Dual-targeted delivery of temozolomide by multi-responsive nanoplatform via tumor microenvironment modulation for overcoming drug resistance to treat glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn2+), oxygen (O2) and TMZ. The hypoxia alleviation via O2 production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O6-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn2+ could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.

Evaluation of Reactive Oxygen Species Scavenging of Polydopamine with Different Nanostructures.

Reactive oxygen species (ROS) play an important role in cellular metabolism and many oxidative stress-related diseases, while excessive accumulation of ROS will lead to genetic changes in cells and promote the occurrence of inflammatory diseases or cell death. Nature-inspired polydopamine (PDA) with tailored nanostructures emerges as an ROS scavenger and is considered as an effective approach to inflammation-related diseases. However, the effects of nanoparticle structure on PDA scavenging efficacy and efficiency remain uncovered. In this work, three typical PDA nanoparticles including solid PDA, mesoporous PDA, and hollow PDA are synthesized, and of which physiochemical properties are characterized. Furthermore, their ROS scavenging performance is investigated by in vitro evaluation of radical removal. Among the three nanoparticles, mesoporous PDA is demonstrated to have the highest scavenging capability, mainly due to its specific surface area. Finally, the study on three in vivo inflammation models is constructed. The results confirm that mesoporous PDA is the most potent scavenger of ROS and more effective in reducing reperfusion injury, improving renal function, and preventing periodontitis progression, respectively. Together with the good biosafety and biocompatibility profiles, PDA nanoparticles, mesoporous PDA in particular, can be a promising avenue of ROS scavenging in fight against the inflammatory diseases.

Bacteria Synergized with PD-1 Blockade Enhance Positive Feedback Loop of Cancer Cells-M1 Macrophages-T Cells in Glioma.

Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative "cold" tumor. Herein, to wake the "hot" tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti-PD-1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD-1 blockade to enhance the effect of immunotherapy, but by introducing bacterial photothermal therapy to promote greater involvement of M1 cells in the immune response. After reaching glioma, the bacteria further target glioma cells and M2 phenotype macrophages selectively, enabling precise photothermal conversion for lysing tumor cells and M2 phenotype macrophages, which thereby enhances the positive feedback loop of cancer cells-M1 macrophages-T cells. Collectively, the bacteria synergized with PD-1 blockade strategy may be the key to overcoming the immunosuppressive glioma microenvironment and improving the outcome of immunotherapy toward glioma.

Electro-responsive micelle-based universal drug delivery system for on-demand therapy in epilepsy.

A universal drug delivery system (DDS) with brain-targeted ability is demanded to enhance antiepileptic therapeutic efficacy and reduce side effects in multiple types of epileptic seizures. In this study, we reported a micelle-based DDS possessing the brain-targeted ability and electro-responsive feature for universal delivery of antiepileptic drugs (AEDs). The system is fabricated by ferrocene (Fc)-conjugated D-a-tocopherol polyethylene glycol succinate and amphiphilic block copolymer, which improve the drug encapsulation of different AEDs. Interestingly, the intrinsic nature of TPGS-Fc including transferrin receptor-mediated transcytosis and efflux pump inhibition endows the system with high permeability across the blood-brain barrier. Based on the hydrophobic-hydrophilic transition of Fc, the micelles can respond to epileptiform discharges and thus release the loaded AEDs. Improved antiepileptic efficacy of the micelles has been demonstrated in acute, continuous, and chronic epilepsy models. In summary, we have developed a universal micelle-based DDS for various AEDs delivery, which provides a promising approach to on-demand therapy of different epileptic seizures.

Spatiotemporal variability in salinity and hydraulic relationship with salt intrusion in the tidal reaches of the Minjiang River, Fujian Province, China.

Salinity is one of the most important factors for tidal-affected water bodies including estuaries and tidal river reaches. However, due to the limitations of simultaneous manual monitoring in long-distance areas, studies of estuaries are preferred to tidal reaches. Hence, in this study, we investigated the tidal reach of the Minjiang River and five sets of field observations were used to determine the influence of saltwater intrusion in different seasons. During the dry and wet season with low discharge, the longitudinal salinity profiles showed that a station located about 45 km from the river mouth still suffered from saltwater intrusion especially when the upstream discharge was under 754 m3 s-1, where the periodical fluctuation in the salinity remained the same with the water level, but there was a time lag of approximately 4 h compared with the discharge process. However, during the wet season in April and May 2016, the monitored salinity was approximately at the detectable limit of 0.02-0.04 ppt at the station close to the river mouth, which indicated that there was no saltwater exchange into the river, although dual flow directions were observed in the survey periods. The major differences among five survey periods were mainly related to upstream discharge rather than the seasons, the tidal range, and tidal excursion. The conclusions of this study have strategic importance for protecting water sources by guiding the government to assess the optimal freshwater release time and discharge rate to prevent saltwater entering the important tidal-affected river reaches.