ABSTRACT
A proof of concept for designing multi-drug-delivery systems suitable for self-drug-delivery is disclosed. Simple coordination chemistry was employed to anchor two kinds of drugs namely isoniazid (IZ - anti-tuberculosis), various non-steroidal-anti-inflammatory-drugs (NSAIDs) namely ibuprofen-IBU, fenoprofen-FEN, naproxen-NAP, diclofenac-DIC and mefenamic acid-MEF and Zn(NO3)2 to synthesize a series of 1D coordination polymers namely IZIBU, IZFEN, IZNAP, IZDIC and IZMEF which were structurally characterized by single crystal X-ray diffraction (SXRD). The coordination polymers wherein both types of drugs were anchored to Zn(II) metal centers could easily be ground to nano-sized particles suitable for biological studies by hand grinding in a mortar and pestle. Zone inhibition studies revealed that all the coordination polymers possessed antibacterial properties against Gram positive, Gram negative and mycobacteria namely Mycobacterium tuberculosis (M.tb). Detailed studies carried out on IZDIC employing flow cytometry and confocal microscopy under various staining conditions established that such antibacterial activity was due to the generation of reactive oxygen species (ROS) such as nitric oxide (NO) and also inhibition of mycolic acid leading to incomplete cell wall formation. It was also established that IZDIC could indeed inhibit the growth of M.tb within a mouse macrophage host cell namely RAW 264.7 thereby simulating the treatment of Tuberculosis (TB) under in vitro conditions. Scratch assay and cell cycle analysis on a human lung cancer cell line (A549) revealed its anti-cancer property, thereby indicating its potential as a multi-drug-delivery system. In vivo toxicity assessment (serum parameters, histopathology, and haemolysis) carried out on BALB/c mice showed that IZDIC was safe up to a concentration of 100 mg kg-1. Finally, a reasonably high yield in bulk synthesis, stability under high temperature and humid conditions, tabletability and, slow and sustained release of the drug component of IZDIC suggested its suitability in real-life applications as multi-drug-delivery systems.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Mice , Animals , Humans , Polymers/chemistry , Naproxen , Isoniazid/pharmacology , Reactive Oxygen Species , Ibuprofen , Mefenamic Acid , Diclofenac , Mycolic Acids , Fenoprofen , Nitric Oxide , Delayed-Action Preparations , Tuberculosis/drug therapy , Tuberculosis/microbiology , Drug Delivery Systems , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Bacterial AgentsABSTRACT
Metallogelators/metallogels derived from a series of multi-NSAID-based Zn(II)-coordination complexes displaying anti-cancer and anti-bacterial properties were designed based on a structural rationale as plausible multi-drug self-delivery systems.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Coordination Complexes/chemistry , Drug Carriers/chemistry , Zinc/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Coordination Complexes/pharmacology , Gels/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hemolysis/drug effects , Mice , Mice, Inbred BALB CABSTRACT
A new series of coordination polymers (CPs) were synthesized and crystallographically characterized by single-crystal X-ray diffraction with the aim of developing drug-delivery systems via metallogel formation. Structural rationale was employed to design such coordination-polymer-based metallogels. As many as nine CPs were obtained by reacting two bis(pyridyl)urea ligands, namely, 1,3-dipyridin-3-ylurea (3U) and 1,3-dipyridin-4-ylurea (4U), and the sodium salt of various nonsteroidal antiinflammatory drugs, namely, ibuprofen (IBU), naproxen (NAP), fenoprofen (FEN), diclofenac (DIC), meclofenamic acid (MEC), mefenamic acid (MEF), and Zn(NO3)2. All of the CPs displayed 1D polymeric chains that were self-assembled through various hydrogen-bonding interactions involving the urea N-H and carboxylate O atoms and, in a few cases, lattice-occluded water molecules. The reacting components of the CPs produced five metallogels in dimethyl sulfoxide/water. The gels were characterized by rheology and transmission electron microscopy. Three selected metallogelators, namely, 3UMEFg, 3UNAPg, and 3UMECg, showed in vitro anticancer, cell imaging, and multidrug delivery for antibacterial applications, respectively. The shear-thinning properties of 3UMECg (rheoreversibility and injectability) make it a potential candidate for plausible topical application.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Coordination Complexes/chemistry , Drug Carriers/chemistry , Gels/chemistry , Polymers/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Inflammatory Agents/chemistry , Cell Line, Tumor , Drug Liberation , Drug Screening Assays, Antitumor , Klebsiella/drug effects , Metal Nanoparticles/chemistry , Mice , Microbial Sensitivity Tests , Silver/chemistry , Silver/pharmacology , Zinc/chemistryABSTRACT
Crystallographically characterized M2 L4 type cationic Cu(II)-metallacryptands [MC(X)] derived from a series of bis-pyridyl-bis-urea ligands (LX ; X = O, S, C) are self-assembled to single-layered vesicular aggregates in DMSO, DMSO/water, and DMSO/DMEM (biological media). One such vesicle is MC(O)-vesicle that is demonstrated to be able to load and release (pH responsive) an anticancer drug, namely doxorubicin hydrochloride (DOX). DOX-loaded MC(O)-vesicle is also successfully transported within MDA-MB-231 cells-a highly aggressive human breast cancer cell line. Such self-assembling behavior to form vesicular aggregates by metallacryptands (MCs) is hitherto unknown.
Subject(s)
Antineoplastic Agents , Doxorubicin , Drug Carriers , Nanoparticles , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Humans , Hydrogen-Ion Concentration , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Neoplasms/metabolism , Neoplasms/pathologyABSTRACT
Flexible and dynamic CuI metal-organic framework [Cu(I)-MOF (1)] with well-defined nanoporous channel built with flexible terpyridine ligand offers a scaffold for the inclusion of different classes of guest molecules through a single-crystal-to-single-crystal (SCSC) transformation in the vapor phase at ambient conditions with visual color change. Thus, Cu(I)-MOF (1) offers a potential platform for molecular recognition and undergoes guest-responsive structural dynamism that can be triggered by interfacial interactions. Despite having the stable conformation of the rotational isomers, it selectively encapsulates the less stable conformation (eclipsed and gauche) into its cavity from their vapor phases in the SCSC process. All of the guest-exchanged processes are reversible. It shows selectivity toward less polar guest in a class. The intermediate of all of the guest-exchanged processes appeared as a black material (H2O@Cu(I)-MOF) (1z) prior to the encapsulation of each guest that happens through the SCSC manner followed by encapsulation of the guests replacing H2O in situ at ambient conditions through SCSC transformation. This confirms that the process is a two-step process leading to a common intermediate. The MOF loses its luminescence behavior with H2O removing lattice solvents in situ and appears as a black material, and it regains its luminescence property with the guests replacing H2O. Thus, the MOF displays both luminescence "turn-off" and "turn-on" before and after incorporation of the guests, respectively, leading to a common turn-off mechanism. A fluorescence titration experiment shows selectivity toward aniline among benzene and its derivatives.
ABSTRACT
A newly synthesized bis-pyridyl ligand having a diphenyl ether backbone (LP6) displayed the ability to form crystalline coordination polymers (CP1-CP6) which were fully characterized by single crystal X-ray diffraction. Most of the resulting polymers were lattice-occluded crystalline solids-a structural characteristic reminiscent to gels. The reactants of the coordination polymers produced metallogels in DMSO/water confirming the validity of the design principles with which the coordination polymers were synthesized. Some of the metallogels displayed material properties like in situ synthesis of Ag nanoparticles and stimuli-responsive gel-sol transition including sensing hazardous gases like ammonia and hydrogen sulfide.