Rings of Power: Controlling SOD Mimic Activity by the Addition of Pyridine Rings within the Pyridinophane Scaffold.

Superoxide dismutase enzymes are a major defense against superoxide, which is a potent reactive oxygen species. Misregulation of reactive oxygen species and subsequent neuronal damage are etiological hallmarks of neurodegenerative disease. Macrocyclic small molecules have offered inroads toward functional SOD1 mimics.

Impact of Indole Inclusion in the Design of Multi-Tactical Metal-Binding Tetra-Aza Macrocycles that Target the Molecular Features of Neurodegeneration.

Numerous small molecules have been studied for their ability to counteract oxidative stress, a key contributor to neurodegenerative diseases such as Alzheimer's. Despite these efforts, the pharmacological properties and structure-activity relationships of these compounds remain insufficiently understood, yet they are critical in evaluating a drug molecule's therapeutic potential. A modified tetra-aza macrocycle has demonstrated strong antioxidant activity through various mechanisms; however, its limited permeability presents challenges for advanced formulation studies.

Prostate Cancer Treatment via CRISPR-Cas9 Gene Editing Facilitated by Polyethyleneimine-Derived Graphene Quantum Dots.

CRISPR-Cas9 is a programmable gene editing tool with a promising potential for cancer gene therapy. This therapeutic function is enabled in the present work via the non-covalent delivery of CRISPR ribonucleic protein (RNP) by cationic glucosamine/PEI-derived graphene quantum dots (PEI-GQD) that aid in overcoming physiological barriers and tracking genes of interest. PEI-GQD/RNP complex targeting the TP53 mutation overexpressed in ~50% of cancers successfully produces its double-stranded breaks in solution and in PC3 prostate cancer cells.

Cancer Therapeutic siRNA Delivery and Imaging by Nitrogen- and Neodymium-Doped Graphene Quantum Dots.

While small interfering RNA (siRNA) technology has become a powerful tool that can enable cancer-specific gene therapy, its translation to the clinic is still hampered by the inability of the genes alone to cell transfection, poor siRNA stability in blood, and the lack of delivery tracking capabilities. Recently, graphene quantum dots (GQDs) have emerged as a novel platform allowing targeted drug delivery and fluorescence image tracking in visible and near-infrared regions. These capabilities can aid in overcoming primary obstacles to siRNA therapeutics.

Dual-Mode Fluorescence/Ultrasound Imaging with Biocompatible Metal-Doped Graphene Quantum Dots.

Sonography offers many advantages over standard methods of diagnostic imaging due to its non-invasiveness, substantial tissue penetration depth, and low cost. The benefits of ultrasound imaging call for the development of ultrasound-trackable drug delivery vehicles that can address a variety of therapeutic targets. One disadvantage of the technique is the lack of high-precision imaging, which can be circumvented by complementing ultrasound contrast agents with visible and, especially, near-infrared (NIR) fluorophores.

Detection of Pancreatic Cancer miRNA with Biocompatible Nitrogen-Doped Graphene Quantum Dots.

Early-stage pancreatic cancer remains challenging to detect, leading to a poor five-year patient survival rate. This obstacle necessitates the development of early detection approaches based on novel technologies and materials. In this work, the presence of a specific pancreatic cancer-derived miRNA (pre-miR-132) is detected using the fluorescence properties of biocompatible nitrogen-doped graphene quantum dots (NGQDs) synthesized using a bottom-up approach from a single glucosamine precursor.

Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells.

We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at adenine-thymine rich regions of DNA. Herein, we describe mechanistic investigations that demonstrate that this class of compounds facilitate the translocation of the ERα-compound complex to the nucleus and induce the expression of ERα target genes.

Effects of Doxorubicin Delivery by Nitrogen-Doped Graphene Quantum Dots on Cancer Cell Growth: Experimental Study and Mathematical Modeling.

