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Biosensors Mar 2022Opioid drugs are extremely potent synthetic analytes, and their abuse is common around the world. Hence, a rapid and point-of-need device is necessary to assess the...
Opioid drugs are extremely potent synthetic analytes, and their abuse is common around the world. Hence, a rapid and point-of-need device is necessary to assess the presence of this compound in body fluid so that a timely countermeasure can be provided to the exposed individuals. Herein, we present an attractive microneedle sensing platform for the detection of the opioid drug fentanyl in real serum samples using an electrochemical detection method. The device contained an array of pyramidal microneedle structures that were integrated with platinum (Pt) and silver (Ag) wires, each with a microcavity opening. The working sensor was modified by graphene ink and subsequently with 4 (3-Butyl-1-imidazolio)-1-butanesulfonate) ionic liquid. The microneedle sensor showed direct oxidation of fentanyl in liquid samples with a detection limit of 27.8 μM by employing a highly sensitive square-wave voltammetry technique. The resulting microneedle-based sensing platform displayed an interference-free fentanyl detection in diluted serum without conceding its sensitivity, stability, and response time. The obtained results revealed that the microneedle sensor holds considerable promise for point-of-need fentanyl detection and opens additional opportunities for detecting substances of abuse in emergencies.
Topics: Analgesics, Opioid; Electrochemical Techniques; Fentanyl; Humans; Platinum; Polymers; Silver
PubMed: 35448258
DOI: 10.3390/bios12040198 -
Nature Communications Nov 2022Platinum (Pt) resistance in cancer almost inevitably occurs during clinical Pt-based chemotherapy. The spontaneous nucleotide-excision repair of cancer cells is a...
Platinum (Pt) resistance in cancer almost inevitably occurs during clinical Pt-based chemotherapy. The spontaneous nucleotide-excision repair of cancer cells is a representative process that leads to Pt resistance, which involves the local DNA bending to facilitate the recruitment of nucleotide-excision repair proteins and subsequent elimination of Pt-DNA adducts. By exploiting the structural vulnerability of this process, we herein report a nuclease-mimetic Pt nanozyme that can target cancer cell nuclei and induce concurrent DNA platination and oxidative cleavage to overcome Pt drug resistance. We show that the Pt nanozyme, unlike cisplatin and conventional Pt nanoparticles, specifically induces the nanozyme-catalyzed cleavage of the formed Pt-DNA adducts by generating in situ reactive oxygen species, which impairs the damage recognition factors-induced DNA bending prerequisite for nucleotide-excision repair. The recruitment of downstream effectors of nucleotide-excision repair to DNA lesion sites, including xeroderma pigmentosum groups A and F, is disrupted by the Pt nanozyme in cisplatin-resistant cancer cells, allowing excessive accumulation of the Pt-DNA adducts for highly efficient cancer therapy. Our study highlights the potential benefits of applying enzymatic activities to the use of the Pt nanomedicines, providing a paradigm shift in DNA damaging chemotherapy.
Topics: Platinum; DNA Adducts; Cisplatin; Endonucleases; Drug Resistance, Neoplasm; DNA; Oxidative Stress; Nucleotides; Neoplasms
PubMed: 36450764
DOI: 10.1038/s41467-022-35022-w -
BMC Cancer Jun 2021Enhancer of zesta homologue 2 (EZH2) is an essential component of polycomb repressive complex 2 (PRC2) that contributes to tumor progression and chemo-resistance. The...
BACKGROUND
Enhancer of zesta homologue 2 (EZH2) is an essential component of polycomb repressive complex 2 (PRC2) that contributes to tumor progression and chemo-resistance. The aim of this study was to comprehensively assess the prognostic value of EZH2 across the morphologic and molecular spectra of high-grade serous ovarian carcinoma (HGSOC) by utilizing both immunohistochemistry (IHC) and proteogenomic technologies.
METHODS
IHC of EZH2 was performed using a tissue microarray of 79 HGSOC scored (+/-) for lymphovascular invasion (LVI), tumor-infiltrating lymphocytic aggregates ≥1 mm (TIL) and architectural growth patterns. The association of EZH2 H-score with response to therapy and overall survival was evaluated by tumor features. We also evaluated EZH2 transcriptional (RNA sequencing) and protein (mass spectrometry) expression from bulk tumor samples from 336 HGSOC from The Cancer Genome Atlas (TCGA). EZH2 expression and co-expression networks were compared by clinical outcomes.
