Synthesis of Benzophenones and in vitro Evaluation of Their Anticancer Potential in Breast and Prostate Cancer Cells

Breast and prostate cancers are frequently treated with chemotherapy. Several novel chemicals are being reported for this purpose, particularly synthetic and natural benzophenones. This work reports the synthesis of substituted 2-hydroxybenzophenones through 1,4-conjugate addition/intramolecular cycloaddition/dehydration of nitromethane on key intermediate chromones. Structures were extensively studied by means of 2D NMR spectroscopy and single-crystal XRD. Their cytotoxicity was evaluated in vitro in two breast cancer cell lines (MDA-MB-231 and T47-D) and one prostate cancer cell line (PC3). The most potent compound exhibited good cytotoxic effects against the three cancer cell lines (IC₅₀ values ranging from 12.09 to 26.49 μm ) and induced cell-cycle retardation only on prostate cancer cells, which suggested that it might exert cell-type-specific effects.     

In vivo evaluation of a mucoadhesive polymeric caplet for intravaginal anti-HIV-1 delivery and development of a molecular mechanistic model for thermochemical characterization

Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.

Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.

Results and discussion: There was a big deviation between the T_g of the polymeric caplet from the T_g's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.

Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents.     

Temperature/pH/magnetic triple‐sensitive nanogel–hydrogel nanocomposite for release of anticancer drug

Hydrogels, nanogels and nanocomposites show increasing potential for application in drug delivery systems due to their good chemical and physical properties. Therefore, we were encouraged to combine them to produce a new compound with unique properties for a long‐term drug release system. In this regard, the design and application of a nanocomposite hydrogel containing entrapped nanogel for drug delivery are demonstrated. To this aim, we first prepared an iron oxide nanocomposite nanogel based on poly(N‐isopropylacrylamide)‐co‐((2‐dimethylaminoethyl) methacrylate) (PNIPAM‐co‐PDMA) grafted onto sodium alginate (NaAlg) as a biocompatible polymer and iron oxide nanoparticles (ION) as nanometric base (PND/ION‐NG). This was then added into a solution of PDMA grafted onto NaAlg. Through dropwise addition of mixed aqueous solution of iron salts into the prepared polymeric solution, a novel hydrogel nanocomposite with excellent pH, thermal and magnetic responsivity was fabricated. The synthesized samples were fully characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy with energy‐dispersive X‐ray analysis, vibrating sample magnetometry and atomic force microscopy. A mechanism for the formation of PNIPAM‐co‐PDMA/NaAlg‐ION nanogel–PDMA/NaAlg‐ION hydrogel and PND/ION nanogel is suggested. Swelling capacity was measured at various temperatures (25 to 45 °C), pH values (from 2 to 11) and magnetic field and under load (0.3 psi) and the dependence of swelling properties of the nanogel–hydrogel nanocomposite on these factors was well demonstrated. The release rate of doxorubicin hydrochloride (DOX) as an anticancer drug was studied at different pH values and temperatures in the presence and absence of a magnetic field. The results showed that these factors have a high impact on drug release from this nanocomposite. The result showed that DOX release could be sustained for up to 12.5 days from these nanocomposite hydrogels, significantly longer than that achievable using the constituent hydrogel or nanogel alone (<1 day). The results indicated that the nanogel–hydrogel nanocomposite can serve as a novel nanocarrier for anticancer drug delivery. © 2019 Society of Chemical Industry     

Multicellular Tumor Spheroids (MCTS) as a 3D In Vitro Evaluation Tool of Nanoparticles

Multicellular tumor spheroid models (MCTS) are often coined as 3D in vitro models that can mimic the microenvironment of tissues. MCTS have gained increasing interest in the nano‐biotechnology field as they can provide easily accessible information on the performance of nanoparticles without using animal models. Considering that many countries have put restrictions on animals testing, which will only tighten in the future as seen by the recent developments in the Netherlands, 3D models will become an even more valuable tool. Here, an overview on MCTS is provided, focusing on their use in cancer research as most nanoparticles are tested in MCTS for treatment of primary tumors. Thereafter, various types of nanoparticles—from self‐assembled block copolymers to inorganic nanoparticles, are discussed. A range of physicochemical parameters including the size, shape, surface chemistry, ligands attachment, stability, and stiffness are found to influence nanoparticles in MCTS. Some of these studies are complemented by animal studies confirming that lessons from MCTS can in part predict the behaviour in vivo. In summary, MCTS are suitable models to gain additional information on nanoparticles. While not being able to replace in vivo studies, they can bridge the gap between traditional 2D in vitro studies and in vivo models.     

