Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

A multi-functional nanoplatform for efficacy tumor theranostic applications

Nanomaterials with multiple functions have become more and more popular in the domain of cancer research. MoS2 has a great potential in photothermal therapy, X-ray/CT imaging and drug delivery. In this study, a water soluble MoS2 nanosystem(MoS2-PEG) was synthesized and explored in drug delivery, photothermal therapy(PTT) and X-ray imaging.Doxorubicin(DOX) was loaded onto MoS2-PEG with a high drug loading efficiency(~69%)and obtained a multifunctional drug delivery system(MoS2-PEG/DOX). As the drug delivery, MoS2-PEG/DOX could efficiently cross the cell membranes, and escape from the endosome via NIR light irradiation, lead to more apoptosis in MCF-7 cells, and afford higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 11.6-fold higher DTX uptake of tumor than DOX. Besides, MoS2-PEG/DOX not only served as a drug delivery system, but also as a powerful PTT agent for thermal ablation of tumor and a strong X-ray contrast agent for tumor diagnosis. In the in vitro and in vivo studies, MoS2-PEG/DOX exhibited excellent tumor-targeting efficacy, outstanding synergistic anti-cancer effect of photothermal and chemotherapy and X-ray imaging property,demonstrating that MoS2-PEG/DOX had a great potential for simultaneous diagnosis and photothermal-chemotherapy in cancer treatment.

Pharmacokinetics of a ternary conjugate based pH-responsive 10-HCPT prodrug nano-micelle delivery system

A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chromatography (UPLC-MS) method is developed to investigate its pharmacokinetics and biodistribution in tumor bearing mice. The results demonstrated that the conjugate circulated for a much longer time in the blood circulation system than commercial 10-HCPT injection, and bioavailability was significantly improved compared with 10-HCPT. In vivo biodistribution study showed that the conjugate could enhance the targeting and residence time in tumor site.

Characteristics of Ni-based ohmic contacts on n-type 4H-SiC using different annealing methods

Nickel is an excellent ohmic-contact metal on 4H-SiC.This paper discusses the formation mechanism of nickel ohmic contact on 4HSiC by assessing the electrical properties and microstructural change.Under high-temperature annealing,the phase of nickel-silicon compound can be observed with X-ray diffraction,and the contact resistance also changes.A comparative experiment was designed to use X-ray diffraction and energy-dispersive spectroscopy to clarify the difference of ohmic-contact material composition and elemental analysis between samples prepared using pulsed laser annealing and rapid thermal annealing.It is found that more Ni2Si and carbon vacancies formed at the interface in the sample prepared using pulsed laser annealing,resulting in a better ohmic-contact characteristic.

Effect of temperature on photoresponse properties of solar-blind Schottky barrier diode photodetector based on single crystal Ga_2O_3

A solar-blind photodetector is fabricated on single crystal Ga_2O_3 based on vertical structure Schottky barrier diode. A Cu Schottky contact electrode is prepared in a honeycomb porous structure to increase the ultraviolet(UV) transmittance.The quantum efficiency is about 400% at 42 V. The Ga_2O_3 photodetector shows a sharp cutoff wavelength at 259 nm with high solar-blind/visible(= 3213) and solar-blind/UV(= 834) rejection ratio. Time-resolved photoresponse of the photodetector is investigated at 253-nm illumination from room temperature(RT) to 85.8℃. The photodetector maintains a high reversibility and response speed, even at high temperatures.

A self-guidance biological hybrid drug delivery system driven by anaerobes to inhibit the proliferation and metastasis of colon cancer

Colorectal cancer is often accompanied by multiple organ metastasis.Anaerobic Bifidobacterium Infantis(BI)bacterial can selectively grow in hypoxic colorectal tumor microenvironment(TME),to own the natural advantage of preferentially colorectal tumor targeting.Herein,a self-guidance biological hybrid drug delivery system(BI-ES-Fe Alg/DOX)based on BI was constructed to inhibit the proliferation and metastasis of colon cancer.Results demonstrated that BI-ES-Fe Alg/DOX could overcome physical barriers to target and accumulate in colon tumor tissues.Then DOX was released to kill tumor cells along with the phase transition(solid to liquid)of Fe Alg hydrogel,due to Fe3+was reduced to Fe^(2+)by intracellular GSH.Meanwhile,BI-ES selectively colonized into tumors and expressed endostatin(ES)protein to down-regulate VEGF and b FGF expression,exerting anti-angiogenic effect.Moreover,Fe Alg catalyzed H_(2)O_(2)in the local tumor to generate cytotoxic·OH,further enhancing the antitumor effect.The pharmacodynamic result in AOM/DSS model proved that BI-ES-Fe Alg/DOX had the best therapeutic effect,with the final V/V0of 2.19±0.57,which was significantly lower than the other groups.Meanwhile,on CT-26tumor-bearing model,it also showed an outstanding anti-tumor effect with inhibition rate of 82.12%±3.08%.In addition,lung metastases decreased significantly in tumor metastasis model after BI-ES-Fe Alg/DOX treatment.

