LWJ-M30, a conjugate of DM1 and B6, for the targeted therapy of colorectal cancer with improved therapeutic effects.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.

Novel Pt(IV) prodrug self-assembled nanoparticles with enhanced blood circulation stability and improved antitumor capacity of oxaliplatin for cancer therapy.

Pt(IV) compounds are regarded as prodrugs of active Pt(II) drugs (i.e. cisplatin, carboplatin, and oxaliplatin) and burgeoned as the most ideal candidates to substitute Pt(II) anticancer drugs with severe side effects. Nanoparticle drug delivery systems have been widely introduced to deliver Pt(IV) prodrugs more effectively and safely to tumors, but clinical outcomes were unpredictable owing to limited in vivo pharmacokinetics understanding. Herein, a novel Pt(IV) prodrug of oxaliplatin(OXA) was synthesized and prepared as self-assembled micellar nanoparticles(PEG-OXA NPs). In vitro, PEG-OXA NPs rapidly released biologically active OXA within 5 min in tumor cells while remaining extremely stable in whole blood or plasma. Importantly, the pharmacokinetic results showed that the AUC0-∞, and t1/2 values of PEG-OXA NPs were 1994 ± 117 h·µg/mL and 3.28 ± 0.28 h, respectively, which were much higher than that of free OXA solution (2.03 ± 0.55 h·µg/mL and 0.16 ± 0.07 h), indicating the longer drug circulation of PEG-OXA NPs in vivo. The altered pharmacokinetic behavior of PEG-OXA NPs remarkably contributed to improve antitumor efficacy, decrease systemic toxicity and increase tumor growth inhibition compared to free OXA. These findings establish that PEG-OXA NPs have the potential to offer a desirable self-delivery platform of platinum drugs for anticancer therapeutics.

Sponge City Planning and Information System Development Based on Geographic Information Fuzzy Processing.

During the development of the urban water system from 1.0 to 3.0, the impervious surface area gradually increased, hindering the natural infiltration and self-purification process of urban rainwater, resulting in serious urban water pollution, urban waterlogging in the rainy season, and groundwater problems. Since water will seep into the ground, serious water pollution will cause damage to the ground. Therefore, in dealing with urban rainwater problems, we want to use the sponge's ability to absorb and store water to build our cities into sponge cities. In this paper, we have constructed a sponge city planning and information system development based on geographic information fuzzy processing. We use differentiated fuzzy processing methods to eliminate classified information to achieve a perfect combination with nearby images and use ordinary fuzzy processing methods to solve the problem of nonconfidential information. This paper discusses the impact of natural topography on the planning and construction of sponge cities, including whether natural topography will affect rainwater, whether it will affect the distribution of different strata, and whether it will affect the utilization of groundwater resources. The basic functions of this platform are provided by a series of functions of GIS, and multiple modules are developed according to management requirements. The initial state of street view data is a lot of fisheye lens photos and corresponding point location information, which are displayed online after data preprocessing, detection information, editing information, and blurring processing.

XHL11, a novel selective EGFR inhibitor, overcomes EGFRT790M-mediated resistance in non-small cell lung cancer.

The first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib significantly improved the therapeutic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the EGFRT790M mutation occurs and results in acquired resistance. Consequently, mutant selective third-generation EGFR TKIs represented by AZD9291 (Osimertinib) have been developed to offer more effective therapeutic treatment, but the clinical application is limited by the acquired resistance and the high costs. A series of 5-chloropyrimidine-2,4-diamine derivatives were synthesized and screened for in vitro antitumor activity on H1975 and A431 cells. XHL11 showed the strongest antineoplastic activity. Compared to AZD9291, XHL11 suppressed cellular proliferation and colony formation and induced apoptosis in H1975 cells with EGFRL858R/T790M mutation. In addition, XHL11 caused expression changes in EGFR and apoptosis-related pathways. Moreover, oral administration of XHL11 suppressed tumor progression in vivo in a H1975 subcutaneous xenograft model. These data demonstrated that XHL11 might be developed as a promising EGFR TKI for the therapeutic use of NSCLC patients.

A rapid and sensitive method for quantification of ibrutinib in rat plasma by UPLC-ESI-MS/MS: validation and application to pharmacokinetic studies of a novel ibrutinib nanocrystalline.

Ibrutinib has an excellent effect in the treatment of mantle cell lymphoma so it has attracted much attention. A novel ibrutinib nanocrystalline was exploited in our study to improve the bioavailability. A fast and reliable UPLC-MS/MS method was established for the accurate quantification of ibrutinib in rat plasma. The chromatographic separation was achieved by an Agilent zorbax SB-C18 rapid solution HD column (2.1 × 50 mm, 1.8 µm). The mobile phase consisted of deionized water (containing 10 mm ammonium acetate and 0.1% formic acid) and pure acetonitrile. Isocratic elution (water-acetonitrile 10:90, v/v) was adopted and the flow rate was 0.4 mL/min. Column temperature was set to 40°C. Vilazodone was used as the internal standard in this analytical method. Multiple reaction monitoring mode with positive electrospray ionization was selected to detect ibrutinib and vilazodone. Acetonitrile was used to precipitate protein to extract plasma samples. There was no endogenous interference for both ibrutinib and vilazodone and the linear range of this method was 1-2000 ng/mL. The recoveries were 98.4, 97.4 and 102.7% at low, medium and high concentrations. Accordingly, the matrix effect was 96.6, 111.1 and 99.6%. The pharmacokinetic difference between ibrutinib crude and a novel ibrutinib nanocrystalline in rats was investigated by this validated method successfully. The peak concentration and area under the concentration-time curve showed significant differences in gender and the bioavailability was improved after oral administration of ibrutinib nanocrystalline.