Journal of Controlled Release最新文献

A cellulose nanocrystal (CNC)-annealed hydrogel (CAH) structure, including doxorubicin (DOX) and 2-deoxy-d-glucose (2DG), was developed for local chemo-metabolic therapy (LCMT) of melanoma. DOX has been used as a chemotherapeutic agent because of its intercalation into DNA and generation of free radicals. 2DG has been used as a glycolytic inhibitor in multiple metabolic therapies in combination with DOX. Covalent and non-covalent (i.e., ionic and hydrogen-bonding) binding approaches between CNC and drug cargo (i.e., DOX and 2DG) were used to tune the rheological properties of the CAH structure to achieve sustained drug release. Reduction of reduced nicotinamide adenine dinucleotide phosphate, adenosine triphosphate, and mitochondrial membrane potential, and elevation of cellular reactive oxygen species and cleaved caspases 3 and 7 were observed following treatment with CNC/DOX/2DG in B16F10 cells. Glutathione depletion, enhanced lipid peroxidation, and decreased lactate levels were observed in the CNC/DOX/2DG group. After intratumoral injection of the CNC/DOX/2DG hydrogel into B16F10 tumor-bearing mice, stronger tumor growth suppression and anti-recurrence capabilities were observed. These findings imply that the viscoelastically modulated CAH hydrogel system can be a strong candidate for LCMT of melanoma.

Since the discovery of D-amino acids, they have been considered inactive and have not been used as potent drugs. Here, we report that simple mixing with poly(vinyl alcohol) (PVA) unleashed latent potentials of D-amino acids in boron neutron capture therapy (BNCT). PVA formed boronate esters with seemingly useless boronated D-amino acids and induced tumor-associated amino acid transporter-superselective internalization and prolonged intracellular retention, accomplishing complete cure of tumors. The superselective internalization was achieved by switching the internalization pathway from ineffective pass through the transporter to the transporter-mediated endocytosis. The acidic environment in the endo-/lysosome dissociated the boronate esters and elicited the stealthiness of the drugs, preventing their externalization and prolonging intracellular retention time. In a subcutaneous tumor model, this system accomplished surprisingly high tumor-selective accumulation that could not be achieved by conventional approaches and induced drastic BNCT effects. PVA may be a unique material to unlock potentials of seemingly inert molecules.

Autophagic dysfunction-induced deterioration of the retinal microenvironment drives the progression of wet age-related macular degeneration (wAMD). The efficacy of single-target anti-VEGF antibodies in treating wAMD has long been suboptimal due to the intricate interplay between autophagy dysfunction, oxidative stress, and angiogenesis. Here, we introduce an intravitreal hydrogel depot, named Rab&Rapa-M@G, consisting of rapamycin-loaded microemulsion (Rapa-M, an mTOR inhibitor), ranibizumab (anti-VEGF antibody), and a thermosensitive hydrogel matrix. A single intravitreal injection of Rab&Rapa-M@G can sustainably deliver Rapa-M and ranibizumab to the retinal pigment epithelium for at least 14 days. This formulation significantly improves retinal autophagic flux homeostasis and reduces oxidative stress injury in wAMD mice by modulating the AMPK/mTOR/HIF-1α/VEGF and AMPK/ROS/HO-1/VEGF pathways. Consequently, it synergistically disrupts the "autophagic dysfunction-oxidative stress-angiogenesis" loop, leading to a remarkable reduction in choroidal neovascularization area and retinal damage compared to ranibizumab alone. Notably, the sequential administration of ranibizumab and Rab&Rapa-M@G further enhances the overall anti-wAMD efficacy, achieved through sequential delivery of Rab and Rapa, allowing for a more precise grasp of the treatment window. In conclusion, this hydrogel depot design, with its sequential and sustained delivery of mTOR inhibitors and anti-VEGF antibodies, offers a promising strategy for multi-target synergistic therapy in wAMD.