查看更多>>摘要：New synthetic compound Raptinal (RAP) was investigated on different biological levels for its potential anticancer activity. RAP showed higher antiproliferative activity on HepG2 cell line with IC50 0.62 mu M compared to MCF-7 and HCT-116 (4.03 and 92.3 mu M) respectively. Moreover, RAP induces early stage of apoptosis in the most sensitive HepG2 treated cells after 24 hr with cell cycle arrest in both sub G(0)-G(1) and G(0)-G(1) phases and minimal cell count in G(2)/M mitotic phase with apoptotic index 9.25-fold higher than to control. RAP induces overexpression of key apoptotic genes such as Fas receptor, Caspase-8, Caspase-9, Bax and P53. Western blotting confirm the observation on protein level via over-expression of Caspase-9, Cytochrome-C and higher ration of Bax/Bcl-2. In addition, RAP was radiolabeled using one of the most important diagnostic radioactive isotopes, technetium-99m (Tc-99m), with a radiochemical yield of 92.7 +/- 0.41 %. Quality control and biological distribution of Tc-99m-RAP in both healthy and HCC rat model were investigated. Biodistribution profile revealed the localization of RAP in liver tissues (20.5 +/- 2.6 %) of HCC models at half an hour post intravenous injection. Histopathological examination confirmed the biodistribution of RAP into liver tissue with induction of karyomegaly in the nuclei of hepatocytes as well as others that proceeded into apoptosis. Molecular docking suggested RAP binds in binding pocket of p53 cancer mutant Y220C making reactivation of the mutant form which is a promising strategy for further investigation on molecular level as a novel anticancer therapeutics. All the results support the use of RAP as a potential anticancer drug in HCC and its Tc-99m complex as an imaging probe.
Limami, YounessLeger, David YannickLiagre, BertrandPecout, Nathalie...
7页
查看更多>>摘要：Musculoskeletal diseases often demand a drug treatment at the specific site of injury or defect site. In this context, the use of calcium phosphates is attractive as it allows both the bone substitution and the local delivery of a drug substance. In this work, we present a drug delivery device that combines calcium phosphate bioceramic granules and ibuprofen, a widely used anti-inflammatory drug.
Martin, Maria JuliaAzcona, PamelaLassalle, VeronicaGentili, Claudia...
14页
查看更多>>摘要：Colorectal cancer (CRC) is a major cause of cancer death with a high probability of treatment failure. Doxorubicin (DOXO) is an efficient antitumor drug; however, most CRC cells show resistance to its effects. Magnetic nanoparticles (MNPs) are potential cancer management tools that can serve as diagnostic agents and also can optimize and personalize treatments. This work aims to evaluate the aptitude of magnetic nanotheranostics composed of magnetite (Fe3O4) nanoparticles coated with folic acid intended to the sustained release of DOXO. The administration of DOXO by means of these MNPs resulted in the enhancement of cell death respect to the free drug administration. Chromatin compaction and cytoplasmic protrusions were observed. Mitochondrial transmembrane potential disruption and increased PARP protein cleavage confirmed apoptosis. The nanosystem was also tested as a vectoring tool by exposing it to the stimuli of a static magnetic field in vitro. CRC-related magnetic nanotechnology still remains in pre-clinical trials. In this context, this contribution expands the knowledge of the behavior of MNPs in contact with in vitro models and proposes the nanodevices studied here as potential theranostic agents for the monitoring of the progress of CRC and the evolution of its treatment.
查看更多>>摘要：UDP-glucuronosyltransferases (UGTs), located in the endoplasmic reticulum of liver cells, are an important family of enzymes, responsible for the biotransformation of several endogenous and exogenous chemicals, including therapeutic drugs. However, the phenomenon of 'latency', i.e., full UGT activity revealed by disruption of the microsomal membrane, poses substantial challenges for predicting drug clearance based on in vitro glucuronidation assays. This work introduces a microfluidic reactor design comprising immobilized human liver microsomes to facilitate the study of UGT-mediated drug clearance under flow-through conditions. The performance of the microreactor is characterized using glucuronidation of 8-hydroxyquinoline (via multiple UGTs) and zidovudine (via UGT2B7) as the model reactions. With the help of alamethicin and albumin effects, we show that conducting UGT metabolism assays under flow conditions facilitates in-depth mechanistic studies, which may also shed light on UGT latency.
