S.

doi:10.1021/nn305466z

Cited by 284 publications

(312 citation statements)

References 85 publications

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“…The capacity of polymers to promote pH-dependent disruption of lipid bilayer membranes was assessed via a red blood cell hemolysis assay as previously described 14 . Polymers were incubated for 1 h at 37 °C in the presence of mouse erythrocytes at 20 μg/mL in 100 mM sodium phosphate buffer (supplemented with 150 mM NaCl) in the pH range of the endosomal processing pathway (7.4, 7.2, 7.0, 6.8, 6.6, and 6.4).…”

Section: Methodsmentioning

confidence: 99%

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A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

“…2f, g). Endosomal disruption for cytosolic delivery was first indicated by a hemolysis assay in red blood cells (RBCs) at different pH values 14 . Results showed that PC7A NP had no hemolytic effect at pH 7.4 but induced strong hemolysis (~90%) at pH below 7.0 upon micelle dissociation.…”

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confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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“…8,18,19 The reversible addition-fragmentation chain transfer (RAFT) polymerization technique has been used for preparation of a number of well-dened polymers having only primary and/or tertiary amine groups. [20][21][22][23][24][25][26][27][28][29][30][31] Some of these polymers could be used efficiently to complex nucleic acid therapeutics and displayed to a certain degree endosome escaping ability possibly through the proton-sponge effect. 27,[29][30][31] A few polymers with proton-sponge capacity were also derived from functional polymer precursors such as oxazoline and pentauorophenyl ester polymers synthesized via RAFT polymerization.…”

Section: -16mentioning

confidence: 99%

A new proton sponge polymer synthesized by RAFT polymerization for intracellular delivery of biotherapeutics

et al. 2014

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A spermine-like polymer was synthesized via reversible addition-fragmentation chain transfer polymerization as a potential endosomal escaping agent. A new methacrylate monomer, 2-((tertbutoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)ethylmethacrylate (BocAEAEMA), was prepared and then polymerized via RAFT polymerization at constant monomer or initiator concentration increase in M n with monomer conversion was also observed. P(BocAEAEMA)s with controlled molecular weights and narrow molecular weight distributions were obtained. The in vitro cytotoxicity and proton sponge capacity of deprotected polymers P(AEAEMA) were investigated in comparison with a widely used endosomal-disruptive polymer, PEI. P(AEAEMA)s were found to possess proton sponge capacity comparable with PEI. More importantly, P(AEAEMA)s were not toxic on NIH 3T3 cells at concentrations where PEI (25 kDa) was highly toxic (0.4 mM and above). P(AEAEMA) was able to fully condense a DNA fragment at nitrogen/phosphate (N/P) ratios of 10 and above, as evidenced by gel electrophoresis. P(BocAEAEMA) was then chain-extended with a model sugar monomer, mannose-acrylate (ManAc), to yield P(AEAEMA)-b-P(ManAc) block copolymers, to potentially provide cell-recognition ability to the polyplex particles. Although the presence of the P(ManAc) block partially inhibited the interaction of P(AEAEMA) with DNA, P(AEAEMA) 13 -b-P(ManAc) 7 was able to form polyplexes with DNA at N/P ratios ranging between 20/1 and 2/1. Dynamic light scattering measurements showed that while P(AEAEMA) (M n ¼ 5.5 kDa) and DNA formed polyplex particles having a hydrodynamic diameter (D h ) of 125 AE 51 nm, P(AEAEMA) 13 -b-P(ManAc) 7 and DNA formed particles with a smaller D h of 38 AE 10 nm.

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“…In the context of vaccination, the rapid diffusion of molecular adjuvants dramatically lowers the ability of antigen and TLR agonist to reach the same antigen-presenting cells in the draining lymph node (DLN), which results in suboptimal immunity to the delivered vaccine antigen and by consequence wasted inflammation (11). Coencapsulation of antigens and TLR agonists inside polymeric carriers through steric, hydrophobic, or electrostatic entrapment as a means to augment B-and T-cell immunity has been pursued by us and others (12)(13)(14)(15)(16)(17)(18). Nevertheless, the procedures applied to entrap TLR agonists inside polymeric carriers are often highly complex and yield ill-defined systems that suffer from burst releases of the TLR agonist (19) following in vivo application.…”

mentioning

confidence: 99%

pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation

Nuhn

Vanparijs

Beuckelaer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

168

190

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Agonists of Toll-like receptors (TLRs) are potent activators of the innate immune system and hold promise as vaccine adjuvant and for anticancer immunotherapy. Unfortunately, in soluble form they readily enter systemic circulation and cause systemic inflammatory toxicity. Here we demonstrate that by covalent ligation of a smallmolecule imidazoquinoline-based TLR7/8 agonist to 50-nm-sized degradable polymeric nanogels the potency of the agonist to activate TLR7/8 in in vitro cultured dendritic cells is largely retained. Importantly, imidazoquinoline-ligated nanogels focused the in vivo immune activation on the draining lymph nodes while dramatically reducing systemic inflammation. Mechanistic studies revealed a prevalent passive diffusion of the nanogels to the draining lymph node. Moreover, immunization studies in mice have shown that relative to soluble TLR7/8 agonist, imidazoquinoline-ligated nanogels induce superior antibody and T-cell responses against a tuberculosis antigen. This approach opens possibilities to enhance the therapeutic benefit of small-molecule TLR agonist for a variety of applications.nanotechnology | Toll-like receptor | dendritic cells | lymph node | vaccine A ctivation of the innate immune system crucially depends on the recognition of evolutionary conserved microbe-associated molecular patterns by host pattern recognition receptors (PRRs). Triggering of PRRs not only elicits a direct antimicrobial and inflammatory cascade but also activates the necessary antigen-presenting cells to subsequently prime antigen-specific T-and B-cell immune responses (1). Agonists of Toll-like receptors (TLRs) are among the most potent activators of the innate immune response identified to date and, thus, are under intensive investigation as adjuvants for vaccination (2) or as agents for anticancer immunotherapy (3). Especially promising in this context are agonists of the endosomal TLR7 and TLR8, which typically recognize singlestranded RNAs generated during viral infection (4) but can also be activated by synthetic small-molecule agonists (5). Molecular adjuvants (6, 7) that are agonists of TLR7/8 indeed activate a broad spectrum of antigen-presenting cells, both in mice (only TLR7) and humans, and typically induce high levels of type I IFN and IL-12, the most vital cytokines to drive the Th1 and cytotoxic T-cell responses required to combat intracellular infections and cancer (7,8).Due to their pharmacokinetic profile, most molecular adjuvants rapidly diffuse after administration and evoke systemic inflammatory responses that cause dose-limiting toxicity (9, 10). In the context of intratumoral administration, these dose-limiting toxicities prevent these compounds from reaching the necessary intratumoral concentration to yield real therapeutic benefit. In the context of vaccination, the rapid diffusion of molecular adjuvants dramatically lowers the ability of antigen and TLR agonist to reach the same antigen-presenting cells in the draining lymph node (DLN), which results in suboptimal immunity to the del...

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pH-Responsive Nanoparticle Vaccines for Dual-Delivery of Antigens and Immunostimulatory Oligonucleotides

Cited by 284 publications

References 85 publications

A STING-activating nanovaccine for cancer immunotherapy

A STING-activating nanovaccine for cancer immunotherapy

A new proton sponge polymer synthesized by RAFT polymerization for intracellular delivery of biotherapeutics

pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation

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