Spatiotemporally co-delivery of triple therapeutic drugs via HA-coating nanosystems for enhanced immunotherapy

There is growing empirical evidence that certain types of chemotherapy and phototherapy trigger immunogenic cell death and enhance the therapeutic anticancer efficacy of genetic immunotherapy. However, the main challenge is spatiotemporally co-delivering different drugs to maximize the therapeutic index of the combination therapy. In this study, a drug delivery system(HTCP-Au/shPD-L1/DOX) was designed with a polysaccharide-wrapped shell and a condensed DNA core. To construct the HTCP-Au vector, dodecyl side chains with a polyethylenimine(PEI) head were grafted onto hyaluronic acid, and Au NPs were grafted via Au-S bonds. During drug loading, PEI arrested shRNA plasmid DNA targeting programmed cell death ligand 1(shPD-L1) via electrostatic interactions. It also formed a PEI-DNA core that was automatically enclosed when aliphatic hydrocarbons pulled the hyaluronic acid backbone. A hydrophobic interlayer consisting of dodecyl bridge chains between the PEI-DNA core and the hyaluronic acid shell was required to accommodate hydrophobic doxorubicin. In vitro and in vivo assays demonstrated that this core-shell drug delivery system could efficiently load and transport three different drugs and effectively target tumors. Moreover, it could activate the immune system, thereby providing promising therapeutic efficacy against tumor growth and metastasis.

Determination of failure degree of 1.2 kV SiC MOSFETs after short-circuit test using an improved test setup

Analysis of the short-circuit characteristics of SiC metal-oxide-semiconductor field-effect transistors(MOSFETs)is very important for their practical application.This paper studies the SiC MOSFET short-circuit characteristics with an improved test setup under different conditions.A high-current Si insulated gate bipolar transistor is used as a circuit breaker in the test circuit rather than the usual short-circuit test conducted without a circuit breaker.The test platform with a circuit breaker does not influence the calculation results regarding the shortcircuitwithstand time and energy,but the SiCMOSFETwill switch off after failure in a very short time.In addition,the degree of failure will be limited and confined to a small area,such that the damage to the chip will be clearly observable,which is significant for short-circuit failure analysis.

In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

In situ triggering antitumor efficacy of alcoholabuse drug disulfiram through Cu-based metalorganic framework nanoparticles

Although approved as an alcohol-abuse drug,disulfiram(DSF)exhibited potential anticancer activity when chelated with copper(Cu).However,the low level of intrinsic Cu,toxicity originated from exogenous Cu supplementation,and poor stability of DSF in vivo severely limited its application in cancer treatment.Herein,we proposed an in situ DSF antitumor efficacy triggered system,taking advantages of Cu-based metal-organic framework(MOF).In detail,DSF was encapsulated into Cu-MOF nanoparticles(NPs)during its formation,and the obtained NPs were coated with hyaluronic acid to enhance the tumor targetability and biocompatibility.Notably,DSF loaded Cu-MOF NPs maintained stability and integrity without Cu;leakage in blood circulation,thus showing excellent biosafety.Once accumulating at tumor site,NPs were internalized into tumor cells via receptor-mediated endocytosis and released DSF and Cu;simultaneously in the hyaluronidase-enriched and acidic intracellular tumor microenvironment.This profile lead to in situ chelation reaction between DSF and Cu;,generating toxic DSF/Cu complex against tumor cells.Both in vitro and in vivo results demonstrated the programmed degradation and recombination property of Cu-based MOF NPs,which facilitated the tumor-specific chemotherapeutic effects of DSF.This system provided a promising strategy for the application of DSF in tumor therapy.

A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy

The typical hallmark of tumor evolution is metabolic dysregulation.In addition to secreting immunoregulatory metabolites,tumor cells and various immune cells display different metabolic pathways and plasticity.Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy.We develop a nanoplatform(CLCeMOF)based on cerium metal-organic framework(CeMOF)by lactate oxidase(LOX)modification and glutaminase inhibitor(CB839)loading.The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species“storm”to elicit immune responses.Meanwhile,LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment,preparing the ground for intracellular regulation.Most noticeably,the immunometabolic checkpoint blockade therapy,as a result of glutamine antagonism,is exploited for overall cell mobilization.It is found that CLCeMOF inhibited glutamine metabolism-dependent cells(tumor cells,immunosuppressive cells,etc.),increased infiltration of dendritic cells,and especially reprogrammed CD8^(+)T lymphocytes with considerable metabolic flexibility toward a highly activated,long-lived,and memory-like phenotype.Such an idea intervenes both metabolite(lactate)and cellular metabolic pathway,which essentially alters overall cell fates toward the desired situation.Collectively,the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.