RESULTS
For HGSOC without TIL (58%), EZH2 expression was almost 2-fold higher in platinum resistant tumors (P = 0.01). Conversely, EZH2 was not associated with platinum resistance among TIL+ HGSOC (P = 0.41). EZH2 expression was associated with reduced survival for tumors with LVI (P = 0.04). Analysis of TCGA found higher EZH2 expression in immunoreactive and proliferative tumors (P = 6.7 × 10) although protein levels were similar across molecular subtypes (P = 0.52). Both mRNA and protein levels of EZH2 were lower in platinum resistant tumors although they were not associated with survival. Co-expression analysis revealed EZH2 networks totaling 1049 mRNA and 448 proteins that were exclusive to platinum sensitive or resistant tumors. The EZH2 network in resistant HGSOC included CARM1 which was positively correlated with EZH2 at both mRNA (r = 0.33, p = 0.003) and protein (r = 0.14, P = 0.01) levels. Further, EZH2 co-expression with CARM1 corresponded to a decreased prognostic significance of EZH2 expression in resistant tumors.
CONCLUSIONS
Our findings demonstrate that EZH2 expression varies based on its interactions with immunologic pathways and tumor microenvironment, impacting the prognostic interpretation. The association between high EZH2 expression and platinum resistance in TIL- HGSOC warrants further study of the implications for therapeutic strategies.
Topics: Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Middle Aged; Neoplasm Grading; Ovarian Neoplasms; Platinum
PubMed: 34140011
DOI: 10.1186/s12885-021-08413-3 -
Journal of Nanobiotechnology Mar 2022Although concurrent chemoradiotherapy (CRT), as one of the most effective antineoplastic therapies in clinic, can successfully inhibit the growth of tumor cells, a risk...
BACKGROUND
Although concurrent chemoradiotherapy (CRT), as one of the most effective antineoplastic therapies in clinic, can successfully inhibit the growth of tumor cells, a risk of developing secondary tumor is still an insurmountable barrier in clinical practice.
RESULTS
Herein, a new platinum prodrug composed of tannic acid (TA) and Pt (TA-Pt) complex film was synthesized on the surface of FeO nanoparticles (NPs) with excellent stability and biocompatibility for enhanced CRT. In this system, TA-Pt complex could respond to the tumor acidic microenvironment and damage the DNA of tumor cells. Moreover, the internal iron core not only improved the effect of subsequent radiotherapy (RT), but also disrupted the iron balance in cells, inducing intracellular ferroptosis and eliminating apoptosis-resistant cells. In vitro and vivo experimental results indicated that more than 90% of tumor cells were depleted and more than 75% of the cured tumor-bearing mice evinced no recurrence or metastasis.
CONCLUSIONS
This work offered a new idea for combining the effective chemotherapy, RT and ferroptosis therapy to enhance the curative effect of CRT and inhibit tumor recurrence and metastasis.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chemoradiotherapy; Cisplatin; Mice; Nanoparticles; Neoplasm Recurrence, Local; Platinum; Prodrugs; Tumor Microenvironment
PubMed: 35279133
DOI: 10.1186/s12951-022-01322-y -
ChemMedChem Oct 2021Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the...
Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of metal-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclooctadiene (COD) complexes. Amongst the 15 compounds studied, the simplest compounds Pt(COD)X (X=Cl, I, Pt1 and Pt2) showed excellent activity against a panel of Gram-positive bacteria including vancomycin and methicillin resistant Staphylococcus aureus. Additionally, the lead compounds show no toxicity against mammalian cells or haemolytic properties at the highest tested concentrations, indicating that the observed activity is specific against bacteria. Finally, these compounds showed no toxicity against Galleria mellonella at the highest measured concentrations. However, preliminary efficacy studies in the same animal model found no decrease in bacterial load upon treatment with Pt1 and Pt2. Serum exchange studies suggest that these compounds exhibit high serum binding which reduces their bioavailability in vivo, mandating alternative administration routes such as e. g. topical application.
