FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance

International audienceAbstractBackgroundIrinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions.MethodsColon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity.ResultsBoth pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance.ConclusionsOur results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2

Primase-based whole genome amplification

In vitro DNA amplification methods, such as polymerase chain reaction (PCR), rely on synthetic oligonucleotide primers for initiation of the reaction. In vivo, primers are synthesized on-template by DNA primase. The bacteriophage T7 gene 4 protein (gp4) has both primase and helicase activities. In this study, we report the development of a primase-based Whole Genome Amplification (pWGA) method, which utilizes gp4 primase to synthesize primers, eliminating the requirement of adding synthetic primers. Typical yield of pWGA from 1 ng to 10 ng of human genomic DNA input is in the microgram range, reaching over a thousand-fold amplification after 1 h of incubation at 37°C. The amplification bias on human genomic DNA is 6.3-fold among 20 loci on different chromosomes. In addition to amplifying total genomic DNA, pWGA can also be used for detection and quantification of contaminant DNA in a sample when combined with a fluorescent reporter dye. When circular DNA is used as template in pWGA, 108-fold of amplification is observed from as low as 100 copies of input. The high efficiency of pWGA in amplifying circular DNA makes it a potential tool in diagnosis and genotyping of circular human DNA viruses such as human papillomavirus (HPV)

Experimental investigation of photocatalytic effects of concrete in air purification adopting entire concrete waste reuse model

This research investigated the capacities of recycled aggregate concrete adopting entire concrete waste reuse model in degrading NO2. Two major issues within environmental sustainability were addressed: concrete waste reuse rate and mitigation of hazards substances in the polluted air. The study consisted of two stages: identification of proper replacement rates of recycled concrete wastes in new concrete mixture design, and the evaluation of photocatalytic performance of recycled aggregate concrete in degrading NO2. It was found that replacement rates up to 3%, 30%, and 50% for recycled power, recycled fine aggregate, and recycled coarse aggregate respectively could be applied in concrete mixture design without deteriorating concrete strength. Recycled aggregates contained both positive attributes (“internal curing”) and negative effects (e.g., lower hardness) to concrete properties. It was found that 30% to 50% of natural coarse aggregate replaced by recycled coarse aggregates coated with TiO2 would significantly improve the photocatalytic performance of concrete measured by degradation rate of NO2. Micro-structures of recycled aggregates observed under microscope indicated that soaking recycled aggregates in TiO2 solution resulted in whiskers that filled the porosity within recycled aggregates which enhanced concrete strength

Controlled Synthesis of Organic/Inorganic van der Waals Solid for Tunable Light-matter Interactions

Van der Waals (vdW) solids, as a new type of artificial materials that consist of alternating layers bonded by weak interactions, have shed light on fascinating optoelectronic device concepts. As a result, a large variety of vdW devices have been engineered via layer-by-layer stacking of two-dimensional materials, although shadowed by the difficulties of fabrication. Alternatively, direct growth of vdW solids has proven as a scalable and swift way, highlighted by the successful synthesis of graphene/h-BN and transition metal dichalcogenides (TMDs) vertical heterostructures from controlled vapor deposition. Here, we realize high-quality organic and inorganic vdW solids, using methylammonium lead halide (CH3NH3PbI3) as the organic part (organic perovskite) and 2D inorganic monolayers as counterparts. By stacking on various 2D monolayers, the vdW solids behave dramatically different in light emission. Our studies demonstrate that h-BN monolayer is a great complement to organic perovskite for preserving its original optical properties. As a result, organic/h-BN vdW solid arrays are patterned for red light emitting. This work paves the way for designing unprecedented vdW solids with great potential for a wide spectrum of applications in optoelectronics

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.Peer reviewe

Post-marketing safety surveillance and re-evaluaiton of Shu-Xue-Ning injection: a real-world study based on 30,122 cases

Objective: This study aims to investigate the safety of Shu-Xue-Ning injection (SXNI) in real-world clinical applications.Methods: A prospective, multi-center, large-sample intensive monitoring method was used to monitor the use of SXNI in several medical institutions across China while collecting patients’ dosing and adverse event information. Patients who suspected as adverse reactions made comparisons with patients who did not report adverse reactions to calculate the correlation between relevant risk factors and suspected adverse reactions. Statistical analysis software SAS 9.1 was used for data analysis.Results: A total of 48 hospitals participated in this intensive monitoring study of SXNI, and 30,122 patients were monitored from July 2015 to December 2018. A total of 1,908 adverse events were reported during the use of SXNI, with an adverse event rate of 6.33% and a 95% confidence interval (CI) of 6.06%–6.61%. Association assessment showed that 54 cases presented with SXNI-related adverse reactions with an incidence of 0.18% and a 95% CI of 0.13%–0.23%, thereby indicating that the incidence of SXNI-related adverse reactions was occasional. SXNI-related adverse reactions involved 9 systems-organs with 20 clinical manifestations, and the most common adverse reactions were rash, pruritus, and other damages of skin and its appendages. No serious adverse reactions were observed; 27.78% of the adverse reactions occurred within 30 min of drug administration and more than half of them occurred within 2 h of drug administration; 96.3% of the adverse reactions were cured or improved. Causal analysis showed that women, long dispensing time, and slow dripping speed rate were considered as risk factors.Conclusion: The incidence of SXNI-related adverse reactions in real-world clinical applications is occasional and in a reasonable range with a good prognosis