A poly(lactic-co-glycolic acid) (PLGA) microsphere formulation was developed which incorporates carboxylic acid groups into the microsphere surface. These functional groups are suitable for coupling to a variety of ligands and form linkages that remain stable in aqueous environments for extended periods of time. The ligand binding capacity of these microspheres compares favorably to that of similarly sized carboxylated polystyrene microspheres, which are commonly used as model particles for targeted delivery studies. Targeting microspheres to specific cell types by ligand-cell surface receptor interactions can increase the site specificity of microspheres administered intravenously or mucosally. The morphology and drug release kinetics of this PLGA microsphere formulation are not significantly different from those made with traditional reagents. This formulation allows for covalent surface modification of degradable microspheres with encapsulated payloads, which will enable studies that evaluate the ability of targeted microspheres to increase the effectiveness of payload delivery to sites of interest compared to nontargeted formulations.

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Small interfering RNA (siRNA) is a novel therapeutic modality that benefits from nanoparticle mediated delivery. The most clinically advanced siRNA-containing nanoparticles are polymer-coated supramolecular assemblies of siRNA and lipids (lipid nanoparticles or LNPs), which protect the siRNA from nucleases, modulate pharmacokinetics of the siRNA, and enable selective delivery of siRNA to target cells. Understanding the mechanisms of assembly and delivery of such systems is complicated by the complexity of the dynamic supramolecular assembly as well as by its subsequent interactions with the biological milieu. We have developed an ex vivo method that provides insight into how LNPs behave when contacted with biological fluids. Pulsed gradient spin echo (PGSE) NMR was used to directly measure the kinetics of poly(ethylene) glycol (PEG) shedding from siRNA encapsulated LNPs in rat serum. The method represents a molecularly specific, real-time, quantitative, and label-free way to monitor the behavior of a nanoparticle surface coating. We believe that this method has broad implications in gaining mechanistic insights into how nanoparticle-based drug delivery vehicles behave in biofluids and is versatile enough to be applied to a diversity of systems.

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