With 18 million new cases diagnosed each year worldwide, cancer strongly impacts both science and society. Current models of cancer cell growth and therapeutic efficacy in vitro are time-dependent and often do not consider the value (the maximum reduction in the growth rate), leading to inconsistencies in the obtained (concentration of the drug at half maximum effect). In this work, we introduce a new dual experimental/modeling approach to model HeLa and MCF-7 cancer cell growth and assess the efficacy of doxorubicin chemotherapeutics, whether alone or delivered by novel nitrogen-doped graphene quantum dots (N-GQDs).

Formation of Platinum Nanocrystals on Silicon Nanotubes and Corresponding Anti-Cancer Activity in Vitro.

Biodegradable porous silicon nanotubes (pSiNTs), functionalized with primary amine moieties via the use of 3-aminopropyltriethoxysilane (APTES), is demonstrated as a template for formation of platinum nanocrystals (Pt NCs) (1-3 nm). Transmission electron microscopy-energy dispersive X-ray analysis (TEM-EDX) indicates a relatively high and tunable concentration of Pt uniformly immobilized on a given nanotube (wt % Pt: 20-60%). In vitro viability and cellular uptake studies are consistent with a time-dependent toxicity of Pt NCs-pSiNTs against HeLa cells that is influenced by the degradation kinetics of the pSiNTs; internalization of the composites inside the cells exerts cellular damage in an apoptotic manner, therefore suggesting promising future applications in anticancer treatments.

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules.

Alzheimer's and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed.

Doped Graphene Quantum Dots for Intracellular Multicolor Imaging and Cancer Detection.

Despite significant advances of nanomedicine, the issues of biocompatibility, accumulation-derived toxicity, and the lack of sensing and in vivo imaging capabilities hamper the translation of most nanocarriers into clinic. To address this, we utilize nitrogen, boron/nitrogen, and sulfur-doped graphene quantum dots (GQDs) as fully biocompatible multifunctional platforms allowing for multicolor visible/near-IR imaging and cancer-sensing. These GQDs are scalably produced in one-step synthesis from a single biocompatible glucosamine precursor, are water-soluble, show no cytotoxicity at high concentrations of 1 mg/mL, and demonstrate substantial degradation at 36 h in biological environments as verified by TEM imaging.

Plant-Derived Tandem Drug/Mesoporous Silicon Microcarrier Structures for Anti-Inflammatory Therapy.

The properties of nanostructured plant-derived porous silicon (pSi) microparticles as potential candidates to increase the bioavailability of plant extracts possessing anti-inflammatory activity are described in this work. pSi drug carriers were fabricated using an eco-friendly route from the silicon accumulator plant bamboo (tabasheer) powder by magnesiothermic reduction of plant-derived silica and loaded with ethanolic extracts of , another silicon accumulator plant rich in polyphenolic compounds. The anti-inflammatory properties of the active therapeutics present in this extract were measured by sensitive luciferase reporter assays; this active extract was subsequently loaded and released from the pSi matrix, with a clear inhibition of the activity of the inflammatory signaling protein NF-κB over a period of hours in a sustained manner.

Multi-Drug/Gene NASH Therapy Delivery and Selective Hyperspectral NIR Imaging Using Chirality-Sorted Single-Walled Carbon Nanotubes.

Single-walled carbon nanotubes (SWCNTs) can serve as drug delivery/biological imaging agents, as they exhibit intrinsic fluorescence in the near-infrared, allowing for deeper tissue imaging while providing therapeutic transport. In this work, CoMoCAT (Cobalt Molybdenum Catalyst) SWCNTs, chirality-sorted by aqueous two-phase extraction, are utilized for the first time to deliver a drug/gene combination therapy and image each therapeutic component separately via chirality-specific SWCNT fluorescence. Each of (7,5) and (7,6) sorted SWCNTs were non-covalently loaded with their specific payload: the PI3 kinase inhibitor targeting liver fibrosis or CCR5 siRNA targeting inflammatory pathways with the goal of addressing these processes in nonalcoholic steatohepatitis (NASH), ultimately to prevent its progression to hepatocellular carcinoma.

Dialing in on pharmacological features for a therapeutic antioxidant small molecule.

