Sabarinathan Rangasamy

Shape-Dependent Skin Penetration of Silver Nanoparticles: Does It Really Matter?

Advancements in nano-structured materials have facilitated several applications of nanoparticles (NPs). Skin penetration of NPs is a crucial factor for designing suitable topical antibacterial agents with low systemic toxicity. Available reports focus on size-dependent skin penetration of NPs, mainly through follicular pathways. Herein, for the first time, we demonstrate a proof-of-concept study that entails variations in skin permeability and diffusion coefficients, penetration rates and depth-of-penetration of differently shaped silver NPs (AgNPs) via intercellular pathways using both in vitro and in vivo models. The antimicrobial activity of AgNPs is known. Different shapes of AgNPs may exhibit diverse antimicrobial activities and skin penetration capabilities depending upon their active metallic facets. Consideration of the shape dependency of AgNPs in antimicrobial formulations could help developing an ideal topical agent with the highest efficacy and low systemic toxicity.

Mitochondria and DNA Targeting of 5,10,15,20-Tetrakis(7-sulfonatobenzo[b]thiophene) Porphyrin-Induced Photodynamic Therapy via Intrinsic and Extrinsic Apoptotic Cell Death

Photodynamic therapy (PDT) selectively targets subcellular organelles and promises an excellent therapeutic strategy for cancer treatment. Here, we report the synthesis of a new water-soluble photosensitizer, 5,10,15,20-tetrakis (7-sulfonatobenzo[b]thiophene) porphyrin (SBTP). Rational design of the porphyrinic molecule containing benzo[b]thiophene moiety at the meso-position led to selective accumulation in both mitochondria and nucleus of MCF-7 cells. This multitarget ability of SBTP can cause damage to mitochondria as well as DNA simultaneously. FACS analysis showed rapid cellular uptake of SBTP. High-content cell-based assay was executed to concurrently monitor increase of cytosolic Ca(2+) levels, mitochondrial permeability transition (MPT), and caspase-3/7/8 activation in MCF-7 cells under the pathological condition caused by PDT action of SBTP. The study of cell death dynamics showed that PDT action of SBTP caused an increase in the MPT followed by an increase in cytosolic Ca(2+) level. The localization of SBTP in the mitochondria activated the intrinsic apoptotic pathway. Additionally, localization of SBTP in the nucleus led to DNA damage in MCF-7 cells. The DNA fragmentation that occurred by PDT action of SBTP was thought to be responsible for extrinsic apoptosis of MCF-7 cells. SBTP demonstrated effective PDT activity of 5 μM IC50 value to MCF-7 cells by bitargeting mitochondria and DNA.

A multifunctional composite of an antibacterial higher-valent silver metallopharmaceutical and a potent wound healing polypeptide: a combined killing and healing approach to wound care

The present study relates to a combined killing and healing approach for the treatment of infected wounds. Herein we report a multifunctional, including antimicrobial and wound healing, composite containing a conjugate of a bi-valent silver polydiguanide that demonstrated high antibacterial activity in vitro and a potent wound healing polypeptide, histatin-1, for the treatment of infected wounds. The synthesis of silver(II) chlorhexidine [Ag(II)CHX] was accomplished by the oxidation of Ag(I), followed by the complexation of the oxidized metal with chlorhexidine (CHX), whereas the metal complex conjugate of the solid phase-synthesized histatin polypeptide (Hst-1), Hst-1-[Ag(II)CHX], was realized by mixing the starting materials in aqueous solution. The change in the Hst-1 structure upon binding with the silver complex was examined by circular dichroism spectroscopy. The wound healing applicability of the histatin polypeptide and its metal complex conjugate was tested using the synthesized Hst-1 and Hst-1-[Ag(II)CHX] complex on 3T3-L1 preadipocytes in a cell-spreading assay. The antibacterial activity of the silver metal complex and its Hst-1 conjugate was tested against several gram positive and gram negative bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-resistant coagulase negative staphylococcus (MRCNS) by a broth microdilution method. The results of these experiments revealed that the polypeptide and silver(II) polydiguanide complex retained their individual wound healing and antimicrobial activity even in their conjugate. The conjugate of an antibacterial higher-valent silver polydiguanide complex with a potent wound healing polypeptide (Hst-1) showed promise as a new multifunctional therapeutic wherein the killing and healing functions of the constituent materials are preserved together for the development of new-generation wound-care agents.

