Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery
Drug-loaded NP3ST anchored with β-CD is crosslinked by hyaluronic acid-ferrocene (HA-Fc) conjugates to large-sized HA-Fc/NP3ST nanoassemblies through multivalent host-guest interactions between β-CD/Fc. After accumulating in atherosclerotic plaque mediated by the HA-CD44 recognition, HA-Fc/NP3ST rapidly disassembles caused by excess ROS in the intima and release smaller NP3ST, allowing for further plaque penetration, macrophage-targeted cholesterol efflux and drug delivery to alleviate atherosclerosis.
Drug-loaded chitosan film prepared via facile solution casting and air-drying of plain water-based chitosan solution for ocular drug delivery
Chitosan is a nature-based polymer with low toxicity, excellent biocompatibility and biodegradability. However, the intractable solubility of chitosan in water and most conventional solvents hampers its biomedical applications. Following the dissolution method for dissolving chitosan in plain water developed by us, chitosan was dissolved in ionic liquid followed by overnight freezing at −20 °C and subsequent solvent exchange with plain water at room temperature. In this study, we fabricated a drug-carrying chitosan film via solution casting and air-drying by using the plain water-based chitosan solution. Specifically, brimonidine tartrate (BT), an antiglaucoma drug, was dissolved in the plain-water based solution and used to prepare BT-loaded chitosan film, i.e., chitosan-BT film. The resulting film is transparent, structurally stable, and mucoadhesive. Micro-sized antiglaucoma BT drug crystals form and are well dispersed in the chitosan film. The chitosan-BT film enables BT to have a high corneal permeability with fast drug release kinetics for potential ocular drug delivery.
“Double-punch” strategy for delivery of viral immunotherapy with prolonged tumor retention and enhanced transfection efficacy
Viral immunotherapy has shown clinical efficacy in treating cancers (e.g., melanoma). Given that viral immunotherapy commonly uses intratumoral injection, prolonging the duration of therapeutic virus at the tumor site can further enhance the antitumor efficacy and reduce potential off-target effects. In this work, we describe a “double-punch” strategy by combining dendrimer platform and injectable hydrogel encapsulation for delivery of an adenovirus encoding Flagrp170 (Adv-Flagrp170), which has been shown to effectively mount a cytotoxic T lymphocyte response through enhanced tumor immunogenicity and optimized antigen cross-presentation. We first complexed PAMAM generation 4 (G4) with Adv (G4/Adv) to strengthen its transfection efficiency and then loaded G4/Adv into a biocompatible and injectable supramolecular hydrogel (SH) made of α-cyclodextrin and 4-arm polyethylene glycol via host-guest interaction. When tested in a murine melanoma model, the G4/Adv complex was shown to have improved retention at the tumor site. The presence of SH facilitated the targeted gene expression in tumor-infiltrating leukocytes, including antigen-presenting dendritic cells. Delivery of Adv-Flagrp170 by both G4 coating and SH encapsulation significantly enhanced its therapeutic efficacy in controlling mouse melanoma (8-fold reduction in tumor volume), which is associated with increased immune activation in the tumor microenvironment as well as decreased adenovirus-reactive antibodies. Taken together, this new formulation may be used to improve the treatment outcome of adenovirus-based cancer immunotherapy.
Glycyrrhetinic acid-cyclodextrin grafted pullulan nanoparticles loaded doxorubicin as a liver targeted delivery carrier
In this work, glycyrrhetinic acid (GA)-β-cyclodextrin grafted pullulan (GCDPu) was synthesized and used to form nanoparticles for liver-specific drug delivery. GCDPu was characterized by Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR). The self-aggregated nanoparticles (GCDPu NPs) with a spherical dimension of about 200 nm were prepared and analyzed by dynamic light scattering (DLS), zeta potential, and transmission electron microscopy (TEM). Doxorubicin (DOX) was selected as an anti-cancer model drug, and the drug-loaded GCDPu NPs were prepared by the emulsion solvent evaporation method. Moreover, the drug loading efficiency (LE%) and loading content (LC%) were determined. Slow DOX release from DOX/GCDPu NPs was confirmed. GCDPu NPs were cytocompatible with Bel-7404 cells and showed high cellular uptake according to the MTT assay, confocal laser scanning microscope (CLSM) and flow cytometry (FCM) results. Compared with free DOX, DOX/GCDPu NPs have exhibited a longer half-life time (t1/2) and a larger area-under-the-curve (AUC). GCDPu NPs significantly increased DOX contents in the liver and decreased in heart and kidney. Furthermore, DOX/GCDPu NPs exhibited a better anticancer therapeutic effect on tumor-bearing mice. These findings suggest that GCDPu can serve a liver-specific drug delivery system.