Redox modulator iron complexes trigger intrinsic apoptosis pathway in cancer cells.

The emergence of multidrug resistance in cancer cells necessitates the development of new therapeutic modalities. One way cancer cells orchestrate energy metabolism and redox homeostasis is through overloaded iron pools directed by iron regulatory proteins, including transferrin. Here, we demonstrate that targeting redox homeostasis using nitrogen-based heterocyclic iron chelators and their iron complexes efficiently prevents the proliferation of liver cancer cells (EC50: 340 nM for IITK4003) and liver cancer 3D spheroids. These iron complexes generate highly reactive Fe(IV)=O species and accumulate lipid peroxides to promote oxidative stress in cells that impair mitochondrial function. Subsequent leakage of mitochondrial cytochrome c activates the caspase cascade to trigger the intrinsic apoptosis pathway in cancer cells. This strategy could be applied to leverage the inherent iron overload in cancer cells to selectively promote intrinsic cellular apoptosis for the development of unique iron-complex-based anticancer therapeutics.

Suitably Incorporated Hydrophobic, Redox-Active Drug in Poly Lactic Acid-Graphene Nanoplatelet Composite Generates 3D-Printed Medicinal Patch for Electrostimulatory Therapeutics.

Polymer carbon composites have been reported for improved mechanical, thermal and electrical properties to provide reduced side effect by 3D printing personalized biomedical drug delivery devices. But control on homogeneity in loading and release of dopants like carbon allotropes and drugs, respectively, in the bulk and on the surface has always been a challenge. Herein, we are reporting a methodological cascade to achieve a model, customizable, 3D printed, homogeneously layered and electrically stimulatory, PLA-Graphene nanoplatelet (hl-PLGR) based drug delivery device, called 3D-est-MediPatch. The medicinal patch has been prepared by 3D-printing a Nic-hl-PLGR composite obtained by incorporating a redox active model drug, niclosamide (Nic) in hl-PLGR. The composite of Nic-hl-PLGR was characterized in three sequentially complex forms─composite film, hot melt extruded (HME) filament, and 3D printed (3DP) patches to understand the effect of filament extrusion and 3D-printing processes on Nic-hl-PLGR composite and overall drug incorporation efficiency and control. The incorporation of graphene was found to improve the homogeneity of the drug, and the hot melt extrusion improved the dispersion of drug and graphene fillers in the composite. The electroresponsive drug release from the Nic-hl-PLGR composite was found to be controllably accelerated compared to the drug release by diffusion, in simulated buffer condition. The released drug concentration was found to reach within the IC50 range for malignant melanoma cell (A375) and showed in vitro selectively, with reduced effects in noncancerous, fibroblast cells (NIH3T3). Further, the feasibility of application for this system was assessed in generating personalized 3D-est-MediPatch for skin, liver and spleen tissues in ex-vivo scenario. It showed excellent feasibility and efficacy of the 3D-est-MediPatch in controlled and personalized release of drugs during electrostimulation. Thus, a model platform, 3D-est-MediPatch, could be achieved by suitably incorporating a hydrophobic, redox-active drug (niclosamide) in poly lactic acid-graphene nanoplatelet composite for electrostimulatory therapeutics with reduced side effects.

Pyridine-2,6-Dicarboxamide Proligands and their Cu(II)/Zn(II) Complexes Targeting Staphylococcus Aureus for the Attenuation of In Vivo Dental Biofilm.

In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram-positive bacteria, this study is an attempt to craft a precision-driven platform characterized by unparalleled selectivity, specificity, and synergistic antimicrobial mechanisms. Leveraging remarkable potential of metalloantibiotics in antimicrobial applications, herein, this work rationally designs, synthesizes, and characterizes a new library of Pyridine-2,6-dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L11 demonstrates robust antibacterial properties against Staphylococcus aureus (Minimum Inhibitory Concentration (MIC) = 2-16 µg mL-1), methicillin and vancomycin-resistant S. aureus (MIC = 2-4 µg mL-1) and exhibit superior antibacterial activity when compared to FDA-approved vancomycin, the drug of last resort. Additionally, the compound exhibits notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2-8 µg mL-1). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM are harnessed, collectively suggesting a mechanistic pathway involving cell wall disruption. Live/dead fluorescence studies further confirm efficacy of L11 and its complexes against S. aureus membranes. This translational exploration extends to a rat model, indicating promising in vivo therapeutic potential. Thus, this comprehensive research initiative has capabilities to transcends the confines of this laboratory, heralding a pivotal step toward combatting antibiotic-resistant pathogens and advancing the frontiers of metalloantibiotics-based therapy with a profound clinical implication.

In situ carbonization metamorphoses porous silica particles into biodegradable therapeutic carriers of lesser consequence on TGF-ß1 mediated fibrosis.

Extensive modifications have been made to the synthesis protocol for porous silica particles to improve the shape, size and yield percentage, but problems associated with improvement in biodegradability and decrease in chances to induce side effects still remain a concern. To circumvent these limitations, a facile modification strategy has been employed through in situ carbonization of porous silica particles. Herein, carbon particles were integrated within porous silica core-shell particles (Si-P-CNPs) during the synthesis process and found to preserve the ordered structural morphology. Curcumin was used as a model drug for loading in prepared Si-P-CNPs whereas lung cancer cells were used as a model system to study the in vitro fate. These Si-P-CNPs showed improved drug loading, drug effectivity, biodegradability and avoidance of interaction with transforming growth factor ß1 (TGF-ß1) indicating the possibility of reducing the chances of lung fibrosis and thereby enhancing the safety profile over conventional porous silica particles.