The Application of Bactericidal Silver Nanoparticles in Wound Treatment

Even with the prevalence of wounds, the medical technology for efficiently managing skin damage is still primitive. The disruption of any of the numerous healing processes can lead to problems in the time-sensitive healing actions of the dermal and epidermal layers. Bacterial infection is one of the major obstacles to proper wound healing as it poses a danger of causing long-term negative effects. Keeping the wound free of bacteria is imperative to the proper and hasty repair of dermal wounds. Silver has been widely used to treat wounds for its bactericidal properties. Although the mechanism of silvers antibacterial action is not fully understood, it exhibits a significant antimicrobial efficacy against a wide spectrum of bacterial species. A number of different approaches to the mechanism are reported and presented in this review. Silver nanoparticles (AgNPs) have been reported to exhibit enhanced antibacterial activity due to their increased surface-area-to-volume ratio. AgNPs are capable of various modifications, significantly broadening the therapeutic properties of the material as a result. This review explores the different aspects of silver and silver nanoparticles, and their antibacterial properties, which can be applied in the field of wound treatments.

Cell death mechanistic study of photodynamic therapy against breast cancer cells utilizing liposomal delivery of 5,10,15,20-tetrakis(benzo[b]thiophene) porphyrin.

5,10,15,20-Tetrakis(benzo[b]thiophene) porphyrin (BTP) is a newly synthesized hydrophobic photosensitizer with fluorescence quantum yield in toluene: ΦF=0.062. Previously, its limitations in solubility had hindered scientific experimentation regarding its photodynamic effects on cancer cells. By utilizing various compositions of liposomes in order to alter the solubility of BTP, the photocytotoxicity, reactive oxygen species generation, and subcellular localization of the liposomal BTP were identified in this work. DNA fragmentation and high content screening assays were performed in order to shed light on the tumoricidal mechanism of the liposomal photosensitizer. The MTT assay results showed promising results in the irradiation specific PDT activity against MCF-7 cells in all liposomal compositions. Production of ROS was confirmed in the liposomal BTP treated MCF-7 cells after irradiation in a concentration dependent manner. The subcellular localization assays revealed that the localization of BTP was dependent on both the photosensitizers chemical properties and the properties of the delivery agent encapsulating aforesaid substance. Significant DNA fragmentation was observed in both nucleus localizing liposomal BTP, BTP encapsulated DOPC and DOPE (DOPC-BTP and DOPE-BTP), treated MCF-7 cells. All liposomal-BTPs were successful in inducing mitochondrial permeability transition, an increase in the permeability of the mitochondrial membrane, and activating caspase-3/7. ER localizing BTP were able to significantly increase the cytosolic calcium levels by photodynamic therapy, confirming the photodynamic ability of ER localized BTP to damage the ER membrane. The application of liposomes in delivering a novel hydrophobic photosensitizer, BTP, and photodynamic therapy treatment against MCF-7 cells were successful. It was confirmed that the MCF-7 cell death pathway via photodynamic therapy was altered in a controlled manner by controlling the intracellular localization of the photosensitizer through lipid composition adjustment.

