Publications by authors named "Chun Nam Lok"

57 Publications

Platinum(II) -heterocyclic carbene complexes arrest metastatic tumor growth.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China;

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [Pt(C^N^N)(NHC)]PF (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= -heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.
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http://dx.doi.org/10.1073/pnas.2025806118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092596PMC
April 2021

Anticancer Gold(III) Compounds With Porphyrin or N-heterocyclic Carbene Ligands.

Front Chem 2020 6;8:587207. Epub 2020 Nov 6.

State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.

The use of gold in medicine has a long history. Recent clinical applications include anti-inflammatory agents for the treatment of rheumatoid arthritis (chrysotherapy), and is currently being developed as potential anticancer chemotherapeutics. Gold(III), being isoelectronic to platinum(II) as in cisplatin, is of great interest but it is inherently unstable and redox-reactive under physiological conditions. Coordination ligands containing C and/or N donor atom(s) such as porphyrin, pincer-type cyclometalated and/or N-heterocyclic carbene (NHC) can be employed to stabilize gold(III) ion for the preparation of anticancer active compounds. In this review, we described our recent work on the anticancer properties of gold(III) compounds and the identification of molecular targets involved in the mechanisms of action. We also summarized the chemical formulation strategies that have been adopted for the delivery of cytotoxic gold compounds, and for ameliorating the toxicity.
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http://dx.doi.org/10.3389/fchem.2020.587207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677586PMC
November 2020

Multifunctional Microparticles Incorporating Gold Compound Inhibit Human Lung Cancer Xenograft.

Pharm Res 2020 Oct 13;37(11):220. Epub 2020 Oct 13.

Department of Chemistry, The University of Hong Kong, Pokfulam, Hong Kong.

Purpose: Gold porphyrin (AuP) is a complex that has been shown to be potent against various tumors. A biocompatible interpenetrating network (IPN) system comprised of polyethyleneglycol diacrylate (PEGdA) and chemically-modified gelatin has been shown to be an effective implantable drug depot to deliver AuP locally. Here we designed IPN microparticles complexed with AuP to facilitate intravenous administration and to diminish systemic toxicity.

Methods: We have synthesized and optimized an IPN microparticle formulation complexed with AuP. Tumor cell cytotoxicity, antitumor activity, and survival rate in lung cancer bearing nude mice were analyzed.

Results: IPN microparticles maintained AuP bioactivity against lung cancer cells (NCI-H460). In vivo study showed no observable systemic toxicity in nude mice bearing NCI-H460 xenografts after intravenous injection of 6 mg/kg AuP formulated with IPN microparticles. An anti-tumor activity level comparable to free AuP was maintained. Mice treated with 6 mg/kg AuP in IPN microparticles showed 100% survival rate while the survival rate of mice treated with free AuP was much less. Furthermore, microparticle-formulated AuP significantly reduced the intratumoral microvasculature when compared with the control.

Conclusion: AuP in IPN microparticles can reduce the systemic toxicity of AuP without compromising its antitumor activity. This work highlighted the potential application of AuP in IPN microparticles for anticancer chemotherapy.
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http://dx.doi.org/10.1007/s11095-020-02931-8DOI Listing
October 2020

Surface optimization of gold nanoparticle mass tags for the sensitive detection of protein biomarkers immuno-capture LI-MS.

Analyst 2020 Sep;145(19):6237-6242

Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong S.A.R., P. R. China.

HPV-induced cervical cancer is one of the most lethal cancers. Therefore, the development of a reliable and accurate method for the early diagnosis of HPV infections is highly important. Here, gold nanoparticles (AuNPs) were utilized as mass tags in an immuno-capture LI-MS assay for the detection of HPV marker proteins. Through the optimization of the amount of antibodies and surface charges on AuNPs, high antigen detection efficiency with minimal non-specific binding was achieved. With optimized antibody-conjugated AuNPs, low attomole amount of HPV proteins in HeLa cell lysate was quantified.
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http://dx.doi.org/10.1039/d0an01121eDOI Listing
September 2020

Delayed application of silver nanoparticles reveals the role of early inflammation in burn wound healing.

Sci Rep 2020 04 14;10(1):6338. Epub 2020 Apr 14.

Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.