Nanocarbon-Enforced Anisotropic MusCAMLR for Rapid Rescue of Mechanically Damaged Skeletal Muscles.

Mechanical damages to skeletal muscles could be detrimental to the active work hours and lifestyle of athletes, mountaineers, and security personnel. In this regard, the slowness of conventional treatment strategies and drug-associated side effects greatly demand the design and development of novel biomaterials, which can rescue such mechanically damaged skeletal muscles. To accomplish this demand, we have developed a musculoresponsive polymer-carbon composite for assisting myotubular regeneration (MusCAMLR). The MusCAMLR is enforced to attain anisotropic muscle-like characteristics while incorporating a smartly passivated nanoscale carbon material in the PNIPAM gel under physiological conditions as a stimulus, which is not achieved by the pristine nanocarbon system. The MusCAMLR establishes a specific mechanical interaction with muscle cells, supports myotube regeneration, maintains excellent mechanical similarity with the myotube, and restores the structural integrity and biochemical parameters of mechanically damaged muscles in a delayed onset muscle soreness (DOMS) rat model within a short period of 72 h. Concisely, this study discloses the potential of smartly passivated nanocarbon in generating an advanced biomaterial system, MusCAMLR, from a regularly used polymeric hydrogel system. This engineered polymer-carbon composite reveals its possible potential to be used as a nondrug therapeutic alternative for rescuing mechanically damaged muscles and probably can be extended for therapy of various other diseases including muscular dystrophy.

Polyphenol-Based Nanoscale Iron Exchangers for Regulating Anticancer Chemotherapy by Modulating the Activity of Intracellular Glutathione.

The elevated glutathione (GSH) level in cancer cells contributes to the poor response to chemotherapy and necessitates the use of maximum tolerated drug doses, leading to myriad side effects. We have developed a biocompatible and fluorescently trackable nanosystem, iron(III)-bound nanocarbonaceous polyphenol (FeNCP), to modulate the available GSH pool in cancer cells for synergistic effects in treatments with a cytotoxic anticancer drug, doxorubicin (Dox). This nanosystem was designed using a nanoscale carbon system as a platform to generate a GSH-responsive gallic acid-iron complex. The effective interaction between FeNCP and GSH was probed in PBS (pH 7.4) and cell lysates using UV-Vis, fluorescence spectrophotometry, 1H NMR, flow cytometry, and confocal and transmission electron microscopic studies. The concurrent treatment of cancer cells with subcytotoxic FeNCP and Dox leads to dose reduction indices of Dox of ∼6.1 for HepG2 (hepatocellular carcinoma) and 6.7 for B16F0 (melanoma) to kill ∼50% of the cell population, which is suggestive of the requirement of a multifold lower dose of Dox. Notably, this combination was relatively more cytotoxic toward cancer cell lines than the model normal cell line, Vero. The increased reactive oxygen species levels in combinatorial treatment reveal that FeNCP serves as a potential candidate for modulating glutathione activity and potentiating cytotoxic effects of Dox. The intelligent multifold design of this nanosystem might enable the applicability in optical detection of GSH and imaging-assisted surgery in the future, in addition to the potential to advance treatment regimens in anticancer chemotherapy.

What makes carbon nanoparticle a potent material for biological application?

Carbon materials are generally utilized in the form of carbon allotropes and their characteristics are exploited as such or for improving the thermal, electrical, optical, and mechanical properties of other biomaterials. This has now found a broader share in conventional biomaterial space with the generation of nanodiamond, carbon dot, carbon nanoparticles (CNPs), and so forth. With properties of better biocompatibility, intrinsic optical emission, aqueous suspendability, and easier surface conjugation possibilities made CNPs as one of the fore most choice for biological applications especially for use in intracellular spaces. There are various reports available presenting methods of preparing, characterizing, and using CNPs for various biological applications but a collection of information on what makes CNP a suitable biomaterial to achieve those biological activities is yet to be provided in a significant way. Herein, a series of correlations among synthesis, characterization, and mode of utilization of CNP have been incorporated along with the variations in its use as agent for sensing, imaging, and therapy of different diseases or conditions. It is ensembled that how simplified and optimized methods of synthesis is correlated with specific characteristics of CNPs which were found to be suitable in the specific biological applications. These comparisons and correlations among various CNPs, will surely provide a platform to generate new edition of this nanomaterial with improvised applications and newer methods of evaluating structural, physical, and functional properties. This may ensure the eventual use of CNPs for human being for specific need in near future. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Biosensing Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Poly-lysinated nanoscale carbon probe for low power two-photon bioimaging.

Effective outcome from dynamic live-cell-imaging requires utilization of a probe with high emission intensity and low photobleaching. It would be preferable to achieve such properties at a low power of the applied laser to avoid any probable damage to biological cells or tissue. Most of the used small-molecule fluorophores have been reported to show significant photobleaching in a time-dependent manner and require high laser power to gain significant intensity for bioimaging. Carbon nanoparticles have recently been successfully used for cell imaging with low bleaching characteristics but require high laser power and lack optical nonlinearity at low power levels. Here, we report the preparation, characterization, and application of a Nanoscale Carbon (NC) which, on being surface decorated with crescent-shaped poly-lysine (PLNC), provides two-photon fluorescence (TPF) and low bleaching properties. PLNC was found to stain the cytoplasm of C2C12 muscle cells in the first four-hours of incubation with high TPF in the infrared range and can be useful for deep tissue imaging with further improvements.