Copelandmolina1694

Photodynamic therapy (PDT) and chemotherapy of cancer both meet respective challenges. Tumor hypoxia, low penetration and high glutathione (GSH) level bear the brunt. Herein, a core-shell nanoparticle, with multi-function of hypoxia-responsiveness, specific oxygen supply and deep tumor penetration, was constructed for smart mutual-promotion between the both to overcome the respective restrictions. The nano platform (GC@MCS NPs) was composed of hypoxia-responsive hyaluronic acid-nitroimidazole (HA-NI) as shells, MnO2 NPs as oxygen modulators and reduction-responsive functionalized poly (l-glutamic acid) derivatives (γ-PFGA) as cores to deliver gambogic acid (GA) and Chlorine6 (Ce6). After endocytosis, the approximately 100 nm of GC@MCS NPs achieved hypoxia-responsive shell degradation and MnO2 release, followed by reduction-activated charge conversion to form positively charged cores. read more With the damage effect of superficial tumor cells by the partially released GA, GA&Ce6-loadedγ-PFGA penetrated deep inside through electronic interaction step by step. Upon irradiated with 638 nm of laser, widely permeated Ce6 was activated for enhanced PDT under the high oxygenation by MnO2 NPs. The generated reactive oxygen species (ROS) in return facilitated the GA-induced paraptosis by clearing high level of GSH. As a result, this mutual promotion strategy contributed to 92.41% of 4T1 tumor inhibition rate, exhibiting outstanding advantages. Our GC@MCS NPs provided a smart combination of chemo-photodynamic therapy and focused on addressing the tumor hypoxia and low penetration issues.The regeneration of smooth muscle with physiological functions has been a key challenge in vascular tissue engineering. Hyaluronan (HA), as a major component of the extracellular matrix, plays a vital role in regulating tissue injury and repair. In this study, a biomimetic vascular graft was prepared by co-electrospinning of synthetic degradable polymers and native ECM components including collagen type-I as well as low and high molecular weight HA (LMW HA and HMW HA). Upon implantation in the rat abdominal aorta, the grafts exhibited sustained HA release that effectively enhanced the regeneration of vascular smooth muscle. Besides, LMW HA loaded vascular grafts demonstrated rapid endothelialization compared to the other groups. More importantly, HA-loaded poly(L-lactide-co-caprolactone) grafts demonstrated an optimal vascular media layer accompanied by well-organized elastin fibers after long-term implantation (6 months), and they maintained potent physiological function up to 1/3 that of the native artery. In contrast, inadequate smooth muscle regeneration was observed in poly(ε-caprolactone) grafts due to slow degradation restricting the regeneration. The mechanism was further investigated and explained by the HA-induced migration of smooth muscle cell (SMC) via CD44-mediated signaling. Besides, low molecular weight HA can promote the migration of vascular progenitor cells that further differentiate into SMCs. These results highlight the importance of HA in the regeneration of functional vascular smooth muscle, and provide a new insight into the fabrication of tissue engineering vascular grafts (TEVGs) via combining rapidly degradable polymers and bioactive ECM components that hold great translational potential.Metastasis is closely associated with high breast cancer mortality. Although nanotechnology-based anti-metastatic treatments have developed rapidly, the anti-metastasis efficiency is still far from satisfactory, mainly due to the poor recognition of circulating tumor cells (CTCs) in blood. Herein, we developed an exosome-like sequential-bioactivating prodrug nanoplatform (EMPCs) to overcome the obstacle. Specifically, the reactive oxygen species (ROS)-responsive thioether-linked paclitaxel-linoleic acid conjugates (PTX-S-LA) and cucurbitacin B (CuB) are co-encapsulated into polymeric micelles, and the nanoparticles are further decorated with exosome membrane (EM). The resulting EMPCs could specifically capture and neutralize CTCs during blood circulation through the high-affinity interaction between cancer cell membrane and homotypic EM. Following cellular uptake, EMPCs first release CuB, remarkably blocking tumor metastasis via downregulation of the FAK/MMP signaling pathway. Moreover, CuB obviously elevates the intracellular oxidative level to induce a sequential bioactivation of ROS-responsive PTX-S-LA. In vitro and in vivo results demonstrate that EMPCs not only exhibit amplified prodrug bioactivation, prolonged blood circulation, selective targeting of homotypic tumor cells, and enhanced tumor penetration, but also suppress tumor metastasis through CTCs clearance and FAK/MMP signaling pathway regulation. This study proposes an integrated approach for mechanism-based inhibition of tumor metastasis and manifests a promising potential of programmable-bioactivating prodrug nanoplatform for cancer metastasis inhibition.Bone regeneration is a complicated physiological process regulated by several growth factors. In particular, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-4 (BMP-4) are regarded as key factors that induce bone regeneration by angiogenesis and osteogenesis. In this study, we developed a double cryogel system (DC) composed of gelatin/chitosan cryogel (GC) surrounded by gelatin/heparin cryogel (GH) for dual drug delivery with different release kinetics. VEGF was loaded in GH (outer layer of DC) for the initial release of VEGF to induce angiogenesis and provide blood supply in the defect area, while BMP-4 was loaded in GC (inner layer of DC) that leads to sustained release for continuous osteogenic induction. After analyzing characteristics of the double cryogel system such as porosity, degradation rate, swelling ratio, and mechanical properties, we evaluated release kinetics of VEGF (initial release) and BMP-4 (sustained-release) by ELISA. Then, the timely release of VEGF and BMP from DC synergistically induced in vitro osteogenic differentiation as confirmed by alkaline phosphatase staining, Alizarin Red S staining, and real-time PCR analysis. Finally, a critical-sized cranial defect model confirmed the enhanced bone regeneration as a result of dual release growth factor mechanisms.