Burn injury is common, and antimicrobial agents are often applied immediately to prevent wound infection and excessive inflammatory response. Although inflammation is essential for clearing bacteria and creating an environment conducive to the healing process, it is unclear what time-frame inflammation should be present for optimal wound healing. This study critically investigated the role of early inflammation in burn wound healing, and also revealed the molecular mechanisms underlying the pro-healing effects of silver nanoparticles (AgNPs). We created a burn injury mouse model using wild-type and Smad3-/- mice, which were topically treated with AgNPs at different post-burn days, and examined the healing processes of the various groups. We also delineated the molecular pathways underlying the anti-inflammation and pro-healing effects of AgNPs by morphological and histological analysis, immuno-histochemistry, and western blotting. Our results showed that (1) AgNPs regulated pro-inflammatory cytokine IL-6 production of keratinocytes and neutrophils infiltration through KGF-2/p38 signaling pathway, (2) Topical AgNPs treatment immediately after burn injury significantly supressed early inflammation but resulted in delayed healing, (3) A short delay in AgNPs application (post-burn day 3 in our model) allowed early inflammation in a controlled manner, and led to optimal burn wound healing. Thus, our current study showed that some degree of early inflammation was beneficial, but prolonged inflammation was detrimental for burn wound healing. Further evaluation and clinical translation of this finding is warranted.
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http://dx.doi.org/10.1038/s41598-020-63464-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156632PMC
April 2020

An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols.

Proc Natl Acad Sci U S A 2020 01 2;117(3):1321-1329. Epub 2020 Jan 2.

State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China;

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the -carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.
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http://dx.doi.org/10.1073/pnas.1915202117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983449PMC
January 2020

Anticancer auranofin engages 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as a target.

Metallomics 2019 11 21;11(11):1925-1936. Epub 2019 Oct 21.

Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China.

Auranofin (AuRF) has been reported to display anticancer activity and has entered several clinical trials; however, its mechanism of action remains largely unknown. In this work, the anticancer mechanism of auranofin was investigated using a proteomics strategy entailing subcellular fractionation prior to mass spectrometric analysis. Bioinformatics analysis of the nuclear sub-proteomes revealed that tumor suppressor p14 is a key regulator of transcription. Through independent analysis, we validated that up-regulation of p14 is associated with E2F-dependent transcription and increased p53 expression. Our analyses further reveal that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), which is the rate-determining enzyme of the mevalonate pathway, is a novel target of auranofin with half maximal inhibitory concentration at micromolar levels. The auranofin-induced cancer cell death could be partially reverted by the addition of downstream products of the mevalonate pathway (mevalonolactone or geranyleranyl pyrophosphate (GGPP)), implying that auranofin may target the mevalonate pathway to exert its anticancer effect.
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http://dx.doi.org/10.1039/c9mt00185aDOI Listing
November 2019

An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target.

Angew Chem Int Ed Engl 2019 08 28;58(32):10914-10918. Epub 2019 Jun 28.

State Key Laboratory of Synthetic Chemistry, Aglaia-KEIIT Laboratory for Drug Discovery and Development and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor Pt complex targeting a tumor-associated protein, rather than DNA, under cellular conditions. Complex [(bis-NHC)Pt(bt)]PF (1 a; Hbt=1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis-NHC-ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active-site cysteine of ASNS.
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http://dx.doi.org/10.1002/anie.201904131DOI Listing
August 2019

A Multifunctional Hydrogel Delivers Gold Compound and Inhibits Human Lung Cancer Xenograft.

Pharm Res 2019 Mar 8;36(4):61. Epub 2019 Mar 8.

Department of Chemistry and Chemical Biology Centre, The University of Hong Kong, Pokfulam, Hong Kong.

Purpose: Interpenetrating network system (IPN), consisting of polyethylene glycol (PEG) -diacrylate (PEGdA) and modified gelatin, is a biocompatible and biodegradable hydrogel and has been studied for the local delivery of bioactive molecules and drugs. Gold(III) porphyrin(AuP) is a stable metal compound in the development for anticancer application when administered systemically. The aim of this work is to develop a novel formulation for AuP based on IPN for local delivery.

Methods: IPN loaded with AuP hydrogel was optimized and synthesized. Drug release kinetics, cytotoxicity against tumor cells, and antitumor activity in lung cancer bearing nude mice were studied.

Results: AuP released from the IPN followed a first order kinetics in vitro. The AuP loaded IPN showed higher cytotoxicity against human lung cancer cell lines compared to IPN only. In mice bearing human lung cancer xenograft, AuP loaded IPN inhibited tumor growth and reduced angiogenesis. No sign of systemic toxicity was observed for all treatment groups.

Conclusion: AuP loaded IPN provides an improved formulation over systemic delivery for tumor inhibition to complement surgical intervention. Graphical Abstract Injectable multifunctional matrix of polyethylene glycol and gelatin derivatives for the delivery of gold porphyrinto inhibit tumor growth.
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http://dx.doi.org/10.1007/s11095-019-2581-zDOI Listing
March 2019

Plasmonic metal nanoparticles as efficient mass tags for ion signal amplification and ultrasensitive detection of protein markers.