Orchestrating antigen delivery and presentation efficiency in lymph node by nanoparticle shape for immune response

Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely unclear.Here,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas.Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes.On lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study.Interestingly,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study.These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment

Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent bile acid transporter-mediated intestinal uptake and lymphatic transportation.In this system,taurocholic acid(TCA)modified poly(lactic-co-glycolic acid)(PLGA)was employed to achieve pancreas location,hydroxychloroquine(HCQ)was loaded to execute therapeutic efficacy,and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC)was introduced as stabilizer together with synergist(PLGA-TCA/DLPC/HCQ).In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction,thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day.In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress,remodeled the inflammatory pancreas microenvironment,and activated PI3K/AKT signaling pathway without obvious toxicity.This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

The“two-pronged”nanosystem to precisely improve lipid metabolism and inflammatory microenvironment for atherosclerotic plaque stabilization

The rupture of atherosclerosis(AS)vulnerable plaque is the major cause of fatal arterial thrombosis related diseases.The lipid dysbolism and pro-inflammatory microenvironment are considered two main driving factors for plaque rupture.Herein,a“two-pronged”nanosystem LCS-Se/Res was designed to efficiently stabilize AS plaques,by precisely regulating lipid metabolism and inflammatory microenvironment.LCS-Se/Res was constructed with the core of resveratrol(Res)loaded selenium(Se)nanoparticles(NPs),and the shell(LCS)of targeting peptide(LSIPPKA)modified chitosan(CS).This system was stable in blood circulation.When it arrived at the plaque site,LCS-Se/Res could actively recognize the highly expressed lectin-like oxidized low-density lipoprotein receptor 1(LOX-1)receptor and accumulate there.Thereafter,Res was released from LCS-Se nanocarriers in situ by responding to acidic plaque microenvironment.On the one hand,Res increased autophagy flux in damaged endothelial cells by activating cAMP-PKA-AMPK-SIRT1 signaling pathway to promote lipid degradation.Interestingly,LCS-Se also promoted cholesterol efflux to improve lipid metabolism.On the other hand,fixed-point separated Res and LCS-Se synergistically improved plaque inflammatory microenvironment by reversing macrophage phenotype(M1 to M2)and alleviating plaque oxidative stress.Pharmacodynamics result proved that the plaque vulnerability index(VI)decreased from 1.39±0.282 to 0.108±0.02 after LCS-Se/Res treatment.In short,this study provided a new therapeutic strategy for the atherosclerosis through the two-pronged approach.

Drug carriers based on highly protein-resistant materials for prolonged in vivo circulation time

Long-circulating drug carriers are highly desirable in drug delivery system.However,nonspecific protein adsorption leaves a great challenge in drug delivery of intravenous administration and significantly affects both the pharmacokinetic profiles of the carrier and drugs,resulting in negatively affect of therapeutic efficiency.Therefore,it is important to make surface modification of drug carriers by protein-resistant materials to prolong the blood circulation time and increase the targeted accumulation of therapeutic agents.In this review,we highlight the possible mechanism of protein resistance and recent progress of the alternative protein-resistant materials and their drug carriers,such as poly(ethylene glycol),oligo(ethylene glycol),zwitterionic materials,and red blood cells adhesion.

Carrier-free programmed spherical nucleic acid for effective ischemic stroke therapy via self-delivery antisense oligonucleotide

Antisense oligonucleotide(ASO)for anti-apoptosis is emerging as a highly promising therapeutic agents for ischemic stroke with complex pathological environment.However,its therapeutic efficacy is seriously limited by a number of challenges including inefficient internalization,low blood-brain barrier(BBB)penetration,poor stability,and potential toxicity of the carrier.Herein,a carrier-free programmed spherical nucleic acid nanostructure is developed for effective ischemic stroke therapy via integrating multifunctional modules into one DNA structure.By co-encoding caspase-3-ASO and transferrin receptor(TfR)aptamer into circle template,the spherical nucleic acid nanostructure(TD)was obtained via self-assembly.The experimental results demonstrated that the developed TD displayed efficient BBB penetration capability(6.4 times)and satisfactory caspase-3 silence effect(2.3 times)due to the dense DNA packaging in TD.Taken together,our study demonstrated that the carrier-free programmed spherical nucleic acid nanostructure could significantly improve the therapeutic efficacy of ischemic stroke and was a promising therapeutic tool for various brain damage-related diseases.

