Puiyan Lee

Silver Nanoparticles Mediate Differential Responses in Keratinocytes and Fibroblasts during Skin Wound Healing

With advances in nanotechnology, pure silver has been recently engineered into nanometer‐sized particles (diameter <100 nm) for use in the treatment of wounds. In conjunction with other studies, we previously demonstrated that the topical application of silver nanoparticles (AgNPs) can promote wound healing through the modulation of cytokines. Nonetheless, the question as to whether AgNPs can affect various skin cell types—keratinocytes and fibroblasts—during the wound‐healing process still remains. Therefore, the aim of this study was to focus on the cellular response and events of dermal contraction and epidermal re‐epithelialization during wound healing under the influence of AgNPs; for this we used a full‐thickness excisional wound model in mice. The wounds were treated with either AgNPs or control with silver sulfadiazine, and the proliferation and biological events of keratinocytes and fibroblasts during healing were studied. Our results confirm that AgNPs can increase the rate of wound closure. On one hand, this was achieved through the promotion of proliferation and migration of keratinocytes. On the other hand, AgNPs can drive the differentiation of fibroblasts into myofibroblasts, thereby promoting wound contraction. These findings further extend our current knowledge of AgNPs in biological and cellular events and also have significant implications for the treatment of wounds in the clinical setting.

ω-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes.

OBJECTIVE Long-term total parenteral nutrition (TPN) in children is often complicated by parental nutrition-associated liver disease and may even lead to liver failure. Recently, the addition of ω-3 fatty acids to TPN has been shown to reduce the risk of parental nutrition-associated liver disease. The purpose of this study was to explore the anti-inflammatory effects of ω-3 fatty acids (eicosapentaenoic acid [EPA]) to demonstrate the protection of the liver against hepatic steatosis and damage. MATERIALS AND METHODS Lipopolysaccharide (LPS) and prostaglandin E(2) (PGE(2)) were used to stimulate human macrophages and hepatocytes (THLE-3) to induce in vitro inflammatory condition. The cells were then incubated with either ω-3 (EPA) or ω-6 (arachidonic acid) fatty acids. Supernatants were collected at different time points for the measurement of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10) using enzyme-linked immunosorbent assay. Furthermore, pretreated macrophages by LPS stimulation and after incubation with EPA were added to prestimulated hepatocytes for the subsequent measurement of cytokine response. RESULTS Eicosapentaenoic acid effectively reduced LPS-induced or PGE(2)-induced TNF-α and IL-6 expression, and increased IL-10 expression significantly when compared with arachidonic acid. Furthermore, supernatant collected after co-culturing EPA with macrophages also suppressed the levels of TNF-α and IL-6 in hepatocytes. This would suggest that EPA not only had an anti-inflammatory effect on macrophages and hepatocytes directly, it could indirectly reduce hepatocyte inflammation through activated macrophages. CONCLUSIONS The addition of ω-3 fatty acids in TPN suppresses the inflammatory response via direct and indirect routes. The findings may help explain the clinical benefits of EPA in pediatric patients receiving long-term TPN.

Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation

Background Development of anticancer drugs is challenging. Indeed, much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity. We have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin. In this study, we investigated the delivery and treatment efficiency of PEG surface-modified lipid nanoparticles as a carrier platform. Methods We encapsulated antitumor drugs into PEG-modified lipid nanoparticles and these were characterized by size, zeta potential, and encapsulation efficiency. The delivery efficiency into tumor tissue was evaluated using a biodistribution study. To evaluate antitumor efficacy, gold porphyrin or camptothecin (a DNA topoisomerase I inhibitor) were encapsulated and compared using an in vivo neuroblastoma (N2A) model. Results We showed that drug encapsulation into PEG-modified lipid nanoparticles enhanced the preferential uptake in tumor tissue. Furthermore, higher tumor killing efficiency was observed in response to treatment with PEG-modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin. The in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity. Surface modification of lipophilic nanoparticles with PEG increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity. Conclusion This specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy.

Cyclometalated Gold(III) Complexes Containing N-Heterocyclic Carbene Ligands Engage Multiple Anti-Cancer Molecular Targets

Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent in vitro and in vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal-NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.