Anal Chim Acta 2019 May 9;1055:1-6. Epub 2019 Jan 9.

Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong S.A.R, PR China. Electronic address:

The development of sensitive and specific analytical methods is critical for the discovery of molecular biomarkers, which assists disease diagnosis and understanding biological processes. Herein, a highly sensitive method is developed using antibody-conjugated plasmonic metal nanoparticles for the detection of targeted biomarkers down to low attomole level via coupling of immunoassay techniques with laser ionization mass spectrometry (LI-MS). The conjugated antibodies target specific antigens, while the metal nanoparticles act as mass tags and ion reservoirs for the signal amplification. With the characteristic localized surface plasmon resonance (LSPR) properties, gold (AuNPs) and silver nanoparticles (AgNPs) undergo explosive ionization upon laser irradiation to generate abundant characteristic mass reporter ions for strong MS signal amplification. With the antibody-conjugated NPs, detection of trace proteins in various biological samples with complex matrix environment, including urine, cell lysates, and animal tissues was demonstrated.
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http://dx.doi.org/10.1016/j.aca.2018.12.057DOI Listing
May 2019

Plasmonic gold nanoparticles as multifaceted probe for tissue imaging.

Chem Commun (Camb) 2019 Feb;55(19):2761-2764

State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong S.A.R., P. R. China.

The localized surface plasmon resonance property of gold nanoparticles enables their application as a versatile and sensitive imaging probe, with intense colour, enhanced fluorescence and strong MS ion intensity for biological tissue imaging.
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http://dx.doi.org/10.1039/c9cc00356hDOI Listing
February 2019

Luminescent ruffled iridium(iii) porphyrin complexes containing N-heterocyclic carbene ligands: structures, spectroscopies and potent antitumor activities under dark and light irradiation conditions.

Chem Sci 2019 Jan 10;10(1):293-309. Epub 2018 Oct 10.

State Key Laboratory of Synthetic Chemistry , Institute of Molecular Functional Materials , HKU-CAS Joint Laboratory on New Materials and Department of Chemistry , The University of Hong Kong , Pokfulam Road , Hong Kong , China . Email:

A panel of iridium(iii) porphyrin complexes containing axial N-heterocyclic carbene (NHC) ligand(s) were synthesized and characterized. X-ray crystal structures of the bis-NHC complexes [Ir(ttp)(IMe)] (), [Ir(oep)(BIMe)] (), [Ir(oep)(I Pr)] () and [Ir(Ftpp)(IMe)] () display ruffled porphyrin rings with mesocarbon displacements of 0.483-0.594 Å and long Ir-C bonds of 2.100-2.152 Å. Variable-temperature H NMR analysis of reveals that the macrocycle porphyrin ring inversion takes place in solution with an activation barrier of 40 ± 1 kJ mol. The UV-vis absorption spectra of Ir(por)-NHC complexes display split Soret bands. TD-DFT calculations and resonance Raman experiments show that the higher-energy Soret band is derived from the MLCT dπ(Ir) → π*(por) transition. The near-infrared phosphorescence of Ir(por)-NHC complexes from the porphyrin-based (π, π*) state features broad emission bands at 701-754 nm with low emission quantum yields and short lifetimes ( < 0.01; < 4 μs). [Ir(por)(IMe)] complexes (por = ttp and oep) are efficient photosensitizers for O generation ( = 0.64 and 0.88) and are catalytically active in the light-induced aerobic oxidation of secondary amines and arylboronic acid. The bis-NHC complexes exhibit potent dark cytotoxicity towards a panel of cancer cells with IC values at submicromolar levels. The cytotoxicity of these complexes could be further enhanced upon light irradiation with IC values as low as nanomolar levels in association with the light-induced generation of reactive oxygen species (ROS). Bioimaging of [Ir(oep)(IMe)] () treated cells indicates that this Ir complex mainly targets the endoplasmic reticulum. [Ir(oep)(IMe)] catalyzes the photoinduced generation of singlet oxygen and triggers protein oxidation, cell cycle arrest, apoptosis and the inhibition of angiogenesis. It also causes pronounced photoinduced inhibition of tumor growth in a mouse model of human cancer.
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http://dx.doi.org/10.1039/c8sc02920bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335621PMC
January 2019

Chemical Printing of Biological Tissue by Gold Nanoparticle-Assisted Laser Ablation.