One-step Synthesis of Shape-controllable Gold Nanoparticles and Their Application in Surface-enhanced Raman Scattering

Gold nanoparticles （NPs） of various shapes were synthesized by a one-step method at ambient temperature in the presence of NaCl. 2-mercaptosuccinic acid （MSA） was used as both reducing agent and stabilizing agent. The shapes of gold NPs were controllable by simply tuning S/Au ratio （S is from MSA molecule, and S/Au ratio is controlled by tuning the volume of added MSA solution）, and triangle, polygonal and spherical nanoparticles were obtained. This result suggested a new way to consider the effects of MSA on the growth of nanoparticles, which showed that MSA is a strong capping agent and facilitates more uniform growth of nanoparticles in every dimension. And other important factors on nanoparticles growth including NaCl and temperature were discussed. Furthermore, a typical probe molecule, 4-aminothiophenol （4-ATP） was used to test the surface-enhanced Raman scattering （SERS） activity of these gold NPs and the results indicated good Raman activity on these substrates. And the enhancement factor （EF） at 1078 cm^- 1 （a1） was estimated to be as large as 6.3 × 10^4 and 5.5 × 10^4 for triangular plates and truncated particles, respectively.

Study on temperature response of the HERD calorimeter cell

Purpose To derive the temperature response of the basic unit of the electromagnetic calorimeter of the high energy cosmic-radiation detection(HERD)facility.Method Tested a method to measure HERD calorimeter cell(HCC)light yield using an ultraviolet Light-Emitting Diode with a wavelength of 300 nm,and established an experimental setup and tested the light yield of the HCC at different temperatures in a thermal chamber.Results and conclusions The result showed that the signal amplitudes variation of the HCC reached up to 10.2% with temperature ranging from 0 to 60℃,if we narrow the temperature range to 0-35℃,the variation was about 3.7% and it showed much better linearity.This result provides a good instruction on the thermal control of the HERD calorimeter(CALO)to improve its performance.

Enhancement of filtration efficiency by electrical charges on nebulized particles

There have been few investigations of effects of electrical charge, carried by lab-generated particles, on filtration efficiency testing. Here, we measured the elementary charge on particles and the fraction of particles carrying that charge with a combined electrometer, differential mobility analyzer, and scanning mobility particle sizer. A typical solid NaCI aerosol and liquid diethylhexyl sebacate （DEHS） aerosol were generated with Collison and Laskin nebulizers, respectively. Our experimental results showed that NaCI aerosols carried more charge after aerosol generation. The average net elementary charge per particle was approximately 0.07. The NaCI aerosol was overall positively charged but contained a mixture of neutral and charged particles. Individual particles could carry at most four elementary charges. According to constant theorem, we speculated that original NaC1 aerosol contained 17% neutral, 45% positive-, and 38% negative-charged particles in the diameter range from 30 to 300nm. A Kr-85 neutralizer was used to decrease the charge on the NaCI particles. Our results indicated that the DEHS aerosol was electrically neutral. The effects of electric charge on particle collection by electret and electroneutral high efficiency particulate air （HEPA） filters were analyzed. Theoretical calculations suggested that charges on original NaCI aerosol particles enhanced the filtration efficiency of HEPA filters,

Hydrogel-mediated drug delivery for treating stroke

Stroke is a common disease and is the major cause of death and disability.It occurs and generates devastating neurological deficits when cerebral blood vessel is blocked(ischemic stroke,IS)or ruptured(hemorrhagic stroke,HS).Hydrogel,being biodegradable and biocompatible,have shown attractive advantages in stroke therapy as a new biomaterial with desirable mechanical properties and tunability of structure,owing to special ability to load different cargoes for multiple treatment strategies,such as pharmacotherapy based on drug-delivery systems and cell therapy including mesenchymal stem cells(MSCs)and neural progenitor cells(NPCs)for improving functional outcomes.However,a comprehensive review of the functional hydrogel for treatment of stroke is still lacking.Therefore,in this work,the main pathological mechanisms of stroke including IS and HS are comprehensively described.The benefits of hydrogel for stroke treatment are also summarized regarding the natural advantages and the delivery advantages.Simultaneously,the application development of hydrogel for treatment of stroke is highlighted.Finally,the unique considerations and challenges in the design and application of hydrogel is discussed for treatment of stroke and clinical application in the future.