Engineering the tumor stroma and tumor-draining lymph nodes is an attractive strategy to mount anti-cancer immunity. Here, we report on a multifunctional delivery platform for activating dendritic cells in the tumor stroma and tumor draining lymph nodes. For this purpose, we take advantage of the transition from neutral to mildly acidic upon phagocytosis for the design of core-crosslinked nanoparticles that unfold into soluble polymers upon cellular uptake. The synthesis route we developed is based on amphiphilic block copolymers synthesized via RAFT polymerization, composed of a hydrophilic block and a solvophobic block. The latter bears pentafluorophenyl reactive ester repeating units which allow for self-assembly in aprotic polar solvents such as DMSO, followed by amide-bond crosslinking and further post-modification into fully hydrophilic nanoparticles. The use of DMSO instead of aqueous medium offers the major advantage of avoiding competitive hydrolysis reactions but reaching high conversion monitored by <sup>19</sup>F NMR. Intracellular unfolding properties are dialed into the nanoparticles using ketal-containing bisamines that are stable at physiological pH, but disintegrate at intracellular over time. Nanoparticles are endowed with immune-stimulatory cues by covalent ligation of an amine-containing imidazoquinoline TLR7/8 agonist. Using RAFT chain transfer agents equipped with an azide group provides access to orthogonally addressable polymer end groups that facilitate nanoparticle surface engineering with cycloalkyne-modified peptide targeting ligands to selectively reach specific immune cell subpopulations. Intracellular unfolding of the nanoparticles was proved by the ligation of the Cy3/Cy5 FRET pair on separate polymer strands and monitoring the loss of FRET signal over time in vitro on dendritic cells and in vivo in the draining lymph nodes. Immune-activation and anti-tumor effects were evaluation in murine models and showed significant tumor growth retardation while avoiding exerted systemic inflammatory toxicity by the imidazoquinoline TLR7/8 agonist in soluble state.

Intracellular unfolding nanoparticles for the delivery of immune-stimulatory cues towards anticancer immunity

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.