ACS Omega 2017 Sep 21;2(9):6031-6038. Epub 2017 Sep 21.

Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China.

A chemical printing method based on gold nanoparticle (AuNP)-assisted laser ablation has been developed. By rastering a thin layer of AuNPs coated on a rat kidney tissue section with a UV laser, biomolecules are extracted and immediately transferred/printed onto a supporting glass substrate. The integrity of the printed sample is preserved, as revealed by imaging mass spectrometric analysis. By studying the mechanism of the extraction/printing process, transiently molten AuNPs were found to be involved in the process, as supported by the color and morphological changes of the AuNP thin film. The success of this molecular printing method was based on the efficient laser-nanomaterial interaction, that is, the strong photoabsorption, laser-induced heating, and phase-transition properties of the AuNPs. It is anticipated that the molecular printing method can be applied to perform site-specific printing, which extracts and transfers biochemicals from different regions of biological tissue sections to different types of supporting materials for subsequent biochemical analysis with the preservation of the original tissue samples.
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http://dx.doi.org/10.1021/acsomega.7b00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044615PMC
September 2017

Shotgun Proteomics and Quantitative Pathway Analysis of the Mechanisms of Action of Dehydroeffusol, a Bioactive Phytochemical with Anticancer Activity from Juncus effusus.

J Proteome Res 2018 07 21;17(7):2470-2479. Epub 2018 Jun 21.

Department of Chemistry, Chemical Biology Center and State Key Laboratory of Synthetic Chemistry , The University of Hong Kong , Hong Kong , China.

Dehydroeffusol (DHE) is a phenanthrene isolated from the Chinese medicinal plant Juncus effusus. Biological evaluation of DHE reveals in vitro and in vivo anticancer effects. We performed a shotgun proteomic analysis using liquid chromatography-tandem mass spectrometry to investigate the changes in the protein profiles in cancer cells upon DHE treatment. DHE affected cancer-associated signaling pathways, including NF-κB, β-catenin, and endoplasmic reticulum stress. Through quantitative pathway and key node analysis of the proteomics data, activating transcription factor 2 (ATF-2) and c-Jun kinase (JNK) were found to be the key components in DHE's modulated biological pathways. Based on the pathway analysis as well as chemical similarity to estradiol, DHE is proposed to be a phytoestrogen. The proteomic, bioinformatic, and chemoinformatic analyses were further verified with individual cell-based experiments. Our study demonstrates a workflow for identifying the mechanisms of action of DHE through shotgun proteomic analysis.
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http://dx.doi.org/10.1021/acs.jproteome.8b00227DOI Listing
July 2018

Anticancer metal-N-heterocyclic carbene complexes of gold, platinum and palladium.

Curr Opin Chem Biol 2018 04 11;43:30-36. Epub 2017 Nov 11.

Department of Chemistry, State Key Laboratory of Synthetic Chemistry and Chemical Biology Centre, The University of Hong Kong, Pokfulam, Hong Kong. Electronic address:

Transition metal compounds are a rich source for anticancer drug development. Judicious application of coordination ligands is a critical success factor in the design of effective anti-tumor compounds. N-heterocyclic carbenes (NHC) are stable ligands that have strong donor strengths in stabilizing metal ions and versatility in structural modifications to provide diverse scaffolds for biological molecular targeting. Remarkable advances have been achieved in the development of metal NHC complexes as anticancer as well as theranostic agents. NHC complexes of gold, platinum and palladium have been designed to elicit potent cancer cell cytotoxicity, effective anti-tumor activities in animal models as well as selective binding to molecular targets (e.g. protein thiols, DNA G-quadraplexes, mismatched DNA). The mechanisms of action of some of these complexes have been elucidated.
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http://dx.doi.org/10.1016/j.cbpa.2017.10.014DOI Listing
April 2018

A multi-functional PEGylated gold(iii) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery.

Chem Sci 2017 Mar 22;8(3):1942-1953. Epub 2016 Nov 22.