The cytotoxic effects of lipidic formulated gold porphyrin nanoparticles for the treatment of neuroblastoma

OBJECTIVE Nanotechnology has been identified as a promising platform in the improvement of the design and development of drug delivery systems. In the present study we investigated the potential of lipidic nanoparticles consisting of gold porphyrin for the treatment of neuroblastoma. MATERIALS AND METHODS To characterize the size of the lipidic gold porphyrin nanoparticles, we used transmission electron microscopy (TEM). The in vitro cytotoxic effect on neuroblastoma activity was examined using XTT cell proliferation assay, then IC50 values were calculated. In vivo safety and toxicity were studied using intraperitoneal injection of gold porphyrin nanoparticles into normal animals. Finally, tumor size measurement and animal survival were studied to investigate the therapeutic effect of lipidic gold porphyrin nanoparticles on neuroblastoma growth. RESULTS We found that incorporation of gold porphyrin into lipidic nanoparticles resulted in a 16-fold increase in size. Subsequent in vitro and in vivo cytotoxicity studies further showed that the lipidic gold porphyrin nanoparticles could decrease systemic toxicity, as well as inhibiting tumor growth following administration into the neuroblastoma bearing mice. CONCLUSION The delivery of lipidic gold porphyrin nanoparticles by incorporation with lipidic formulation is feasible approach to treat neuroblastoma. We await further studies to evaluate tumor killing kinetics.

A Macrocyclic Ruthenium(III) Complex Inhibits Angiogenesis with Down-Regulation of Vascular Endothelial Growth Factor Receptor-2 and Suppresses Tumor Growth In Vivo.

A macrocyclic ruthenium(III) complex [RuIII (N2 O2 )Cl2 ]Cl (Ru-1) is reported as an inhibitor of angiogenesis and an anti-tumor compound. The complex is relatively non-cytotoxic towards endothelial and cancer cell lines in vitro, but specifically inhibited the processes of angiogenic endothelial cell tube formation and cancer cell invasion. Moreover, compared with known anti-cancer ruthenium complexes, Ru-1 is distinct in that it suppressed the expression of vascular endothelial growth factor receptor-2 (VEGFR2), and the associated downstream signaling that is crucial to tumor angiogenesis. In addition, in vivo studies showed that Ru-1 inhibited angiogenesis in a zebrafish model and suppressed tumor growth in nude mice bearing cancer xenografts.

Silver nanoparticle treatment ameliorates biliary atresia syndrome in rhesus rotavirus inoculated mice

Biliary atresia (BA) is a neonatal biliary system disease closely associated with viral infection and bile duct inflammation. Silver nanoparticles (AgNps) have previously revealed antiviral and anti-inflammatory properties. In this study, we have investigated the effects of AgNps in the treatment of the Rhesus rotavirus inoculation induced BA in mice. The morphology, liver histopathology, clinical biochemistry examination, and inflammatory cells were analyzed in BA mice. Results indicated that AgNps could significantly increase the survival rate of BA mice, and reduce jaundice and weight lost and the liver enzymes and bilirubin metabolism clinical parameters were close to the normal levels. Diminished numbers of NK cells were observed by flow cytometry analysis and immunohistochemical staining. Furthermore, the viral load was reduced and transcripts for TGF-β mRNA were augmented after AgNps treatment. Collectively, our results suggest that AgNps treatment has beneficial effects on the BA mouse model partially through upregulation of TGF-β.

Emerging Nanomedicine for Skin Cancer

Skin cancer is a common cancer and is associated with significant morbidity and mortality. Topical treatment is an attractive option compared with systemic route due to the reduced association with systemic toxicity. Nonetheless, skin is a natural barrier under physiological conditions for topical drug delivery as it is crucial to provide protection to the body. Such barrier will limit the drug uptake into skin. Common strategies consisting of physical and chemical approaches to overcome this have been reported to improve topical delivery efficacy. However, safety concerns caused by possible irreversible skin damage remain. Due to the heterogeneous physical and chemical property of the skin, current methods limits the variety of drugs suitable for effective delivery into skin. Here, in this review, we showed the promise in engineering lipidic nanoparticles in treating skin cancer.

Lipophilic-Formulated Gold Porphyrin Nanoparticles for Chemotherapy

Lipophilic formulation is an invaluable technique for the delivery of cancer drugs. Incorporation of poorly soluble and toxic compounds into a lipophilic carrier vehicle improves both the stability and compatibility in blood and body fluids. Currently, although a large proportion of novel cancer drugs are poorly water soluble, most existing drug carriers are only able to encapsulate hydrophilic drugs. As the ultimate goal of drug delivery (in particular cancer drug delivery) is to achieve high therapeutic effect with minimal toxicity, it would thus be beneficial to invest substantial efforts in the development of lipophilic carrier systems. Here we describe our technique to synthesize a lipophilic carrier for hydrophobic and toxic potent cancer drugs, such as gold(III) porphyrin.