含膦酸酯结构单元的磺胺衍生物合成与抗菌活性

为了寻找抗菌候选化合物,采用基于片段的药物发现方法,以氨基膦酸酯和磺酰氯为原料,设计合成了15个含膦酸酯结构单元的磺胺衍生物,经IR、1HNMR和13CNMR确认结构。采用两倍稀释法测定目标化合物的MIC(最小抑菌浓度)。结果表明:部分目标化合物呈潜在的抗菌活性,对所测试标准菌和耐药菌均有抑制活性。其中,化合物Ⅱf〔N-[(二乙氧基膦酰基)-4-氟苯甲基]-4-甲氧基苯磺酰胺〕对金黄色葡萄球菌(S. aureus)、大肠埃希菌(E. coli)、耐甲氧西林金黄色葡萄球菌(MRSA)及耐氟喹诺酮类大肠杆菌(MREC)的MIC分别为32、64、128和128μg/mL,化合物Ⅱl〔N-[(二乙氧基膦酰基)-4-氟苯甲基]-4-氟苯磺酰胺〕对S. aureus、E. coli、MRSA及MREC的MIC分别为32、32、64和64μg/mL,抗菌活性优于对照药磺胺嘧啶。     

A General Role for Early Onset Cues and Intra-Event Learning; Comment on McDonald and Siegel (2004).

Research on classical conditioning with drug unconditional stimuli has had a profound effect on the understanding of general conditioning processes. The experiment reported by R. V. McDonald and S. Siegel (see record 2004-10475-001) demonstrates that cues coincident with the onset of an event can become associated with the rest of the event. This sort of learning is probably ubiquitous and has been proposed as a mechanism behind the development of panic disorder, in which interoceptive cues coincident with the start of a panic attack can be associated with the rest of the attack and can eventually come to elicit full-blown panic on their own. Evidence that extinction exposure to early onset cues can reduce their power is especially important. Drug conditioning research continues to provide a powerful testing ground for important general principles of learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rheological and drug‐release behaviour of a scleroglucan gel matrix at different drug loadings

The aim of this study was to investigate the drug‐loading effects on release and mechanical properties of a scleroglucan gel, with the intention of considering them in delivery systems formulations. The rheological and kinetic properties of a 2 % w/w scleroglucan gel matrix loaded with 0, 0.02, 0.04, 0.06, 0.2 and 0.4 % w/w of theophylline (Th, used as a model drug) were investigated. Rheological measurements were performed in a controlled‐stress rotational‐shear rheometer under isothermal conditions. For theophylline release from the gel a flat Franz cell was used and the kinetic parameters were derived applying a semi‐empirical power law. The influence of scleroglucan molar weight on kinetic and rheological behaviour was also studied. Results suggest two possible effects of drug loading on the gel network: in the 0.04–0.06 % w/w Th range a plasticizing effect and in the 0.2–0.4 % w/w Th range a rigidization effect. In the first range mentioned, the changes in the gel structural properties tested by means of rheological measurements are coincident with changes in drug‐release kinetics. Copyright © 2005 Society of Chemical Industry     

迪银片治疗银屑病临床疗效观察

目的观察迪银片治疗银屑病的临床疗效。方法30例银屑病患者,口服迪银片8周,采用PASI评分法评价治疗前后效果,并观察有无不良反应发生。结果患者痊愈率56.7%,显效率36.7%,总有效率93.3%,无明显的不良反应。结论迪银片是临床治疗银屑病的有效药物之一。