Agarwal, PrashantGreene, Daniel G.Sherman, ScottWendl, Kaitlyn...
12页
查看更多>>摘要：Sustained-release formulations are important tools to convert efficacious molecules into therapeutic products. Hydrogels enable the rapid assessment of sustained-release strategies, which are important during preclinical development where drug quantities are limited and fast turnaround times are the norm. Most research in hydrogel-based drug delivery has focused around synthesizing new materials and polymers, with limited focus on structural characterization, technology developability and implementation. Two commercially available thermosensitive hydrogel systems, comprised of block copolymers of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PLGA) and poly(lactide-co-caprolactone)-b-poly(ethyleneglycol)-b-poly (lactide-co-caprolactone) (PLCL), were evaluated during this study. The two block copolymers described in the study were successfully formulated to form hydrogels which delayed the release of lysozyme (> 20 days) in vitro. Characterization of formulation attributes of the hydrogels like Tsol-gel temperature, complex viscosity and injection force showed that these systems are amenable to rapid implementation in preclinical studies. Understanding the structure of the gel network is critical to determine the factors controlling the release of therapeutics out of these gels. The structures were characterized via the gel mesh sizes, which were estimated using two orthogonal techniques: small angle X-ray scattering (SAXS) and rheology. The mesh sizes of these hydrogels were larger than the hydrodynamic radius (size) of lysozyme (drug), indicating that release through these gels is expected to be diffusive at all time scales rather than sub-diffusive. In vitro drug release experiments confirm that diffusion is the dominating mechanism for lysozyme release; with no contribution from degradation, erosion, relaxation, swelling of the polymer network or drug-polymer interactions. PLGA hydrogel was found to have a much higher complex viscosity than PLCL hydrogel, which correlates with the slower diffusivity and release of lysozyme seen from the PLGA hydrogel as compared to PLCL hydrogel. This is due to the increased frictional drag experienced by the lysozyme molecule in the PLGA hydrogel network, as described by the hydrodynamic theory.
Parasuraman, Jaya MadhuraKloprogge, FrankStanding, Joseph FrankAlbur, Mahableshwar...
8页
查看更多>>摘要：Aim: Intraventricular vancomycin is an effective treatment for neonatal ventriculitis, as the cerebrospinal fluid (CSF) vancomycin levels reach adequate concentrations to achieve microbiological cure. There is no robust data on intraventricular vancomycin pharmacokinetics in the preterm population. This pilot population pharmacokinetic modelling study examines the pharmacokinetic behaviour of intraventricular vancomycin in the preterm population of < 28 weeks gestation, to inform the feasibility of future prospective studies.
Aljalamdeh, RehamPrice, RobertJones, Matthew D.Bolhuis, Albert...
9页
查看更多>>摘要：Pseudomonas aeruginosa is the predominant opportunistic bacterium that causes chronic respiratory infections in cystic fibrosis (CF) patients. This bacterium can form biofilms, which are structured communities of cells encased within a self-produced matrix. Such biofilms have a high level of resistance to multiple classes of antibiotics. A widely used treatment of P. aeruginosa lung infections in CF patients is tobramycin dry powder inhalation. The behaviour of particles in the lung has been well studied, and dry powder inhalers are optimised for optimal dispersion of the drug into different zones of the lung. However, one question that has not been addressed is whether the size of an antibiotic particle influences the antibiofilm activity against P. aeruginosa. We investigated this by fractionating tobramycin particles using a Next Generation Impactor (NGI). The fractions obtained were then tested in an in vitro model on P. aeruginosa biofilms. The results indicate that the antibiofilm activity of tobramycin dry powder inhaler can indeed be influenced by the particle size. Against P. aeruginosa biofilms of two clinical isolates, smaller tobramycin particles (aerodynamic diameter <2.82 mu m) showed better efficacy by approximately 20% as compared to larger tobramycin particles (aerodynamic diameter <11.7 mu m) However, this effect was only observed when biofilms were treated for 3 hours, whereas there was no difference after treatment for 24 hours. This suggests that in our model the rate of dissolution of larger particles limits the effectiveness of tobramycin over a 3-hour time period, which is relevant as this is equivalent to the time in which most tobramycin is cleared from the lung.
