Synthesis and functionalization of virus-mimicking cationic block copolymers with pathogen-associated carbohydrates as potential vaccine adjuvants

Abstract

We report the synthesis of a family of amphiphilic pentablock polymers with different cationic blocks and with controlled architectures as potential vaccine carriers for subunit vaccines. The temperature and pHdependent micellization and gelation of these pentablock copolymers can provide a depot for sustained protein and gene delivery. The amphiphilic central triblock promotes cellular endocytosis, good gene delivery and has been used effectively as a vaccine adjuvant. The pentablock copolymer outer blocks condense DNA spontaneously as a result of electrostatic interactions for sustained combinational therapy. This family of polymers with different cationic groups was evaluated based on DNA complexation-ability and cytotoxicity to select promising candidates as DNA-based subunit vaccine adjuvants. Modification of other polymer systems with carbohydrates like mannose has been shown to enhance immunogenicity by activating pattern recognition receptors on antigen presenting cells and increasing uptake in these cells. Here, we report the synthesis of a virus-mimicking pentablock copolymer vaccine platform by successful functionalization of these polymers with mannose through an azide-alkyne Huisgen cycloaddition. The synthesis of a mannoside with the alkyne linker was achieved by a recently reported bismuth(V)-mediated activation of a thioglycoside that proved to leave the alkyne intact. The carbohydrate modification was shown not to interfere with the ability of these virus-mimicking block copolymers to complex DNA, thereby making this family of modified materials promising candidates for DNA-based vaccine delivery. Disciplines

Safety and biocompatibility of injectable vaccine adjuvants composed of thermogelling block copolymer gels

“…13 After an initial comparison between the PBC families, the PDEAEM PBC ( Fig. 11 The average molar mass of the biocompatible polymers in all cases was kept below 17,000 g/mol to allow for renal clearance. 11 The average molar mass of the biocompatible polymers in all cases was kept below 17,000 g/mol to allow for renal clearance.…”

“…11 The average molar mass of the biocompatible polymers in all cases was kept below 17,000 g/mol to allow for renal clearance. 11 Our research group has demonstrated the preservation of primary, secondary, and tertiary structures as well as antigenicity of released protein from these modified hydrogels. 11 Our research group has demonstrated the preservation of primary, secondary, and tertiary structures as well as antigenicity of released protein from these modified hydrogels.…”

“…All other materials including Multistix 10 SG Reagent Strips were purchased from Fisher Scientific (Pittsburgh, PA). 11 This provided polymers that were functionalized with mannose at both end blocks of the polymer. 13 PBC synthesis PBC was synthesized from Pluronic F127 via ATRP.…”

“…7,8 Amphiphilic block copolymers consisting of polyoxypropylene and polyoxyethylene blocks, including the widely used surfactant Pluronic F127 that has been approved by the FDA for other applications, 9 have been evaluated as injectable drug and vaccine delivery systems with tunable release rates based on polymer concentration. 11 Based on these characteristics, PBCs offer an improvement over current vaccine adjuvant technologies. Pentablock copolymers (PBCs) based on Pluronic, synthesized in our laboratories with cationic outer blocks (Fig.…”

“…1), have been shown to electrostatically complex DNA and can be easily functionalized with microbial associated molecular patterns (MAMPs) to create pathogen mimics that stimulate animmune response. 11 Based on these characteristics, PBCs offer an improvement over current vaccine adjuvant technologies.…”