Biodegradable polymers hold great therapeutic value, especially through the addition of additives for controlled drug release. Nanocellulose has shown promise in drug delivery, yet usually requires chemical crosslinking with harsh acids and solvents. Nanocellulose fibrils (NFCs) and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO)-mediated oxidized nanocellulose fibrils (TNFCs) with poly (vinyl alcohol) (PVA) could be aqueously formulated to control the release of model drug acetaminophen over 144 h. The release was evaluated with a multiphase release mechanism to determine which mechanism(s) contribute to the overall release and to what degree. Doing so indicated that the TNFCs in PVA control the release of acetaminophen more than NFCs in PVA. Modeling showed that this release was mostly due to burst release—drug coming off the immediate surface, rather than diffusing out of the matrix.

Polymeric microparticles with covalently attached biotin are proposed as versatile targeting vehicles for drug delivery. The proposed microparticles made of 85/15 poly (lactic-co-glycolic acid) (PLGA) will have biotin available on the outside of the particle for the further attachment with an avidin group. Taking advantage of biotin’s high affinity for avidin, and avidin’s well-known chemistry, the particle has the potential to be easily coated with a variety of targeting moieties. This paper focuses on the design and resulting effect of adding biotin to PLGA microparticles using an integrated experimental and modeling approach. A fluorescent-tagged avidin (488-streptavidin) was used to confirm the presence and bioavailability of biotin on the outside of the particles. For the purpose of this study, bovine serum albumin (BSA) was used as a model therapeutic drug. Microparticles were created using two different types of polyvinyl alcohol 88 and 98 mol% hydrolyzed, which were then analyzed for their size, morphology, and encapsulation capacity of BSA. Release studies performed in vitro confirmed the slow release of the BSA over a 28-day period. Based on these release profiles, a release kinetics model was used to further quantify the effect of biotinylation of PLGA microparticles on their release characteristics by quantitatively extracting the effective drug diffusivity and drug desorption rate from the release profiles. It was found that the biotinylation of the PLGA microparticles slowed down both the drug desorption and drug diffusion process, which confirmed that biotinylated PLGA microparticles can be used for controlled drug release. The presented technology, as well as the proposed integrated experimental and modeling approach, forms a solid foundation for future studies using a cell-specific ligand that can be attached to avidin and incorporated onto the microparticles for targeted delivery.

Osteoarthritis (OA) is a whole-joint disorder in which cartilage, synovium, subchondral bone, meniscus, and the infrapatellar fat pad deteriorate under chronic inflammatory and mechanical stress. To date, no disease-modifying osteoarthritis drug (DMOAD) has reached approval, largely due to single-pathway targeting, insufficient joint-specific exposure, and heterogeneous OA phenotypes. Polyphenols and flavonoids are well-known natural compounds and have been extensively studied for their potential applications in OA and drug delivery. This review looks beyond commonly known polyphenols and flavonoids to profile underexplored natural chemotypes with intrinsically multi-node biology and credible potential for intra-articular (IA) translation: alkaloids, phytosteroids/withanolides, phytosterols, rare triterpenoids, marine sulfated polysaccharides, polynucleotides, humic/fulvic (including Shilajit-derived) fractions, and plant-derived oligosaccharides. For each class, this review summarizes mechanisms (anti-inflammatory, anti-catabolic, pro-anabolic, anti-angiogenic, and redox/mitochondrial) and OA-relevant evidence across pre-clinical and clinical models. Connections are then drawn between pharmacology and delivery science, including IA depots (PLGA microspheres), shear-thinning or in-situ gelling hydrogels, and advanced options such as lipidic/polymeric nanocarriers, cartilage-binding motifs, and stimuli-responsive linkers (e.g., ROS/MMP-cleavable), alongside distilling practical design rules: particle size for joint retention, charge/affinity for cartilage penetration, and compartment-aware targeting of synovium versus osteochondral interfaces. Collectively, engineered joint exposure paired with multi-node natural pharmacology offers a plausible route to first-in-class natural DMOADs.

