Programmable double-unlock nanocomplex self-supplies phenylalanine ammonia-lyase for precise phenylalanine deprivation of tumors

Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor growth.To efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous deprivation without precise control will introduce toxicity to normal cells.Herein,a programmable double-unlock nanocomplex(ROCK)was prepared,which could self-supply phenylalanine ammonia-lyase(PAL)to tumor cells for phenylalanine(Phe)deprivation.ROCK was double-locked in physiological conditions when administered systemically.While ROCK actively targeted to tumor cells by integrinαvβ3/5 and CD44,ROCK was firstly unlocked by cleavage of protease on tumor cell membrane,exposing CendR and R8 to enhance endocytosis.Then,hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells,in which ROCK was secondly unlocked,resulting in pro-moting endo/lysosome escape and PAL plasmid(pPAL)release.Released pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe,thereby block-ing the protein synthesis and killing tumor cells specifically.Overall,our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells,providing new insights to efficiently remove intratumoral nutrition for cancer therapy.

Improving Self-Supply of Urban Water and Sanitation Projects through Microfinancing in Nigeria

Most water and sanitation projects in poor neighbourhood of urban Nigeria are executed through self-supply option. This is defined as an incremental improvement of WASH products e.g. water and sanitation structures by a household or small group of households which are financed by their own effort and investment. It is indeed a concept which complements conventional water supply and sanitation funded by government. The aim of this paper is, therefore, to investigate the extent of the use of innovative financing especially group saving approach to improve water and sanitation projects in Awka town, Nigeria. Towards achieving the aim, data were collected through questionnaires which were designed and administered on the respondents between January and April, 2016 and from other secondary sources. Data were analyzed using Principal Component Analysis and Component scores to establish the extent of the use of this option in the 9 component quarters of the town. Result shows that some quarters have perfected using the self-supply option while in others, it is yet to be widely accepted. It is finally recommended among others that the urban water policy as well as urban water safety plan should be revised to include the option as a way of improving domestic water supply and sanitation in the town.

Adenosine triphosphate-responsive carbon dots nanoreactors for T_(1)-weighted magnetic resonance imaging-guided tumor chemodynamic therapy

There are various strategies to conduct tumor microenvironment(TME)stimulus-responsive(e.g.,acid,H_(2)O_(2)or glutathione)nanoreactors for increasing the efficiency of chemodynamic therapy(CDT).Among these,the exploitation of adenosine triphosphate(ATP,another overexpressed biomarker in TME)-responsive nanoreactors for tumor CDT is still challenging.Herein,the ATP-responsive iron-doped CDs(FeCDs)were firstly prepared and then coassembled with glucose oxidase(GOx)to obtain FeCDs/GOx liposomes as ATP-responsive nanoreactors.Under TME conditions,the nanoreactors initially released FeCDs and GOx.Subsequently,with the existence of ATP,iron ions were rapidly released from the FeCDs to trigger Fenton/Fenton-like reactions for generating·OH.Meanwhile,the T_(1)-weighted magnetic resonance imaging(MRI)was achieved due to the released iron ions.Moreover,the GOx converted endogenous glucose in tumor to gluconic acid and H_(2)O_(2)to satisfy the requirement of·OH generation.In vitro as well as in vivo experiments illustrated that the obtained ATP-responsive CD nanoreactors could be used as a versatile nanotheranostics for simultaneously T_(1)-weighted MRI-guided tumor CDT.This work presents a new ATP-responsive nanoreactor with selfsupplied H_(2)O_(2)for multifunctional nanotheranostic applications.

Targeting self-enhanced ROS-responsive artesunatum prodrug nanoassembly potentiates gemcitabine activity by down-regulating CDA expression in cervical cancer

Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution and side effects).It's noted the conversion of gemcitabine(GEM)to inactive ingredients under the action of cytidine deaminase(CDA)during metabolism in vivo limits its clinical effect.A high level of reactive oxygen species(ROS)results in a high level of oxidative stress in tumor cells,which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance.In this study,the ROS responsive and ROS self-supplied prodrug of artemisia(ART)-thioacetal bond(TK)-GEM was synthesized and self-vectors based on ART-TK-GEM(TK@FA NPs)was prepared by using nano precipitation.ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues.The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM,and the accumulated ROS can also induce apoptosis of tumor cells,realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines.This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance,which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.

A biologically stable, self-catalytic DNAzyme machine encapsulated by metal-phenolic nanoshells for multiple microRNA imaging

DNAzyme machines play critical roles in the fields of cell imaging, disease diagnosis, and cancer therapy. However, the applications of DNAzyme machines are limited by the nucleases-induced degradation,non-specific binding of proteins, and insufficient provision of cofactors. Herein, protected DNAzyme machines with different cofactor designs(referred to as Pro Ds) were nanoengineered by the construction of multifunctional metal-phenolic nanoshells to deactivate the interferential proteins, including nucleases and non-specific binding proteins. Moreover, the nanoshells not only facilitate the cellular internalization of Pro Ds but provide specific metal ions acting as cofactors of the designed DNAzymes. Cellular imaging results demonstrated that Pro Ds could effectively and simultaneously monitor multiple tumor-related micro RNAs in living cells. This facile and rapid strategy that encapsulates DNAzyme machines into the protective metal-phenolic nanoshells is anticipated to extend to a wide range of functional nucleic acidsbased biomedical applications.

