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Timosaponin AIII (TAIII), as a steroid saponin in , has favorable potential as an antitumor candidate. However, its hydrophobicity and low bioavailability severely limit its in vivo antitumor efficacy. To overcome this drawback, TAIII-loaded liposomes (LP) were prepared to improve TAIII solubility and extend its circulation time. Furthermore, anti-CD44 antibody-modified LP (CD44-LP) was prepared to enhance the therapeutic index of TAIII. The LP and CD44-LP were also characterized through their biological activity, target selective binding and uptake, and in vivo pharmacokinetics. Compared with free TAIII, both LP and CD44-LP possessed a desirable sustained-release profile in vitro, with ~14.2- and 10.7-fold longer TAIII half-life, respectively, and 1.7- and 1.9-fold larger area under the curve, respectively. LP and CD44-LP enhanced TAIII antitumor activity against HepG2 cells and in a xenograft mouse model without detectable toxicity. In particular, CD44-LP exhibited notably higher cytotoxicity than did LP, with a lower half-maximal inhibitory concentration (48 h). CD44-LP exhibited stronger tumor inhibition, and the tumor inhibitory effect was 1.3-fold that of LP. Furthermore, confocal laser scanning microscopy and in vivo near-infrared imaging of a xenograft mouse model revealed that compared with LP, CD44-LP could effectively enhance tumor accumulation. Taken together, the results indicate that both CD44-LP and LP can considerably extend TAIII circulation time, increase tumor-targeted accumulation, and enhance antitumor activity. Thus, the anti-CD44 antibody-modified liposome is a promising candidate for treating CD44-positive cancer with considerable antitumor effects.

Therapeutics are habitually characterized by short plasma half-lives and little affinity for targeted cells. To overcome these challenges, nanoparticulate systems have entered into the disease arena. Poly(d,l-lactide-co-glycolide) (PLGA) is one of the most relevant biocompatible materials to construct drug nanocarriers. Understanding the physical chemistry of this copolymer and current knowledge of its biological fate will help in engineering efficient PLGA-based nanomedicines. Surface modification of the nanoparticle structure has been proposed as a required functionalization to optimize the performance in biological systems and to localize the PLGA colloid into the site of action. In this review, a background is provided on the properties and biodegradation of the copolymer. Methods to formulate PLGA nanoparticles, as well as their in vitro performance and in vivo fate, are briefly discussed. In addition, a special focus is placed on the analysis of current research in the use of surface modification strategies to engineer PLGA nanoparticles, i.e., PEGylation and the use of PEG alternatives, surfactants and lipids to improve in vitro and in vivo stability and to create hydrophilic shells or stealth protection for the nanoparticle. Finally, an update on the use of ligands to decorate the surface of PLGA nanomedicines is included in the review.

Background/Objectives: Magnetic drug targeting (MDT) using polyethene glycol (PEG)-coated magnetoresponsive nanoclusters (MNCs) can localize therapeutics, but washout from high-shear arterial flow limits efficacy. This study assesses how PEG molecular weight influences MNC deposition and washout resistance under a pulsatile flow. Methods: Magnetite MNCs were synthesized via solvothermal polyol reactions and PEGylated with PEG-2000, PEG-6000, or PEG-10,000. Characterization included TEM, DLS, zeta potential, FTIR, TGA, XPS, magnetic analysis, and rheology. In vitro assays used a 3 mm diameter glass phantom with pulsatile flow (0.10–0.45 m/s, 1 Hz) and a rectangular NdFeB (N35) permanent magnet (30 × 20 × 20 mm, 0.45 T) positioned 11 mm from the vessel wall. Washout performance was quantified by obstruction degree (OD), magnet coverage degree (MCd), washout degree (WD), washout rate constant (kout), and half-life (τ1/2). Results: MNC-6000 balanced magnetic responsiveness (Ms = 72 emu/g), colloidal stability (ζ = +13.1 mV), and hydrodynamic size (535 nm), yielding superior retention (MCd = 72.3%, OD = 19.6%, WD = 17.9%, τ1/2 = 6.93 min). MNC-2000 exhibited faster loss (kout = 0.14 min−1, τ1/2 = 4.95 min), while MNC-10,000 produced higher OD (≈53%) with embolic risk. Magnetic mapping indicated vessel wall thresholds of B ≥ 0.18 T and ∇B ≥ 10 T/m for stable capture. Limitations: Limitations of this work include the use of a single-magnet geometry, an in vitro phantom model without endothelial biology, and a maximum targeting depth of ~12–14 mm. Conclusions: The PEG molecular weight modulates MDT performance through its effects on nanocluster stability, deposition morphology, and washout kinetics. The proposed OD, MCd, and WD metrics provide clinically relevant endpoints for optimizing MDT nanoparticle design and magnet configurations.

