Drug crystallization is a fundamental approach to extending release through enhanced solid‑state stability and tunable particle size. Drug-release kinetics can be further modulated through co-crystallization, which alters drug-molecule-to-drug-molecule interactions, and can be used to simultaneously deliver agents with synergistic potency. However, co-formulating physicochemically diverse drugs into a common system can be challenging. Here, we investigate solvent/anti‑solvent crystallization as a simple and versatile method for producing single‑drug as well as co‑formulated crystalline depots using curcumin and piperine as a model system. We evaluate the effects of drug concentration, drug ratio, and solvent/anti‑solvent ratio on crystal formation, structure, and release behavior. Our results demonstrate that the solvent/anti-solvent ratio strongly modulates crystal properties and accelerated release kinetics for single‑drug formulations. In co‑formulated systems, the interaction between drug ratio and solvent/anti-solvent ratio mediates actual (as opposed to theoretical) curcumin or piperine loading within the crystals and solids yield. In vivo, all formulations exhibited low and extended curcumin release, consistent with solubility‑limited kinetics, while piperine release was more sensitive to formulation composition. Additionally, most crystals remained within bead explants after 14 days, suggesting the potential for longer release of curcumin. These findings illustrate the tunability of solvent/anti‑solvent crystallization for engineering single‑ and multi‑drug crystalline depots and provide insight into how crystallization parameters influence release from co‑formulated small‑molecule systems.
Jamie L. Hernandez, Neeti R. Prasad, J. Daniel et al.· International journal of pha...· 0 citations
Beyond their deployment as COVID-19 vaccines, lipid nanoparticles (LNPs) have emerged as versatile vehicles for therapeutic nucleic acid delivery. However, achieving efficient and cell-targeted transfection in extrahepatic tissues, particularly pancreatic β cells, remains a major challenge. Here, we develop a dual-targeting LNP engineering strategy that integrates high-throughput compositional screening with surface conjugation of β cell-specific targeting ligands to enable selective gene delivery to pancreatic β cells. Compositional optimization identified LNP formulations that achieved over a 148-fold increase in β cell transfection efficiency in vitro and more than an 8-fold increase in pancreatic selectivity in vivo compared to the Moderna LNP formulation. Surface conjugation of the ZnT8-specific monoclonal antibody (mAb43), which recognizes the zinc transporter ZnT8 highly expressed on murine β cells, further increased pancreatic transgene expression by more than 2-fold and achieved over 70% β cell transfection in murine models. To improve translational potential, we conjugated a high-affinity camelid single-domain antibody (4hD29 nanobody) targeting dipeptidyl peptidase-6 (DPP6), a biomarker enriched on human β cells, to compositionally optimized LNPs to deliver human STAT2-siRNA. These dual-targeting LNPs reduced STAT2 expression in human β cells under IFN-α stimulation to below baseline levels observed in unstimulated controls and induced > 4-fold increase in PDL1 expression. Together, this integrated LNP design for β cell-directed gene delivery establishes a versatile platform for RNA therapeutics and gene-editing applications in a pro-inflammatory type 1 diabetes context.
Di Yu, Yining Zhu, A. Roca-Rivada et al.· ACS Nano· 0 citations
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