Background: Osteoarthritis (OA), affecting approximately 240 million people worldwide, currently lacks targeted, long-acting therapeutic options. This study investigates how physicochemical properties (i.e., size, surface charge, polydispersity) influence poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) diffusion into articular cartilage for enhanced corticosteroid delivery. Methods: PLGA MSs were synthesized via oil/water emulsions to create a variety of sizes and surface charges. MSs were loaded with corticosteroid (H-17-B) and release kinetics were studied in vitro and analyzed via HPLC. Diffusion of the MSs was investigated via a bovine explant model. Results: Unmodified PLGA MSs (approximately 0.58–0.98 µm) were synthesized via single-stage oil/water emulsion with varying poly(vinyl alcohol) concentrations and sonication intensities. All formulations exhibited near-neutral surface charges (−0.27 to 4.28 mV). Smaller particles achieved greater cartilage penetration, with bi-exponential diffusion models (R² = 0.706–0.999) outperforming classical Fickian approaches. However, multi-timepoint validation demonstrated fundamentally non-diffusive transport, likely governed by steric exclusion from the dense collagen network (0.05–0.06 µm pore size). Surface functionalization with avidin/palmitic acid or polyethylene glycol (PEG)/biotin yielded microspheres with controlled properties (0.36–0.97 µm; PDI: 0.10–0.32). In vitro release studies with hydrocortisone-17-butyrate (H-17-B; encapsulation efficiency of 79.8% ± 4.8%) demonstrated biphasic kinetics best fit by bi-exponential models (R² > 0.95). Unmodified microspheres exhibited 7.1% cumulative release by Day 14. High-performance liquid chromatography revealed that H-17-B undergoes ester hydrolysis to hydrocortisone during release, with surface modifications significantly affecting drug stability. Specifically, PEGylated microspheres maintained 96% of the drug in H-17-B form at Day 14 compared to only 37% for unmodified particles. Release was governed by PLGA degradation with concentration-independent kinetics, enabling predictable dose scalability. Conclusions: This work establishes that the behavior of PLGA microspheres in cartilage is controlled by size, charge, and surface functionalization. Surface modifications overcome physical barriers while stabilizing the encapsulated corticosteroid against premature hydrolysis, providing a framework for designing intra-articular drug delivery systems for osteoarthritis treatment.

New methods in nanoparticle development have aimed to develop customized carriers suited for specific purposes. Micelles, due to their highly tailorable nature, are prime candidates for this customizable methodology. In order to maximize drug loading and tailor release, groups of the micelle core should be carefully selected in order to exploit inherent interactions between the selected drug and the carrier core. Small variations within the composition of these groups can greatly affect micelle characteristics (e.g., size, stability, loading and release). While covalent bonding of drug-to-carrier has enhanced drug loading, drawbacks include inhibited release and altered drug properties. As a result, drug/carrier non-covalent interactions such as hydrophobic attraction, hydrogen bonding and π-π stacking have all garnered great interest, allowing for both enhanced loading as well as bond dissociation to aid in drug release. Just as important, external composition of these micelles should be suited for specific therapeutic applications. Examples include providing stabilization, enhanced circulation times and site-specific targeting. Poly (sialic acid) (PSA), a naturally occurring polysaccharide, has been shown to exhibit all three of these properties yet remains relatively unexplored in the field of micelle-based cancer drug delivery applications. Here, we have grafted various phenyl-terminated alkyl groups (PTAGs) onto the backbone of PSA (PTAG-g-PSA), each selected in order to exploit a specific non-covalent interaction (hydrophobic attraction, hydrogen bonding and π-π stacking) between the PTAG group and the anthracycline chemotherapeutic doxorubicin (DOX) (Figure 1). Upon aqueous self-assembly, these amphiphiles formed micelles which exhibited variation in size, stability, cytotoxicity and DOX loading/release based upon the PTAG selected. For example, PTAGs selected to exploit either hydrogen bonding or π-π stacking loaded in a similar fashion yet varied greatly in release properties. Therefore, the synergistic effect of these small-scale modifications in core groups selected can greatly effect micelle characteristics and result in highly tailorable carriers.