Two key aspects take the highlight in developing anti-cancer vaccines, being the use of a vaccine adjuvant and the need for an efficient delivery system. Among all of the adjuvants, imidazoquinolines (IMDQ) have gained special attention as small molecule TLR 7/8 agonists. We and others have previously shown that covalent modification of an TLR 7/8 agonist to crosslinked nanoparticle leads to a strong localised immune activation in the draining lymph nodes. Here we report on a next generation of IMDQ-delivery systems based on novel amphiphilic block copolymers bearing a acid-cleavable benzylic moiety and an activated ester in the hydrophobic domain. The activated ester allows for post polymerisation functionalisation with an IMDQ derivative or fluorescent labelling. The benzylic moiety in the hydrophobic block promotes self-assembly into 50 nm micellar nanoparticles with increased stability due to π-π interactions. The use of an acid-sensitive ketal spacer allows the benzylic moiety to be cleaved of at lysosomal pH resulting in a fully water-soluble polymer that can present it’s shielded TLR agonists. The concept of stable, but acid-degradable nanoparticles is shown in both an <i>in vitro</i> as well as <i>in vivo </i>setting based on Cy3/Cy5 FRET coupling. The lymphatic drainage was dramatically superior for the amphiphilic polymer compared to fully water-soluble polymer. Covalent modification of an IMDQ derivative to the micelle forming polymer yields a highly potent lymph node directing vaccine formulation with a strong localised immune activation.

Lymph node targeting of potent TLR7/8 agonist via acid sensitive amphiphilic polymers with high serum stability

256th National Meeting (2018)

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