State Key Laboratory of Synthetic Chemistry , Department of Chemistry and Chemical Biology Centre , The University of Hong Kong , Pokfulam Road , Hong Kong , China . Email:

Gold(iii) porphyrin-PEG conjugates [Au(TPP-COO-PEG-OCH)]Cl () and [Au(TPP-CONH-PEG-OCH)]Cl () have been synthesized and characterized. Based on the amphiphilic character of the conjugates, they were found to undergo self-assembly into nanostructures with size 120-200 nm and this did not require the presence of other surfactants or components for nano-assembly, unlike most conventional drug nano-formulations. With a readily hydrolyzable ester linkage, chemotherapeutic [Au(TPP-COOH)] exhibited triggered release from the conjugate in acidic buffer solution as well as and without the formation of toxic side products. The nanostructures of showed higher cellular uptake into cancer cells compared to non-tumorigenic cells, owing to their energy-dependent uptake mechanism. This, together with a generally higher metabolic rate and more acidic nature of cancer cells which can lead to faster hydrolysis of the ester bond, afforded with excellent selectivity in killing cancer cells compared with non-tumorigenic cells . This was corroborated by fluorescence microscopy imaging and flow cytometric analysis of co-culture model of colon cancer (HCT116) and normal colon (NCM460) cells. experiments showed that treatment of nude mice bearing HCT116 xenografts with resulted in significant inhibition of tumor growth and, more importantly, minimal systemic toxicity as revealed by histopathological analysis of tissue sections and blood biochemisty. The latter is explained by a lower accumulation of in organs of treated mice at its effective dosage, as compared to that of other gold(iii) porphyrin complexes. Co-assembly of and doxorubicin resulted in encapsulation of doxorubicin by the nanostructures of . The nanocomposites demonstrated a strong synergism on killing cancer cells and could overcome efflux pump-mediated drug-resistance in a doxorubicin-resistant ovarian cancer cell line (A2780adr) which was found in cells incubated with doxorubicin alone. Also, the nanocomposites accumulated more slowly in non-tumorigenic cells, resulting in a lower toxicity toward non-tumorigenic cells. These results indicate the potential application of not only as an anti-cancer agent but also as a nanoscale drug carrier for chemotherapy.
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http://dx.doi.org/10.1039/c6sc03210aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384453PMC
March 2017

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

Angew Chem Int Ed Engl 2017 03 1;56(14):3892-3896. Epub 2017 Mar 1.

State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

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, Pt and Pd 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.
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http://dx.doi.org/10.1002/anie.201612583DOI Listing
March 2017

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

Nanomedicine 2017 04 25;13(3):1041-1050. Epub 2016 Nov 25.

Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nano.2016.11.013DOI Listing
April 2017

A macromolecular cyclometalated gold(iii) amphiphile displays long-lived emissive excited state in water: self-assembly and in vitro photo-toxicity.

Chem Commun (Camb) 2016 Nov;52(90):13273-13276

State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, HKU-CAS Joint Laboratory on New Materials, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China. and HKU-Shenzhen Institute of Research and Innovation, Shenzhen 518053, China.

We report an amphiphilic macromolecule containing a cyclometalated gold(iii) complex that self-assembles into nano-sized micelles and also displays a long-lived emissive triplet excited state with a lifetime of 84 μs in degassed water. This amphiphilic Au complex exhibits good biocompatibility and activity towards in vitro photo-toxicity, as well as enhanced permeability and retention effects in vivo.
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http://dx.doi.org/10.1039/c6cc06767kDOI Listing
November 2016

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

Angew Chem Int Ed Engl 2016 10 26;55(43):13524-13528. Epub 2016 Sep 26.

State Key Laboratory of Synthetic Chemistry, Chemical Biology Centre and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P.R. China.

A macrocyclic ruthenium(III) complex [Ru (N O )Cl ]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.
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http://dx.doi.org/10.1002/anie.201608094DOI Listing
October 2016

Cyclometalated Palladium(II) N-Heterocyclic Carbene Complexes: Anticancer Agents for Potent In Vitro Cytotoxicity and In Vivo Tumor Growth Suppression.

Angew Chem Int Ed Engl 2016 09 29;55(39):11935-9. Epub 2016 Aug 29.

State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

Palladium(II) complexes are generally reactive toward substitution/reduction, and their biological applications are seldom explored. A new series of palladium(II) N-heterocyclic carbene (NHC) complexes that are stable in the presence of biological thiols are reported. A representative complex, [Pd(C^N^N)(N,N'-nBu2 NHC)](CF3 SO3 ) (Pd1 d, HC^N^N=6-phenyl-2,2'-bipyridine, N,N'-nBu2 NHC=N,N'-di-n-butylimidazolylidene), displays potent killing activity toward cancer cell lines (IC50 =0.09-0.5 μm) but is less cytotoxic toward a normal human fibroblast cell line (CCD-19Lu, IC50 =11.8 μm). In vivo anticancer studies revealed that Pd1 d significantly inhibited tumor growth in a nude mice model. Proteomics data and in vitro biochemical assays reveal that Pd1 d exerts anticancer effects, including inhibition of an epidermal growth factor receptor pathway, induction of mitochondrial dysfunction, and antiangiogenic activity to endothelial cells.
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http://dx.doi.org/10.1002/anie.201602814DOI Listing
September 2016

Identification of "sarsasapogenin-aglyconed" timosaponins as novel Aβ-lowering modulators of amyloid precursor protein processing.

