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Glyconanoparticles that exhibit multivalent binding to lectins are desirable for molecular recognition and therapeutic applications. Herein we explore the use of glycogen nanoparticles as a biosourced glycoscaffold for engineering multivalent glyconanoparticles. Glycogen nanoparticles, a naturally occurring highly branched polymer of glucose, was functionalized with lactose, achieved through copper(I)-catalyzed alkyne-azide cycloaddition chemistry, for targeted interaction with lectins ex situ and on prostate cancer cells. The lactosylated glycogen, which contains terminal β-galactoside moieties, is termed galacto-glycogen (GG), and is found to interact strongly with peanut agglutinin (PNA), a β-galactoside-specific lectin, as observed by optical waveguide lightmode spectroscopy, dynamic light scattering, and quartz crystal microbalance measurements. The GG nanoparticles exhibit multivalent binding to PNA with an affinity constant of 3.4 × 10 5 M -1 , and the GG-PNA complex cannot be displaced by lactose, demonstrating the competitive binding of GG to the lectin. These GG nanoparticles were tested for association with prostate cancer cell membranes in vitro, where the particles exhibited a high affinity for the membrane, as observed from flow cytometry and confocal microscopy. This is inferred to result from specific extracellular galectin-1 targeting. Furthermore, the GG nanoparticles induce aggregation between prostate cancer cells. Our results highlight a strategy for engineering a biosourced polysaccharide with surface moieties that exhibit strong multivalent interactions with lectins, and targeted interaction with prostate cancer cells.

A protein corona, which forms on engineered particles as soon as they are introduced into biological environments, is known to provide particles with a "biological identity". Protein coronas derived from various biological environments have been demonstrated to alter the cell internalization mechanism, to diminish targeting ability and to induce nanoparticle aggregation. So far, most of these studies have challenged engineered particles with a static biological environment. However, the extracellular environment is highly dynamic due to the process termed "cell-conditioning", in which cells deplete and secrete biomolecules. In this work, we demonstrate that protein coronas formed on engineered particles from such cell-conditioned media affect the biophysical particle properties and protein adsorption differently to protein coronas derived from an unconditioned environment. When investigating particles with protein coronas formed in various biologically relevant environments for their interaction with immune cells, we observed differences in pro-inflammatory cytokine secretion and immune cell apoptosis. We found that the particles either increased or mitigated the secretion of a specific cytokine, depending on the environment where the protein corona was formed. Our study suggests that the use of protein coronas could be useful to engineer drug carriers for elongated circulation, enhanced biocompatibility, and lower toxicity by triggering a specific immune response.

We engineered metal-phenolic capsules with both high targeting and low nonspecific cell binding properties. The capsules were prepared by coating phenolic-functionalized hyaluronic acid (HA) and poly(ethylene glycol) (PEG) on calcium carbonate templates, followed by cross-linking the phenolic groups with metal ions and removing the templates. The incorporation of HA significantly enhanced binding and association with a CD44 overexpressing (CD44+) cancer cell line, while the incorporation of PEG reduced nonspecific interactions with a CD44 minimal-expressing (CD44-) cell line. Moreover, high specific targeting to CD44+ cells can be balanced with low nonspecific binding to CD44- cells simply by using an optimized feed-ratio of HA and PEG to vary the content of HA and PEG incorporated into the capsules. Loading an anticancer drug (i.e., doxorubicin) into the obtained capsules resulted in significantly higher cytotoxicity to CD44+ cells but lower cytotoxicity to CD44- cells.