GSH-responsive camptothecin prodrug-based hybrid micellar nanoparticles enable antitumor chemo-immunotherapy by PD-L1 knockdown

The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.

New Silver Nanosensor for Nickel Traces. Part II： Urinary Nickel Determination Associated to Smoking Addiction

A new fluorescence silver nanosensor assisted by surfactant has been recently synthesized and applied to ultra trace nickel determination. The methodology was validated by the standard addition method and satisfactorily applied to nickel determination in urine without previous treatment, coming from subjects with different smoking addiction levels and second hand smokers. Within-day precision was better than 0.011 CV. The reproducibility （between-days precision） was also evaluated over 3 days by performing six determinations each day with a CV of 0.025. The proposed methodology represents a promising approach in the area of biological monitoring due to its low operation cost, simplicity of instrumentation, high sampling speed and non-polluting solvents. Obtained results of urinary nickel concentration were successfully correlated with the tobacco addiction.

New Silver Nanosensor for Nickel Traces： Synthesis, Characterization and Analytical Parameters

A new fluorescence silver nanosensor assisted by surfactant has been synthesized and applied to ultra trace nickel determination. Operational variables which influence nanomaterial synthesis have been studied and optimized. Synthesis was very fast and simple using non polluting solvents; silver chemical reduction was carried out at room temperature. Spectroscopic studies were carried out in order to assure the uniformed of nanomaterial obtained. Fluorescent signal of silver nanoparticles resulted enhanced in presence of Ni（II）. At optimal experimental conditions, a detection limit of 0.036 pg＇L1 and quantification limit 0.12 pg＇L~ were obtained. The calibration sensitivity was 2 x 1014 L.pg-l.cm1 for the new methodology, with a range of linearity of six orders of magnitude between 0.12 and 2.93 × 10^5 pg L^-1. The tolerance levels for potential interferent ions were studied with good results. The proposed methodology represents a promising approach for Ni（II） traces quantification due to its low operation cost, simplicity of instrumentation, high sampling speed and non-polluting solvents.

A novel aptamer-based small RNA delivery platform and its application to cancer therapy

Major challenges such as nuclease degradation, rapid renal clearance, non-specific delivery, poor cellular uptake and inflammatory response have limited the clinical application of small RNA-mediated gene silencing. To overcome these challenges, we designed a novel targeting small RNA delivery platform comprising of three oligonucleotides: (1) a guide RNA sequence, (2) part of a passenger sequence linked to a DNA aptamer via a PEG linker, and (3) another passenger sequence conjugated to cholesterol, which assemble through complementary base pair annealing. Remarkably, in the presence of magnesium, this molecule self-assembled into a nanoparticle with a hydrophobic cholesterol core, hydrophilic RNA oligonucleotide shell and PEG-linked DNA aptamer flare. The nanoparticles conferred protection to the RNA oligonucleotides against nuclease degradation, which increased bioavailability, and reduced systemic inflammatory responses. The aptamer allowed targeted delivery of RNA therapeutics through cell-specific surface markers, and once inside the cell, the nanoparticles induced lysosomal leakage that released the RNA oligonucleotides into the cytosol to achieve gene silencing. We created a c-Kit-targeting miR-26a delivery particle that specifically accumulated in c-Kit^(+) breast cancer, significantly increased T cell recruitment, and inhibited tumor growth. Regression of large established tumors were achieved when the nanoparticle was used in combination with anti-CTLA-4 monoclonal antibody.