Chem Sci 2016 May 22;7(5):3206-3214. Epub 2016 Jan 22.

Department of Chemistry , The University of Hong Kong , Chemical Biology Centre , 8/F., The Hong Kong Jockey Club Building for Interdisciplinary Research, 5, Sassoon Road, Pokfulam , Hong Kong , China . Email: ; ; Tel: +852-28592154.

The inhibition of amyloid β (Aβ) peptide production is a key approach in the development of therapeutics for the treatment of Alzheimer's disease (AD). We have identified that timosaponins consisting of sarsasapogenin (SSG) as the aglycone can effectively lower the production of Aβ peptides and stimulate neurite outgrowth in neuronal cell cultures. Structure-activity relationship studies revealed that the -fused AB ring, 3β-configuration, spiroketal F-ring and 25-configuration of SSG are the essential structural features responsible for the Aβ-lowering effects and neurite-stimulatory activity. New synthetic derivatives that retain the SSG scaffold also exhibited an Aβ lowering effect. Treatment of cells with timosaponins led to modulation of amyloid precursor protein (APP) processing through the suppression of β-cleavage and preferential lowering of the production of the 42-amino acid Aβ species (Aβ) without affecting another γ-secretase substrate. The SSG and "SSG-aglyconed" timosaponins also penetrated brain tissue and lowered brain Aβ levels in mice. Our studies demonstrate that timosaponins represent a unique class of steroidal saponins that may be useful for the development of AD therapeutics.
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http://dx.doi.org/10.1039/c5sc02377gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005341PMC
May 2016

Luminescent platinum(II) complexes with functionalized N-heterocyclic carbene or diphosphine selectively probe mismatched and abasic DNA.

Nat Commun 2016 Feb 17;7:10655. Epub 2016 Feb 17.

State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre, and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

The selective targeting of mismatched DNA overexpressed in cancer cells is an appealing strategy in designing cancer diagnosis and therapy protocols. Few luminescent probes that specifically detect intracellular mismatched DNA have been reported. Here we used Pt(II) complexes with luminescence sensitive to subtle changes in the local environment and report several Pt(II) complexes that selectively bind to and identify DNA mismatches. We evaluated the complexes' DNA-binding characteristics by ultraviolet/visible absorption titration, isothermal titration calorimetry, nuclear magnetic resonance and quantum mechanics/molecular mechanics calculations. These Pt(II) complexes show up to 15-fold higher emission intensities upon binding to mismatched DNA over matched DNA and can be utilized for both detecting DNA abasic sites and identifying cancer cells and human tissue samples with different levels of mismatch repair. Our work highlights the potential of luminescent Pt(II) complexes to differentiate between normal cells and cancer cells which generally possess more aberrant DNA structures.
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http://dx.doi.org/10.1038/ncomms10655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757794PMC
February 2016

Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60.

Angew Chem Int Ed Engl 2016 Jan 9;55(4):1387-91. Epub 2015 Dec 9.

State Key Laboratory of Synthetic Chemistry, Chemical Biology Center, and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, Hong Kong.

Identification of the molecular target(s) of anticancer metal complexes is a formidable challenge since most of them are unstable toward ligand exchange reaction(s) or biological reduction under physiological conditions. Gold(III) meso-tetraphenylporphyrin (gold-1 a) is notable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities. Herein, extensive chemical biology approaches employing photo-affinity labeling, click chemistry, chemical proteomics, cellular thermal shift, saturation-transfer difference NMR, protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat-shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of gold-1 a in vitro and in cells. Structure-activity studies with a panel of non-porphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand.
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http://dx.doi.org/10.1002/anie.201509612DOI Listing
January 2016

Silver nanoparticles promote osteogenesis of mesenchymal stem cells and improve bone fracture healing in osteogenesis mechanism mouse model.

Nanomedicine 2015 Nov 15;11(8):1949-59. Epub 2015 Aug 15.

Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China. Electronic address:

Unlabelled: The potential use of osteo-conducive biomaterials in the promotion of bone fracture healing has attracted wide attention. This study investigated if silver nanoparticles (AgNps) could promote the proliferation and osteogenesis of mesenchymal stem cells (MSCs), and improve bone fracture healing. We showed that AgNps promoted MSCs' proliferation and osteogenic differentiation in vitro. Using a mouse femoral facture model, AgNps encapsulated in collagen promoted the formation of fracture callus, and induced early closure of the fracture gap. AgNps may promote the formation of the callus and the subsequent end joining of the fracture bone via multiple routes: (i) chemo-attraction of MSCs and fibroblasts to migrate to the fracture site; (ii) induction of the proliferation of MSCs; (iii) induction of osteogenic differentiation of MSCs via induction/activation of TGF-β/BMP signaling in MSCs. We concluded that AgNps might be beneficial as an adjunct treatment for bone fracture healing clinically.