Presenting both a panoramic introduction to the essential disciplines of drug discovery for novice medicinal chemists as well as a useful reference for veteran drug hunters, this book summarizes the state-of-the-art of medicinal chemistry. It covers key drug targets including enzymes, receptors, and ion channels, and hit and lead discovery. The book hen surveys a drug's pharmacokinetics and toxicity, with a solid chapter covering fundamental bioisosteres as a guide to structure-activity relationship investigations.

INTRODUCTION The results of the CLARITY‐AD, GRADUATE I and II, and TRAILBLAZER‐ALZ 2 trials have rekindled discussion on the impact of amyloid‐targeting drugs. We use a Bayesian approach to quantify how rational observers would have updated their prior beliefs based on new trial results. METHODS We used publicly available data from the CLARITY‐AD, GRADUATE I and II, and TRAILBLAZER‐ALZ 2 trials to estimate the effect of reducing amyloid on the clinical dementia rating scale, sum of boxes (CDR‐SB) score. A range of prior positions were then updated according to Bayes’ theorem using these estimates. RESULTS After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR‐SB score. DISCUSSION For a range of starting beliefs and assuming the veracity of the underlying data, rational observers would conclude there is a small benefit of amyloid reductions on cognition. This benefit must be weighed against opportunity cost and side‐effect risk. Highlights The results of recent trials of amyloid‐targeting drugs have rekindled discussion on the impact of amyloid reductions achieved with amyloid‐targeting drugs on cognition. Prior to the announcement of trial results, beliefs about the effects of altering amyloid levels varied. For a range of starting beliefs, one would conclude there is a small benefit of amyloid reductions due to amyloid‐targeting drugs on cognition. The perceived value of individual drugs must balance the magnitude of this benefit against opportunity cost and risk of side effects.

Background/Objectives: Nanoparticle-based drug delivery systems improve pharmacokinetic aspects, including controlled release and drug targeting, increasing therapeutic efficacy, and reducing toxicity in conventional colon cancer treatment. The superparamagnetism of magnetic nanoparticles (MNP) appears to be a potential alternative for magnetothermal therapy, inducing tumor cell death by an external magnetic field. Therefore, this study aimed to develop chitosan (CS) and folate-chitosan (FA-CS)-coated MNP to improve the stability and targeting of the system for quercetin (Q) delivery. Methods: After FA-CS synthesis and 32 factorial design, polymer-functionalized MNPs were produced for quercetin loading, characterized, and evaluated by drug dissolution and cytotoxicity assay. Results: The factorial design indicated the positive influence of CS on MNPs’ Zeta potential, followed by the CS–temperature interaction. Optimized formulations had hydrodynamic diameters of 122.32 ± 8.56 nm, Zeta potentials of +30.78 ± 0.8 mV, and loading efficiencies of 80.45% (MNP-CS-Q) and 54.4% (MNP-FA-CS-Q). The 24 h drug release was controlled in MNP-CS-Q (up to 6.4%) and MNP-FA-CS-Q (up to 7.7%) in a simulated tumor medium, with Fickian diffusion release mechanism correlated to the Korsmeyer–Peppas model (R > 0.99). The cytotoxicity assay in HCT-116 showed a higher (p < 0.001) dose-dependent antitumor effect of quercetin-loaded MNP compared to free drug, with IC50s of 1.46 (MNP-CS) and 1.30 µg·mL−1 (MNP-FA-CS). Conclusions: Therefore, this study contributes to the development of biomedical nanotechnology and the magnetic debate by highlighting the antitumor potential of quercetin magnetic nanoparticles. The experimental design allows the discussion of critical manufacturing variables and the determination of optimal parameters for the formulations.

