Effect of Alkaline Electrolyzed Water on Performance Improvement of Green Concrete with High Volume of Mineral Admixtures

The strength and durability of concrete will be significantly reduced at high volume of mineral admixture,and the poor early strength of concrete also still needs to be solved.In this investigation,a highly active alkaline electrolyzed waters was used as mixing water to improve the early strength and enhance the durability of green concrete with high volume mineral admixture,the influences of alkaline electrolyzed water(AEW)on hydration activity of mineral admixture and durability of concrete were determined.The results showed that compared with natural tap water,AEW can accelerate early hydration process of cement in concrete and produce comparatively more hydrated products,leading to a 13.6%higher compressive strength than that of ordinary concrete at early age,but the improvement effect of AEW concrete was relatively reduced at long-term age.Meanwhile,the activity of mineral admixtures could be stimulated by AEW to some extent,the strength and durability performance of AEW concrete after double doping 25%slag and 25%fly ash can still reach the level of ordinary cement concrete without mineral admixtures.The SEM micromorphology of 7 d hydrated natural tap water cement paste was observed to be flaky and tabular,but the AEW cement pastes present obvious cluster and granulation phenomenon.The SEM microstructure of AEW concrete with mineral admixtures is more developed and denser than ordinary tap water concrete with mineral admixtures.Therefore,the AEW probably could realize the effective utilization of about 50%mineral admixture amount of concrete without strength loss,the cement production cost and associated CO_(2) emission reduced,which has a good economic and environmental benefit.

Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

Co-delivery of mitochondrial targeted lonidamine and PIN1 inhibitor ATRA by nanoparticulate systems for synergistic metastasis suppression

Mitochondria are highly involved in the metastasis of cancer cells.However,tumor cells impede the efficiency of mitochondrial targeted drugs by protecting mitochondria through an intrinsic and adaptive antioxidant mechanism.We aim to disturb the redox homeostasis by prolyl-isomerase PIN1 inhibitor all-trans retinoic acid(ATRA)to improve the therapeutic efficacy of mitochondrial targeted lonidamine(TL).The combination of ATRA and TL with a ratio of 2:1 was found to have the best synergistic effect in inhibiting the proliferation and metastasis of metastatic 4T1 breast cancer cells.Dual-drug loaded nanoparticles(TL-ATRA NPs)were further developed by self-assembly and were observed to disturb the redox homeostasis drastically and triggered a robust mitochondrial disruption on metastatic 4T1 breast cancer cells.The molecular mechanism was related to the downregulation of nuclear factor E2-related factor 2(NRF2),a critical transcription factor that regulated antioxidant responses,and its downstream molecules.As a result,TL-ATRA NPs significantly suppressed the growth of primary tumors and the formation of lung metastasis nodes.Collectively,our findings showed that sensitizing mitochondria to anti-cancer drugs by disturbing redox homeostasis achieved a satisfactory therapeutic effect to inhibit tumor growth and metastasis.

Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting

Multidrug resistance(MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here,based on the previous research of N-(2-hydroxypropyl)methacrylamide(HPMA) polymer–drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin(Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide(MPP) and then attached to(HPMA) copolymers(P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells via endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species(ROS) as well as reduction of adenosine triphosphate(ATP)production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.