From The Clinical Editor: Silver nanoparticles are widely used in wound management in the clinical setting. In this article, the authors demonstrated a novel application in that these nanoparticles were efficient in promoting osteoblastic differentiation in both in-vitro and in-vivo studies. The findings may provide a new treatment direction for bone fracture in the future.
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http://dx.doi.org/10.1016/j.nano.2015.07.016DOI Listing
November 2015

Luminescent platinum(ii) complexes with self-assembly and anti-cancer properties: hydrogel, pH dependent emission color and sustained-release properties under physiological conditions.

Chem Sci 2015 Jul 28;6(7):3823-3830. Epub 2015 Apr 28.

State Key Laboratory of Synthetic Chemistry , Institute of Molecular Functional Materials , Chemical Biology Centre and Department of Chemistry , The University of Hong Kong , Pokfulam Road , Hong Kong , China . Email:

Supramolecular interactions are of paramount importance in biology and chemistry, and can be used to develop new vehicles for drug delivery. Recently, there is a surge of interest on self-assembled functional supramolecular structures driven by intermolecular metal-metal interactions in cellular conditions. Herein we report a series of luminescent Pt(ii) complexes [Pt(C^N^N)(C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 NR)] [HC^N^N = 2-phenyl-6-(1-pyrazol-3-yl)-pyridine)] containing pincer type ligands having pyrazole moieties. These Pt(ii) complexes exert potent cytotoxicity to a panel of cancer cell lines including primary bladder cancer cells and display strong phosphorescence that is highly sensitive to the local environment. The self-assembly of these complexes is significantly affected by pH of the solution medium. Based on TEM, SEM, ESI-MS, absorption and emission spectroscopy, and fluorescence microscopy together with cell based assays, [Pt(C^N^N)(C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 NR)] complexes were observed to self-assemble into orange phosphorescent polymeric aggregates driven by intermolecular Pt(ii)-Pt(ii) and ligand-ligand interactions in a low-pH physiological medium. Importantly, the intracellular assembly and dis-assembly of [Pt(C^N^N)(C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 NR)] are accompanied by change of emission color from orange to green. These [Pt(C^N^N)(C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 NR)] complexes accumulated in the lysosomes of cancer cells, increased the lysosomal membrane permeability and induced cell death. One of these platinum(ii) complexes formed hydrogels which displayed pH-responsive and sustained release properties, leading to low-pH-stimulated and time-dependent cytotoxicity towards cancer cells. These hydrogels can function as vehicles to deliver anti-cancer agent cargo, such as the bioactive natural products studied in this work.
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http://dx.doi.org/10.1039/c4sc03635bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707448PMC
July 2015

Chemical biology of anticancer gold(III) and gold(I) complexes.

Chem Soc Rev 2015 Dec 14;44(24):8786-801. Epub 2015 Apr 14.

State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

Gold complexes have recently gained increasing attention in the design of new metal-based anticancer therapeutics. Gold(III) complexes are generally reactive/unstable under physiological conditions via intracellular redox reactions, and the intracellular Au(III) to Au(I) reduction reaction has recently been "traced" by the introduction of appropriate fluorescent ligands. Similar to most Au(I) complexes, Au(III) complexes can inhibit the activities of thiol-containing enzymes, including thioredoxin reductase, via ligand exchange reactions to form Au-S(Se) bonds. Nonetheless, there are examples of physiologically stable Au(III) and Au(I) complexes, such as [Au(TPP)]Cl (H2TPP = 5,10,15,20-tetraphenylporphyrin) and [Au(dppe)2]Cl (dppe = 1,2-bis(diphenylphosphanyl)ethane), which are known to display highly potent in vitro and in vivo anticancer activities. In this review, we summarize our current understanding of anticancer gold complexes, including their mechanisms of action and the approaches adopted to improve their anticancer efficiency. Some recent examples of gold anticancer chemotherapeutics are highlighted.
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http://dx.doi.org/10.1039/c5cs00132cDOI Listing
December 2015

Anti-cancer iron(II) complexes of pentadentate N-donor ligands: cytotoxicity, transcriptomics analyses, and mechanisms of action.

