Development of pH-Responsive Hyaluronic Acid-Based Antigen Carriers for Induction of Antigen-Specific Cellular Immune Responses

Abstract

Cancer immunotherapy has gained much attention because of the recent success of immune checkpoint inhibitors. Nevertheless, clinical therapeutic effects of immune checkpoint inhibitors remain limited, probably because most patients have other immune checkpoint molecules or because they lack cancer-specific cytotoxic T lymphocytes. Induction of cancer-specific cytotoxic T lymphocytes requires efficient antigen delivery systems that can convey cancer antigens specifically to antigen presenting cells, promote the endosomal escape of antigen into cytosol, and activate immune cells. Earlier, we reported cytoplasmic delivery systems of antigen using pH-sensitive polymer-modified liposomes. Adjuvant molecules were further incorporated into these liposomes to provide activation properties of cellular immune responses. This study further introduced cell specificity to these liposomal systems using hyaluronic acid-based pH-sensitive polymers, which are recognized by CD44 expressing on antigen presenting cells. pH-Sensitive hyaluronic acid derivative-modified liposomes showed much higher cellular association to antigen presenting cells than to fibroblasts with less CD44 expression. These liposomes achieved the delivery of model antigenic proteins into cytosol of dendritic cells and promoted Th1 cytokine production from the cells. Subcutaneous administration of these liposomes to mice induced antigen-specific cellular immune response in the spleen, leading to tumor regression in tumor-bearing mice. The results show that pH-sensitive hyaluronic acid derivative-modified liposomes are promising as multifunctional antigen carriers having cell-specificity, cytoplasmic antigen delivery performance, and adjuvant property to induce antigen-specific cellular immunity.

Stimulus-responsive liposomes for biomedical applications

“…HA-g-DEAP0.40 -containing LPs showed spontaneous receptor-mediated endocytosis, fast endosomal escape, and efficient antitumor activity after protonation of DEAP and destabilization at pH < 7.0. Miyazaki et al [119] studied model antigenic protein ovalbumin delivery into antigenpresenting cells by pH-sensitive HA-modified LPs. MGlu-HA and carboxycyclohexane-1-carboxylated (CHex) HA derivatives were synthesized and tested for their ability to achieve cytoplasmic delivery of antigenic proteins.…”

Polysaccharide-based nanomedicines for cancer immunotherapy: A review

“…Moreover, these loaded OVA and NIR irradiation generated ROS could promote the enhancement in CD8 + T cells-mediated anti-tumor immune responses, endowing this HA-Au nanomaterial as an excellent platform candidate to boost antitumor immunity, but ensure the targeting delivery of antigens with negligible toxicity. Alternatively, pH-sensitive HA derivative-modified liposomes have been developed to achieve targeted delivery of exogenous antigens to DCs [ 236 ]. These antigen-loaded nanomaterials could increase the production of anti-tumor cytokines by Th1 cells and induce strong anti-tumor responses, leading to effective tumor growth inhibition in the tumor-bearing mice.…”

Bioresorbable Polymers: Advanced Materials and 4D Printing for Tissue Engineering

“…Once pH disparities occur in various parts of the human body, the responsiveness of these materials can be further explored in the field tissue engineering [ 170 ]. Several biocompatible and bioresorbable natural and synthetic polymers have been studied for this purpose, such as chitosan [ 217 , 218 , 219 ], hyaluronic acid [ 220 ], gelatin [ 221 ], alginic acid [ 222 , 223 ], dextran [ 224 ], PLGA [ 225 ], poly(histidine) (PHIS) [ 226 ], and poly(aspartic acid) (PASA) [ 227 , 228 ].…”