Nanoparticle (NP) drug carriers have revolutionized medicine and increased quality of life for patients. Many clinically approved formulations succeed primarily because of reduced off-target toxicity of the cargo, not because of increased accumulation at the site of disease. Therefore, precisely increasing carrier concentration has garnered much attention and remains one of the biggest challenges nanomedicine currently faces. Novel multivalent ligand displays and self-assembled constructs have been reported to enhance cell-association, but myriad reports of individual constructs have made comparisons between architectures difficult, hindering progress in the field. To overcome these issues, we leverage the well-characterized hyaluronic acid (HA)-CD44 binding pair to probe how varied NP surface architecture of HA promotes enhanced association with ovarian cancer cells, known to overexpress CD44. We functionalized liposomal nanoparticles with 5 kDa HA via two methods: either surface grafting through click chemistry; or by electrostatically self-assembling utilizing the layer-by-layer (LbL) adsorption method. We ran flow cytometry and observed a consistent enhancement of NP-cell association with the self-assembled LbL NPs as compared to the grafted NPs. We further increased the surface available HA by synthesizing an HA bottlebrush glycopolymer composed of a polynorbornene backbone and pendent 5 kDa HA, enabling us to layer onto the same colloidal template as before. This pendent display of HA resulted in superior NP-cell association compared to the linear 5 kDa HA layered NPs, determined by flow cytometry and further supported by visualization with deconvoluted optical microscopy. Finally, decreasing the density of HA bottlebrush side chains by replacing 25% of them with a chemically-inert PEG filler had minimal impact on LbL NP stability and, critically, NP-cell association. Ultimately, these studies suggest that LbL surface modification can improve cell-targeting relative to covalent conjugation of ligands, and can be further enhanced with synthetic bottlebrush displays of multiple targeting ligands of interest.

Varied hyaluronic acid surface presentation from layer-by-layer nanoparticles dictates cellular association

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ACS Fall 2022

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