Chemistry 2015 Feb 17;21(7):3062-72. Epub 2014 Dec 17.

State Key Laboratory of Synthetic Chemistry, Department of Chemistry and Chemical Biology Centre, The University of Hong Kong, Pokfulam Road, Hong Kong (PR China).

Two cytotoxic iron(II) complexes [Fe(L)(CH3 CN)n ](ClO4 )2 (L=qpy for Fe-1 a, Py5 -OH for Fe-2 a) were synthesized. Both complexes are stable against spontaneous demetalation and oxidation in buffer solutions. Cyclic voltammetry measurements revealed the higher stability of Fe-2 a (+0.82 V vs Fc) against Fe(II) to Fe(III) oxidation than Fe-1 a (+0.57 V vs Fc). These two complexes display potent cytotoxicity at micromolar level against a panel of cancer cell lines (Fe-1 a=0.8-3.1 μM; Fe-2 a=0.6-3.4 μM), and induce apoptosis that involves caspase activation. Transcriptomic and Connectivity Map analyses revealed that the changes of gene expression induced by Fe-1 a and Fe-2 a are similar to that induced by ciclopirox, an antifungal compound whose mode of action involves formation of intracellular cytotoxic iron chelates. Both Fe-1 a and Fe-2 a caused cellular nuclear DNA damage, as revealed by Comet assay and H2 AX immunofluorescence experiments. The cytotoxicity is associated with production of reactive oxygen species (for Fe-1 a), cell cycle regulation, and stress kinase pathways. The relative contributions of these to the overall cytotoxic mechanism is significantly affected by the structure of penta-N-donor ligand.
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http://dx.doi.org/10.1002/chem.201404749DOI Listing
February 2015

Dendrimer encapsulation enhances anti-inflammatory efficacy of silver nanoparticles.

J Pediatr Surg 2014 Dec 1;49(12):1846-51. Epub 2014 Oct 1.

Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address:

Background: Our previous studies revealed that silver nanoparticles (AgNPs) promoted wound healing in part through their anti-inflammatory actions. As recent reports also suggested anti-inflammatory effects of dendrimers, we therefore undertook this study using dendrimer as the delivery system for AgNP to explore any potential synergistic anti-inflammatory efficacy.

Methods: Lipopolysaccharide (LPS) was added to cultured RAW264.7 and J774.1 cells to mimic in vitro inflammation condition, followed by the addition of either silver dendrimer nanocomposite (Ag-DNC), AgNPs, or dendrimer. The levels of inflammatory markers TNF-alpha and interleukin-6 were assessed using ELISA assay. Furthermore, in vivo effects such of Ag-DNC, AgNPs, or dendrimer were studied in a burn wound model in mice.

Results: Our results confirmed that both naked dendrimer and AgNPs had anti-inflammatory properties. In in vitro study, Ag-DNC was shown to have the best anti-inflammatory efficacy than AgNPs or dendrimer alone. In-vivo experiments also indicated that animals in the Ag-DNC group had the fastest healing time with the least inflammation.

Conclusion: Our study would suggest that dendrimer could provide additional anti-inflammatory benefits and might be an excellent delivery system for silver nanoparticles for future clinical application.
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http://dx.doi.org/10.1016/j.jpedsurg.2014.09.033DOI Listing
December 2014

Luminescent cyclometalated platinum(II) complex forms emissive intercalating adducts with double-stranded DNA and RNA: differential emissions and anticancer activities.

Angew Chem Int Ed Engl 2014 Sep 15;53(38):10119-23. Epub 2014 Jul 15.

State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong (China).

Luminescent metallo-intercalators are potent biosensors of nucleic acid structure and anticancer agents targeting DNAs. There are few examples of luminescent metallo-intercalators which can simultaneously act as emission probes of nucleic acid structure and display promising anticancer activities. Herein, we describe a luminescent platinum(II) complex, [Pt(C^N^N)(C≡NtBu)]ClO4 (1 a, HC^N^N= 6-phenyl-2,2'-bipyridyl), that intercalates between the nucleobases of nucleic acids, accompanied by an increase in emission intensity and/or a significant change in the maximum emission wavelength. The changes in emission properties measured with double-stranded RNA (dsRNA) are different from those with dsDNA used in the binding reactions. Complex 1 a exhibited potent anticancer activity towards cancer cells in vitro and inhibited tumor growth in a mouse model. The stabilization of the topoisomerase I-DNA complex with resulting DNA damage by 1 a is suggested to contribute to its anticancer activity.
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http://dx.doi.org/10.1002/anie.201405384DOI Listing
September 2014
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