Gas-blasting nanocapsules to accelerate carboplatin lysosome release and nucleus delivery for prostate cancer treatment

To improve therapeutic effect and reduce severely side effects of carboplatin(CBP),the gas-generating nanocapsules were developed to accelerate CBP lysosome release and nucleus delivery.CBP/SB-NC was prepared by co-loading CBP and NaHCO 3(SB)in nanocapsules using w/o/w emulsification solvent evaporation.They exhibited vesicle-like spherical morphology,uniform particle size and negative zeta potential.Reaching the tumor site with a relatively high concentration is the first step for CBP delivery and the results showed that CBP/SB-NC could effectively increase drug accumulation at tumor site.After that,the drug delivery carriers need to be internalized into tumor cells and the in vitro cellular uptake ability results showed CBP/SB-NC could be internalized into RM-1 cells more efficient than CBP solution.After internalized by RM-1 cells,the gas-blasting release process was tested in acid environment.It was demonstrated that 5 mg/ml NaHCO 3 was optimal to achieve pH-responsive gas-blasting release.In vitro release results showed that CBP significantly rapid release in acid environment(pH 5.0)compared to neutral pH(pH 7.4)(P<0.05).Meanwhile,TEM and the change of the concentration of H+results exhibited that the explosion of CBP/SB 5-NC was more easily happened in lysosome acid environment(pH 5.0).The blasting release can accelerate CBP lysosome release to cytoplasm.Furthermore,the nucleus delivery results showed CBP/SB 5-NC can promote pH-triggered rapid nucleus delivery.And the results of Pt-DNA adduct assay showed that the binding efficiency between CBP and DNA of CBP/SB 5-NC was higher than CBP solution.At last,in vitro and in vivo anti-tumor efficacy proved that CBP/SB 5-NC could enhance anti-tumor activity for prostate cancer therapy.CBP/SB 5-NC also showed superior safety in vitro and in vivo by hemolysis assay and histopathological study.All of the results demonstrate that CBP/SB 5-NC would be an efficient gas-blasting release formulation to enhance prostate cancer treatment.

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

The spatial and temporal effects of Fog-Haze pollution on the influenza transmission

The energy-intensive industrial economy results in frequent Fog-Haze weather which increases the risk of influenza spread and brings new challenges for the prevention and control of influenza.Therefore,the study of spread mechanics and controlling strategies of influenza based on Fog-Haze will be scientifically meaningful.Considering that when the concentration of Fog-Haze is low,Fog-Haze contributes to the number of infectious individuals and Fog-Haze suppresses the transmission of the influenza virus when the concentration of Fog-Haze is high,we establish the Fog-Haze dynamics model.Then we prove the global existence and boundedness of the solution,and the global asymptotic stability of the solution is given by constructing a suitable Lyapunov functional.Under the Fog-Haze weather,we study the inffuenza virus transmission model that incorporates the incidence rate to reflect the Fog-Haze-dependent saturation effect and investigate the effect of Fog-Haze pollution on the transmission of influenza.We show that the basic reproduction number R_(0) determines the global dynamics of the system:if R_(0)<1,the disease-free equilibrium is global asymptotically stable;the unique endemic equilibrium is global asymptotically stable if R_(0)>1.Simulations are carried out to validate the theoretical results.Our study provides further understanding of the dynamics of Fog-Haze and the effect of Fog-Haze pollution on the transmission of influenza.

Microstructure and properties of as-cast Cu-Cr-Zr alloys with lanthanum addition

Cu-0.45 Cr-0.2 Zr-xLa（x = 0-0.48） alloys were prepared by vacuum casting. The effects of La addition and orientation on the microstructure and properties of the as-cast alloy were investigated by an optical microscope, a scanning electron microscope with an energy dispersive X-ray spectrometer, a tensile testing machine and an electrical conductivity tester. The result shows that the addition of La significantly refines the columnar grainsize and decreases the secondary dendrite arm spacing. Trace addition of La improves the room temperature ultimate tensile strength,elongation and electrical conductivity mainly by purifying during melting and casting. The ultimate tensile strength, elongation and electrical conductivity significantly decrease with the increase of La content due to formation of coarse particles and oxides, which severely harm the performance of the Cu-0.45 Cr-0.2 Zr-xLa alloys. The Cu-0.45 Cr-0.2 Zr-0.13 La alloy possesses a good combination of room temperature ultimate tensile strength, elongation and electrical conductivity. In addition, room temperature ultimate tensile strength and electrical conductivity along transverse direction of the ingot are higher than that along longitudinal direction,which is mainly ascribed to different distribution of grain boundary and grain orientation.