We present a motif-targeting phosphoproteome analysis workflow utilizing in vitro kinase reaction to enrich a subset of peptides with specific primary sequence motifs. Phosphopeptides are enriched and dephosphorylated with alkaline phosphatase, followed by in vitro kinase reaction to phosphorylate substrate peptides with specific primary-sequence motifs. These phosphopeptides are enriched again, TMT-labeled, dephosphorylated to enhance MS-detectability, and analyzed by LC/MS/MS. We applied this approach to inhibitor-treated cancer cells, and successfully profiled the inhibitory spectra of multiple kinase inhibitors. We anticipate this approach will be applicable to target specific subsets of the phosphoproteome using the wide variety of available recombinant protein kinases.

We aimed to magnetically guide and locally confine nanoparticles in desired locations within the spinal canal to achieve effective drug administration for improved treatment of chronic pain, cancers, anesthesia and spasticity. We developed a physiologically and anatomically consistent human spine model to test the feasibility of intrathecal magnetic drug targeting. Gold-coated magnetite nanoparticles were infused into the model and targeted to specific regions using external magnetic fields. Experiments and simulations aiming to determine the effect of key parameters, such as magnet strength, duration of magnetic field exposure, magnet location and ferrous implants, on the collection efficiency of superparamagnetic nanoparticles in targeted regions were performed. An 891% increase in nanoparticle collection efficiency within the target region was achieved using intrathecal magnetic drug targeting when compared with the control. Nanoparticle collection efficiency at the target region increased with time and reached a steady value within 15 min. Ferrous epidural implants generated sufficiently high-gradient magnetic fields, even when magnets were placed at a distance equal to the space between a patient s epidermis and spinal canal. Our experiments indicate that intrathecal magnetic drug targeting is a promising technique for concentrating and localizing drugs at targeted sites within the spinal canal for treating diseases affecting the CNS. Original submitted 27 June 2012; Revised submitted 11 March 2013

Lymphatic filariasis (LF) continues to impact 657 million individuals worldwide, resulting in lifelong and chronic impairment. The prevalent anti-filarial medications—DEC, albendazole, and ivermectin—exhibit limited adulticidal efficacy. Despite ongoing LF eradication programs, novel therapeutic strategies are essential for effective control. This study examines the mechanism of action of Ocimum sanctum on the filarial parasites Setaria cervi via a synergistic biochemical and proteomics methodology. The ethanolic extract of Ocimum sanctum (EOS) demonstrated potential anti-filarial action in the MTT reduction experiment, with an LC50 value of 197.24 µg/mL. After EOS treatment, an elevation in lipid peroxidation (51.92%), protein carbonylation (48.99%), and NADPH oxidase (88.88%) activity, along with a reduction in glutathione (GSH) (−39.23%), glutathione reductase (GR) (−60.17%), and glutathione S transferase (GST) (−50.48%) activity, was observed. The 2D gel electrophoresis identified 20 decreased and 11 increased protein spots in the EOS-treated parasites relative to the control group. Additionally, in drug docking analysis, the EOS bioactive substances ursolic acid, rutin, and rosmarinic acid show a significant binding affinity with the principal differentially expressed proteins. This paper demonstrates, for the first time, that the anti-filarial efficacy of EOS is primarily facilitated by its impact on energy metabolism, antioxidant mechanisms, and stress response systems of the parasites.

Polymers have played a critical role in the rational design and application of drug delivery systems that increase the efficacy and reduce the toxicity of new and conventional therapeutics. Beginning with an introduction to the fundamentals of drug delivery, Engineering Polymer Systems for Improved Drug Delivery explores traditional drug delivery techniques as well as emerging advanced drug delivery techniques. By reviewing many types of polymeric drug delivery systems, and including key points, worked examples and homework problems, this book will serve as a guide to for specialists and non-specialists as well as a graduate level text for drug delivery courses.