The pyridinophane molecule L2 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) has shown promise as a therapuetic for neurodegenerative diseases involving oxidative stress and metal ion misregulation.

A new triazine bearing a pyrazolone group capable of copper, nickel, and zinc chelation.

Interests in inorganic applications of triazines is growing. In this report, metal complexes of copper(II), nickel(II), and zinc(II) and a novel class of chelates comprising a triazine ring substituted with a hydrazine group and pyralozone are evaluated using spectrophotometric methods, single crystal X-ray diffractometry, and electrochemistry. Complexes with copper(II) include a single chelate and two chloride atoms to satisfy a trigonal bipryamidal coordination sphere.

Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule.

Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems.

In Vitro Gene Delivery with Large Porous Silicon Nanoparticles Fabricated Using Cost-Effective, Metal-Assisted Chemical Etching.

The cytocompatibility, cell membrane affinity, and plasmid DNA delivery from surface oxidized, metal-assisted stain-etched mesoporous silicon nanoscale particles (pSiNPs) to human embryonic kidney (HEK293) cells is demonstrated, suggesting the possibility of using such material for targeted transfection and drug delivery.

Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease.

Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer's disease (AD). This process includes the production of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small molecule, lipoic cyclen, which has been designed to target molecular features of AD.

DNA site-specific N3-adenine methylation targeted to estrogen receptor-positive cells.

A compound that can target cells expressing the estrogen receptor (ER), and produce predominantly 3-MeA adducts in those cells has been designed and synthesized. This compound produces mainly the 3-MeA adduct upon reaction with calf thymus DNA, and binds to the ER with a relative binding affinity of 51% (estradiol = 100%). The compound is toxic to ER-expressing MCF-7 breast cancer cells, and pre-treatment with the ER antagonist fulvestrant abrogates the toxicity.

The role of nanostructured mesoporous silicon in discriminating in vitro calcification for electrospun composite tissue engineering scaffolds.

The impact of mesoporous silicon (PSi) particles-embedded either on the surface, or totally encapsulated within electrospun poly (ε-caprolactone) (PCL) fibers-on its properties as a tissue engineering scaffold is assessed. Our findings suggest that the resorbable porous silicon component can sensitively accelerate the necessary calcification process in such composites. Calcium phosphate deposition on the scaffolds was measured via in vitro calcification assays both at acellular and cellular levels.

High-porosity poly(epsilon-caprolactone)/mesoporous silicon scaffolds: calcium phosphate deposition and biological response to bone precursor cells.

In this study, the fabrication and characterization of highly porous composites composed of poly(epsilon-caprolactone) and bioactive mesoporous silicon (BioSilicon) prepared using salt-leaching and microemulsion/freeze-drying methods are described. The role of silicon, along with porosity, in the scaffolds on calcium phosphate deposition was assessed using acellular in vitro calcification analyses. The presence of bioactive silicon in these scaffolds is essential for the deposition of calcium phosphate while the samples are immersed in simulated body fluid (SBF).

Accelerated calcification in electrically conductive polymer composites comprised of poly(epsilon-caprolactone), polyaniline, and bioactive mesoporous silicon.

In this study the fabrication and characterization of an electrically conductive composite material comprised of poly(epsilon-caprolactone) (PCL), polyaniline (PANi), and bioactive mesoporous silicon (BioSilicon) is discussed. The influence of PANi and silicon on calcium phosphate induction was assessed via ex vitro calcification analyses (by acellular simulated body fluid (SBF) exposure) both with and without electrical bias. Acceleration of calcium phosphate formation is one possible desirable feature of "smart" synthetic scaffolds for selected orthopedic-relevant applications.

Proteolytic activation of protein kinase C-epsilon by caspase-mediated processing and transduction of antiapoptotic signals.

Several novel protein kinase C (PKC) isozymes have been identified as substrates for caspase-3. We have previously shown that novel PKCepsilon is cleaved during apoptosis in MCF-7 cells that lack any functional caspase-3. In the present study, we show that in vitro-translated PKCepsilon is processed by human recombinant caspase-3, -7, and -9.