查看更多>>摘要：Gut microbiota and bile acids possess the ability to modify absorption and pharmacokinetic profile of numerous drugs. Since the variability of gliclazide response in patients cannot be explained only by genetic factors, the influence of gut microbiota and bile acids should be considered. The aim of this study was to determine the effects of probiotic bacteria and bile acids on the gliclazide permeability. The permeability of gliclazide with and without probiotic bacteria and bile acids (cholic acid, CA and deoxycholic acid, DCA) was tested using in vitro PAMPA model, at three different pH values (5.8, 6.5 and 7.4). Concentrations of gliclazide were determined by HPLC analysis. The interactions of gliclazide and bile acids were also investigated by molecular mechanics calculations (MM2). Probiotic bacteria significantly increased the permeability of gliclazide across the PAMPA membrane at all observed pH values while the total amount of gliclazide during incubation with bacteria was significantly reduced at pH 7.4, which could be a consequence of partial metabolism of the drug by enzymes of probiotic bacteria. Bile acids decreased the permeability of gliclazide through PAMPA membrane, with more pronounced effects of DCA, by forming more stable complexes with gliclazide. Given that probiotic bacteria and bile acids are naturally present in the gut and that each individual has a specific bacterial fingerprint, future research should extend the explanation of their effect on the gliclazide bioavailability and therapy individualization in in vivo conditions.
Galindo-Rosales, Francisco J.Campo-Deano, LauraVicente, JoaoSemiao, Viriato...
10页
查看更多>>摘要：The present works contributes with a rheological characterization of the most commonly used polymers and solvents to formulate amorphous solid dispersions by means of spray drying process: copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and a copolymer of methacrylic acid and methyl methacrylate (1:1 ratio and commercially known as Eudragit L100). The organic-based solutions are characterized in terms of surface tension, shear viscosity and relaxation time. HPMC and HPMCAS solutions exhibit shear thinning behaviour, i.e. decrease of shear viscosity with the increasing shear rate imposed, while the samples with Eudragit L100 can be considered Boger fluids, showing a constant viscosity but maintaining its viscoelastic character. Under uniaxial extensional flow, these polymers solutions exhibit a viscoelastic behavior with an increasing relaxation time with an increasing concentration, and in some cases showed a 'beads-on-string' effect. In contrast, copovidone showed a Newtonian fluid behavior, with the absence of elasticity. The fundamental understanding and characterization of the present work may be further applied to atomization modelling and support and expedite spray drying process development.
Macedo, Luiza de O.Barbosa, Eduardo J.Lobenberg, RaimarBou-Chacra, Nadia A....
15页
查看更多>>摘要：Anti-inflammatory drugs have been prescribed extensively for a wide range of diseases. Combined with over-the-counter use, approximately 30 billion doses of non-steroidal inflammatory drugs (NSAIDs) are consumed annually in the USA. The global market of glucocorticoids (GCs) is forecast to reach US$ 8.6 billion by 2025. Severe adverse effects have been reported for NSAIDs, GCs, and COX-2 selective NSAIDs (COXIBs). Furthermore, the overwhelming majority of these drug substances are BCS class II, which limits their bioavailability due to poor water solubility. Drug nanocrystals, a carrier-free nanosystem, can increase saturation solubility, dissolution rate, and the mucoadhesiveness of these drugs. The enhancement of these properties was highlighted in our findings. These features improve the efficacy and safety of anti-inflammatory drugs. In this review, we show that drug nanocrystals are an attractive strategy that contributes to an important shift in the development of innovative products for different routes of administration. The possibility of targeting can minimize the adverse effects and improve the efficacy in the management of inflammatory conditions. We comprehensively review the critical quality attributes (CQAs) in the anti-inflammatory drug nanocrystals preparation, which are fundamental to developing a successful marketable product. Despite the advantages, maintaining properties such as average particle size, surface properties, and physicochemical stability of these preparations during shelf life poses challenges to be overcome.
NSTL
Elsevier