Topics: Alkadienes; Animals; Coordination Complexes; Dose-Response Relationship, Drug; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Structure; Moths; Platinum; Structure-Activity Relationship
PubMed: 34018686
DOI: 10.1002/cmdc.202100157 -
Angewandte Chemie (International Ed. in... Jan 2021Total synthesis allowed the constitution of the cytotoxic marine macrolides of the formosalide family to be confirmed and their previously unknown stereostructure to be...
Total synthesis allowed the constitution of the cytotoxic marine macrolides of the formosalide family to be confirmed and their previously unknown stereostructure to be assigned with confidence. The underlying blueprint was inherently modular to ensure that each conceivable isomer could be reached. This flexibility derived from the use of strictly catalyst controlled transformations to set the stereocenters, except for the anomeric position, which is under thermodynamic control; as an extra safety measure, all stereogenic centers were set prior to ring closure to preclude any interference of the conformation adopted by the macrolactone rings of the different diastereomers. Late-stage macrocyclization by ring-closing alkyne metathesis was followed by a platinum-catalyzed transannular 6-exo-dig hydroalkoxylation/ketalization to craft the polycyclic frame. The side chain featuring a very labile unsaturation pattern was finally attached to the core by Stille coupling.
Topics: Cyclization; Humans; Macrolides; Molecular Structure; Platinum; Stereoisomerism
PubMed: 32946141
DOI: 10.1002/anie.202011472 -
Nucleic Acids Research Oct 2018Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy...
Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin- and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies.
Topics: CRISPR-Cas Systems; Cell Line, Tumor; Cisplatin; Colorectal Neoplasms; DNA Damage; DNA Repair; DNA Replication; Humans; Oxaliplatin; Platinum; Reactive Oxygen Species; Transcription, Genetic
PubMed: 30137419
DOI: 10.1093/nar/gky764 -
Inorganic Chemistry Apr 2024In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are...
In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.
Topics: Animals; Chick Embryo; Humans; Female; Cell Line, Tumor; Ovarian Neoplasms; Antineoplastic Agents; Platinum; Cobalt; Coordination Complexes; Apoptosis
PubMed: 38502532
DOI: 10.1021/acs.inorgchem.3c03696 -
Angewandte Chemie (International Ed. in... Jan 2022Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active...
Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of Pt -TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA-intercalating fluorophore-into Pt -TFOs constructs, enhanced target binding and discrimination between target and off-target sequences was achieved.
Topics: Alkynes; Click Chemistry; Coordination Complexes; DNA; Oligonucleotides; Platinum
PubMed: 34652881
DOI: 10.1002/anie.202110455 -
Scientific Reports Jan 2023A novel antibacterial immunostimulant using Platinum nanoparticles (PtNPs) and lectin from Metapenaeus dobsoni (Md-Lec) was developed. The Md-Lec and PtNPs (Pt-lec)...
A novel antibacterial immunostimulant using Platinum nanoparticles (PtNPs) and lectin from Metapenaeus dobsoni (Md-Lec) was developed. The Md-Lec and PtNPs (Pt-lec) hybrid formed through non-covalent interaction exhibits antimicrobial activity against fish specific pathogens by affecting membrane integrity and producing excess reactive oxygen species. The therapeutic efficacy of Pt-lec was demonstrated through rescuing Aeromonas hydrophila infected Nile Tilapia. Pt-lec prevents the infection spreading and reduces the bacterial bioburden in less than 12 h, and as a result of this the fish were restored to normalcy. To assess immunostimulation, we studied the expression of three different immune related genes, namely LEC, Myd88 and COX-2 in the gills, liver, spleen and kidney of fish under various experimental conditions. Our results showed that Pt-lec treatment appeared to be better when compared to lectin alone in enhancing the expression of Myd88 and COX-2, but LEC was not as expected. These results suggest that Pt-lec has the ability to protect Nile Tilapia against bacterial infection by restricting bacterial bioburden through their direct effects on the bacterial membrane and indirectly through their effects on host immune-related gene expression. This hybrid could have potential "green" application in fish farming in rescuing infected animals when compared to widely and unregulated antibiotics.
Topics: Animals; Aeromonas hydrophila; Anti-Bacterial Agents; Anti-Infective Agents; Cichlids; Cyclooxygenase 2; Fish Diseases; Gram-Negative Bacterial Infections; Immunization; Lectins; Metal Nanoparticles; Myeloid Differentiation Factor 88; Penaeidae; Platinum
PubMed: 36631627
DOI: 10.1038/s41598-022-26719-5