Investigating the versatility of multifunctional silver nanoparticles: preparation and inspection of their potential as wound treatment agents

Silver nanoparticles (AgNPs) are capable of inhibiting the growth of a broad spectrum of bacterial species. The minute size of the nanoparticulates enhances their biocidal activity and is thus widely utilized as antibacterial agents. The most recently researched and recognized antibacterial and wound-healing properties of published AgNPs were investigated in this article. The following parameters of the AgNPs affecting their properties and potency were explored: particle size, shape, and type of ligand or stabilizing agent. Research regarding the antibacterial activity enhancement of high-valent silver nanoparticles compared to those of the lower valent forms were summarized and analyzed. Nanocrystalline silver is capable of binding to components that may enhance their preparation and antibacterial properties. By forming complexes with ligands that exhibit desired properties, silver nanoparticles can be synthesized to exhibit those desired properties without compromising their performance. This review will provide a detailed discussion regarding the parameter-dependent bactericidal properties of silver nanoparticles and nanocomposite silver complexes as potent multifunctional wound-healing agents.Graphical Abstract

Nanosized silver (II) pyridoxine complex to cause greater inflammatory response and less cytotoxicity to RAW264.7 macrophage cells

AbstractWith advancements in nanotechnology, silver has been engineered into a nanometre size and has attracted great research interest for use in the treatment of wounds. Silver nanoparticles (AgNPs) have emerged as a potential alternative to conventional antibiotics because of their potential antimicrobial property. However, AgNPs also induce cytotoxicity, generate reactive oxygen species (ROS), and cause mitochondrial damage to human cells. Pyridoxine possesses antioxidant and cell proliferation activity. Therefore, in the present investigation, a nanosilver-pyridoxine complex (AgPyNP) was synthesized, and its cytotoxicity and immune response was compared with AgNPs in macrophage RAW264.7 cells. Results revealed that AgPyNPs showed less cytotoxicity compared with AgNPs by producing a smaller amount of ROS in RAW264.7 cells. Surprisingly, however, AgPyNPs caused macrophage RAW264.7 cells to secrete a larger amount of interleukin-8 (IL-8) and generate a more active inflammatory response compared to AgNPs. It activated TNF-α, NF-κB p65, and NF-κB p50 to generate a more vigorous immune protection that produces a greater amount of IL-8 compared to AgNPs. Overall findings indicate that AgPyNPs exhibited less cytotoxicity and evoked a greater immune response in macrophage RAW264.7 cells. Thus, it can be used as a better wound-healing agent than AgNPs. Graphical AbstractFigurative representation of the comparison of AgNPs and AgPyNPs in macrophage RAW264.7 cells in terms of cytotoxicity and immune response.

Insulin-mimetic and anti-inflammatory potential of a vanadyl-Schiff base complex for its application against diabetes

Insulin signalling causes the translocation of glucose transporter 4 (GLUT4) to the plasma membrane to facilitate cellular glucose uptake. Numerous observations indicate that the prime cause of type 2 diabetes mellitus (T2DM) is inflammation, the occurrence of which increases in obese individuals. Inflammatory mediators induce an insulin-resistance (IR) state where impaired insulin signalling fails to promote the glucose transporters for intracellular uptake of glucose. Hence compounds, which possess insulin-mimetic and anti-inflammatory potentials, may be effective in the treatment of obesity-induced IR during T2DM. Previous studies showed that vanadium oxo complexes possess insulin-mimetic activities whereas the tryptamine moiety offers anti-inflammatory potential. Hence a vanadyl-Schiff base complex (VOTP) consisting of the tryptamine moiety was synthesized by condensation of pyridoxal hydrochloride and tryptamine and its subsequent complexation with VOSO4. HEK-293 cells, expressing a GLUT4-myc-GFP fusion protein, were treated with VOTP and GLUT4 translocation was quantified by total internal reflection fluorescence (TIRF) microscopy. Results indicated that VOTP could efficiently act as an insulin-mimetic substance. A high-content cell based assay using quantum dot–antibody conjugates showed that VOTP restored insulin signaling during IR by the inactivation of c-Jun N-terminal kinase-1 (JNK-1) and subsequent phosphorylation and activation of the tyrosine moiety of insulin receptor substrate (IRS). Also, high levels of phosphorylated Forkhead box O1 (FOXO) indicated low levels of gluconeogenesis. Hence VOTP has insulin-mimetic and anti-inflammatory potentials. Moreover, VOTP is highly effective at nanomolar treatment ranges, thus evades the toxicity issues. Collectively, these findings encourage us for future use of this compound as a potential anti-diabetic agent.