Development of pH-sensitive Dextran Derivatives with Strong Adjuvant Function and Their Application to Antigen Delivery

Abstract

To achieve efficient cancer immunotherapy, the induction of cytotoxic T lymphocyte-based cellular immunity is necessary. In order to induce cellular immunity, antigen carriers that can deliver antigen into cytosol of antigen presenting cells and can activate these cells are required. We previously developed 3-methyl glutarylated dextran (MGlu-Dex) for cytoplasmic delivery of antigen via membrane disruption ability at weakly acidic pH in endosome/lysosomes. MGlu-Dex-modified liposomes delivered model antigens into cytosol of dendritic cells and induced antigen-specific cellular immunity. However, their antitumor effects were not enough to complete the regression of the tumor. In this study, antigen delivery performance of dextran derivatives was improved by the introduction of more hydrophobic spacer groups next to carboxyl groups. 2-Carboxycyclohexane-1-carboxylated dextran (CHex-Dex) was newly synthesized as pH-responsive dextran derivative. CHex-Dex formed stronger hydrophobic domains at extremely weak acidic pH and destabilized lipid membrane more efficiently than MGlu-Dex. CHex-Dex-modified liposomes were taken up by dendritic cells 10 times higher than MGlu-Dex-modified liposomes and delivered model antigen into cytosol. Furthermore, CHex-Dex achieved 600 times higher IL-12 production from dendritic cells than MGlu-Dex. Therefore, CHex-Dex is promising as multifunctional polysaccharide having both cytoplasmic antigen delivery function and strong activation property of dendritic cells for induction of cellular immunity.

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

“…More advanced strategies to facilitate immunogenic delivery into the cytosol depend on the lower pH of the early/late endosome . For example, CaP skeleton as a shell protects CpG oligonucleotides from clearance by macropinocytosis and responds to acidic organelle environment for on‐command release in cytosol .…”

Hyaluronic Acid-Based pH-Sensitive Polymer-Modified Liposomes for Cell-Specific Intracellular Drug Delivery Systems

“…29 We further introduced these pH-sensitive units to naturally occurring polysaccharides such as dextran, mannan, and curdlan. [31][32][33] Carboxylated polysaccharides also showed pH-responsive properties. These polysaccharide-modified liposomes delivered model proteins into cytosol of target cells effectively via membrane fusion with endosomes.…”

“…These polysaccharide-modified liposomes delivered model proteins into cytosol of target cells effectively via membrane fusion with endosomes. [31][32][33] Polysaccharides are important as base materials because of their biodegradability and easy functionalization. In addition, the cell surface has many kinds of lectins, polysaccharide-specific receptors, which are useful for targeting ligands to specific cells.…”

Engineering anti-cancer nanovaccine based on antigen cross-presentation

“…Alternatively, targeted delivery using pH-responsive dextran derivative, 2-Carboxycyclohexane-1-carboxylated dextran was coated on to liposome. This dextran having hydrophobic spacer groups created strong hydrophobic domains at weak acidic pH of endosomes thus efficiently destabilizing the lipid membrane for delivering antigens that were actively taken up by the DCs and delivered to cytosol resulting at very high levels of IL-12 production [108]. Another fascinating attempt by the same group was performed using hyaluronic acid (HA) based pH-sensitive polymers that target cells expressing CD44, a cancer cell surface marker.…”