Journal of Controlled Release最新文献

Prior research has demonstrated the therapeutic potential of peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate on diabetic retinopathy. In the present study, a novel non-fibrate PPARα agonist, A190, was designed with higher potency and selectivity than fenofibrate in PPARα agonism. A190 was encapsulated in biodegradable microparticles (A190-MP) to ensure sustained drug release, with detection in the retina up to 6 months following a single intravitreal injection. A190-MP alleviated retinal dysfunction as shown by electroretinography in Vldlr^-/- (wet-AMD model) and Abca4^-/-/Rdh8^-/- (dry-AMD model) mice. A190-MP also attenuated the decreases in cone photoreceptor density and outer nuclear layer thickness as demonstrated by optical coherence tomography and histology. Moreover, A190-MP reduced vascular leakage and neovascularization in Vldlr^-/- mice, suggesting an anti-inflammatory and anti-angiogenic effect. A190-MP upregulated expression of PPARα, PGC1α, and TOMM20 in the retina of Vldlr^-/- and Abca4^-/-/Rdh8^-/- mice. A190-MP also improved retinal mitochondrial function as shown by Seahorse analysis using retinal biopsy. In vitro, A190 attenuated oxidative stress and preserved cell viability in a photoreceptor-derived cell line exposed to 4-HNE and improved mitochondrial function, via a PPARα-dependent mechanism. These findings revealed sustained therapeutic effects of A190-MP in wet and dry AMD models, through improving mitochondrial function by activating PPARα.

Molecular imaging of breast cancer is increasingly recognized as a valuable tool for optimizing therapeutic interventions. Among potential targets for molecular imaging reporters, Carbonic Anhydrase IX (CAIX) stands out for its overexpression in tumors characterized by large hypoxic areas and aggressive phenotypes. CAIX, a transmembrane glycoprotein involved in pH regulation, displays a unique proteoglycan-like (PG) domain, not present in other isoforms, that could represent a specific target for imaging and therapy. While high sensitivity imaging techniques such as Positron Emission Tomography (PET) and optical imaging have been applied for CAIX targeting, no in vivo study utilizing Magnetic Resonance Imaging (MRI) to target CAIX has yet been reported. Herein, we address this gap by applying CAIX PG-targeting functionalized liposomes in the first in vivo MRI study on a murine model of breast cancer. TS/A cells were subcutaneously injected to generate primary tumors in mice, and targeted liposomes were delivered intravenously after 15 days. Internalization of the targeted liposomes by receptor-mediated endocytosis led to an enhanced MRI signal in the tumor region. Cytoplasmic and endosomal distribution of the liposomes' payload was observed. Conversely, non-functionalized liposomes and liposomes bearing a scrambled peptide, while entering tumor cells in smaller amounts, localized only to endosomes as expected. The findings reported herein suggest that CAIX PG domain-targeting liposomal formulations exploiting receptor-mediated endocytosis can lead to improved diagnostic capabilities and open avenues for targeted therapeutic delivery for the treatment of tumors overexpressing CAIX, particularly breast cancer.

This work explores cell-cell fusion mediated by measles virus (MeV) as a potential new cell therapy modality that achieves direct-to-cytosol (DTC) drug delivery. MeV induces receptor-mediated fusion at the cell surface via its hemagglutinin (H) and fusion glycoproteins (F), bypassing endocytic membrane transport, and enabling direct cytosolic mixing between a fusogenic donor and host target cell. Fusion of this type gives rise to large syncytia formed by the inclusion of additional target cells over time. Fusion receptor specificity was first examined in CHO "non-target" and CHO "target" cells exogenously expressing the measles target SLAM (CHO-SLAM) by mono- or co-transfection of each cell type with plasmids encoding MeV-H and MeV-F. Fusion was observed only in CHO-SLAM cells which were co-transfected with both plasmids, which verified receptor-specificity without false-triggering of fusion in co-transfected "non-target" CHO or in MeV-F mono-transfectants of either cell type. Next, CHO donor cells with constitutive mCherry expression were co-transfected with MeV-H and MeV-F, and mCherry-positive syncytia were observed when cells were mixed with CHO-SLAM demonstrating the ability to deliver the mCherry payload via DTC. Increasing the cell dose does not affect the size distribution of resulting syncytia but contributes to a higher total mCherry delivery. Further, control of MeV stoichiometry can modulate the degree of syncytia formation and protein delivery, demonstrating that limiting MeV-H and increasing MeV-F favors fusion and cytosolic delivery. Taken together, these results demonstrate MeV cell-fusion-based, DTC delivery as a robust and tunable system for achieving targeted cytosolic delivery and controlled syncytia formation.