一种兼具程序性缓释双氢青蒿素和Fe^(2+)自供应能力的智能纳米药物用于肿瘤协同治疗

双氢青蒿素(DHA)作为一种新型的抗癌药物引起了全世界的广泛关注.然而,DHA的固有缺陷降低了其在血液系统中的运输效率,而肿瘤细胞中铁含量不足进一步导致疗效不佳.因此,构建一个可同时负载DHA和Fe^(3+)并在肿瘤微环境中特异性释放出DHA/Fe的纳米药物具有重大意义.本文报道了一种智能纳米药物CaCO_(3)@DHA@Fe^(3+)-TA@PEG(CDFP NPs)用于肿瘤协同治疗.Fe^(3+)-TA壳层的包覆赋予CDFP NPs良好的光热性能.此外,CDFP NPs在酸性的肿瘤微环境中可以快速降解并释放出TA,Fe^(3+),DHA和Ca^(2+).Fe^(3+)与TA反应生成Fe^(2+),Fe^(2+)与DHA相互作用生成高毒性的自由基.此外,在氧化应激状态下,Ca^(2+)过载导致线粒体功能紊乱,最终诱导肿瘤细胞死亡.在光热治疗,活性氧,Ca^(2+)过载的协同作用下,CDFP NPs在体内外均表现出良好的治疗效果.

Rod-shape inorganic biomimetic mutual-reinforcing MnO2-Au nanozymes for catalysis-enhanced hypoxic tumor therapy

Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy.However,engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors.Herein,a rod-like biomimetic hybrid inorganic MnO2-Au nanozymes are developed,where MnO2 and ultrasmall Au nanoparticles(NPs)are successively deposited on the mesoporous silica nanorod to cooperatively improve the O2 content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging.Under the catalyzing of MnO2,the intratumoral H2O2 is decomposed to greatly accelerate O2 generation,which could boost the curative effect of radiation therapy(RT)and further enhance the Au-catalyzed glucose oxidation.Mutually,the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment,thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO2 with the self-supplied H2O2/H+.As a result,this mutual-reinforcing cycle can endow the nanoplatform with accelerated O2 generation,thus alleviating hypoxic environment and further boosting RT effect.Furthermore,acute glucose consuming can induce downregulation expression of heat shock protein(HSP),achieving starvation-promoted mild photothermal therapy.This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.

Cyanobacteria-based near-infrared light-excited self-supplying oxygen system for enhanced photodynamic therapy of hypoxic tumors

Tumor hypoxia has been considered to induce tumor cell resistance to radiotherapy and anticancer chemotherapy,as well as predisposing for increased tumor metastases.Therefore,strategies for the eradication of the hypoxic tumor are highly desirable.Photodynamic therapy(PDT)is a new technique that can be used to treat tumors using laser irradiation to photochemically activate a photosensitizer.Compared to traditional radiotherapy and chemotherapy,photodynamic therapy has many advantages,such as good selectivity,low toxicity,and less trauma and resistance.However,PDT is oxygen-dependent,and the lack of oxygen in hypoxic tumors renders photodynamic therapy ineffective.Cyanobacteria,the earliest photosynthetic oxygen-generating organisms,can utilize water as an electron donor to reduce CO_(2) into organic carbon compounds along with continuously releasing oxygen under sunlight.Inspired by this,herein,cyanobacteria were used as a living carrier of photosensitizer conjugated upconversion nanoparticles(UCNP)to construct a self-supplying oxygen PDT system.Improvement in the PDT efficiency for hypoxic tumors can be achieved as a result of in situ oxygen production by cyanobacteria under near-infrared(NIR)light using UCNP as a light harvesting antenna.A successful demonstration of this concept would be of great significance and could open the door to a new generation of carrier systems in the field of hypoxia-targeted drug transport platforms.

Co-delivery of enzymes and photosensitizers via metal-phenolic network capsules for enhanced photodynamic therapy

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers(PSs) result in unsatisfied efficiency of photodynamic therapy(PDT).To enhance the PDT efficiency against solid tumors,a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase(CAT),chlorin e6(Ce6) and metal-phenolic network(MPN) capsule.It is demonstrated that the CAT encapsulated in the capsules(named CCM capsules) could catalyze the degradation of hydrogen peroxide(H;O;) to produce molecular oxygen(O;),which could be converted into cytotoxicity reactive oxygen species(ROS) by surface-loaded Ce6 under 660 nm laser irradiation,leading to synergistic anticancer effects in vitro and in vivo.Therefore,the application of CCM capsule could be a promising strategy to improve PDT effectiveness.

Application of self-supplying iron cathode prepared by gas sludge in Electro-Fenton

This study is a new method for recovery and utilization of waste gas sludge from iron and steel industry.Because the gas sludge contains iron and carbon elements,the gas sludge is prepared into an Electro-Fenton(E-Fenton)cathode in this study.In this paper,the gas sludge was treated at high temperature to prepare the electrode.X-ray diffraction(XRD)and X-ray photoelectron spectroscopy(XPS)were used to characterize the gas sludge to determine the valence state of iron.The linear voltammetry curve was swept for the gas sludge electrode.The degradation effect of azo dye X3B was more than 90%in 25 min.The dissolution of total Fe and Fe^2+,the formation of hydrogen peroxide(H2O2)andiron hydroxyl radicals($OH)were also detected.The results show that there is an E-Fenton reaction in the process of gas sludge cathodic degradation of X3B.