Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities.

BACKGROUND: Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy. OBJECTIVES: The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor. METHODS: The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2. RESULTS: The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43 µM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80 µM and 9.34 µM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7. CONCLUSION: The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.

Hot-melt extruded in situ gelling systems (MeltDrops Technology): Formulation development, in silico modelling and in vivo studies.

In situ gelling systems (ISGS) can prolong retention time and bioavailability of ophthalmic solutions. The complexity and cost of ISGS avert their industrial scale-up and clinical implementation. In this study, we demonstrate novel application of hot-melt extrusion (HME) technology for continuous manufacturing of ISGS (MeltDrops Technology). Timolol maleate (TIM) and dorzolamide hydrochloride (DRZ) loaded MeltDrops were successfully developed using HME for glaucoma management, thereby resolving issues with batch manufacturing of ISGS, prolonging retention time thus improving bioavailability. The MeltDrops technology involves one-step, i.e., passing all the ingredients through an extruder at a screw speed between 20 and 50 rpm and barrel temperature of 80 °C. The comparative evaluation of MeltDrops and batch-processed ISGS demonstrated that MeltDrops exhibited better physical and chemical content uniformity. The extrusion temperature and screw speed were critical factors influencing content uniformity and properties of the MeltDrops. MeltDrops showed sustained drug release for > 12 h in vitro (TIM = 83.07%; DRZ = 60.43%, 12 h) versus marketed eyedrops. The developed MeltDrops followed Peppas-Sahlin model, combining Fickian diffusion and swelling processes. The in vivo study in New Zealand rabbits revealed superior effectiveness and safety of the MeltDrops as compared to the marketed eyedrops. Herein we conclude, MeltDrops would serve as a cutting-edge platform technology that can be used to manufacture various ISGS with one-step processability, cost-effectiveness, and improved product quality, which are otherwise processed by batch manufacturing that involves numerous complex processing steps.

Transforming Wound Management: Nanomaterials and Their Clinical Impact.

Wound healing is a complex process that can be further complicated in chronic wounds, leading to prolonged healing times, high healthcare costs, and potential patient morbidity. Nanotechnology has shown great promise in developing advanced wound dressings that promote wound healing and prevent infection. The review article presents a comprehensive search strategy that was applied to four databases, namely Scopus, Web of Science, PubMed, and Google Scholar, using specific keywords and inclusion/exclusion criteria to select a representative sample of 164 research articles published between 2001 and 2023. This review article provides an updated overview of the different types of nanomaterials used in wound dressings, including nanofibers, nanocomposites, silver-based nanoparticles, lipid nanoparticles, and polymeric nanoparticles. Several recent studies have shown the potential benefits of using nanomaterials in wound care, including the use of hydrogel/nano silver-based dressings in treating diabetic foot wounds, the use of copper oxide-infused dressings in difficult-to-treat wounds, and the use of chitosan nanofiber mats in burn dressings. Overall, developing nanomaterials in wound care has complemented nanotechnology in drug delivery systems, providing biocompatible and biodegradable nanomaterials that enhance wound healing and provide sustained drug release. Wound dressings are an effective and convenient method of wound care that can prevent wound contamination, support the injured area, control hemorrhaging, and reduce pain and inflammation. This review article provides valuable insights into the potential role of individual nanoformulations used in wound dressings in promoting wound healing and preventing infections, and serves as an excellent resource for clinicians, researchers, and patients seeking improved healing outcomes.

Progressive hemifacial atrophy with ciliary body atrophy and ocular hypotony.

Progressive hemifacial atrophy (PHA) is a disease of unknown etiology affecting one-half of the face. Ocular involvement is uncommon. Atrophy of iris is rare, with only a few cases of partial atrophy being reported in the literature. We report a case of total atrophy of iris and ciliary body with associated ocular hypotony in a 16-year-old girl with PHA. We believe this is the first reported case of complete atrophy of iris and ciliary body in PHA. Ocular hypotony in PHA was thought to be due to intra-ocular inflammation. However in our case it appears to be secondary to severe atrophy of the ciliary body.