Iron porphyrin-based porous organic polymer with high peroxidase-like activity as colorimetric sensor for glutathione and ascorbic acid assay.

A new iron porphyrin-based organic polymer (Fe-POP) was synthesized through the William ether reaction. The as-prepared Fe-POP presented high chemical stability, wide pore distribution, high iron content, and strong affinity with 3,3',5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide (H2O2), which contributed to its excellent peroxidase-mimicking performance. In the presence of H2O2, Fe-POP could catalyze the transparent TMB into blue ox-TMB, which could be easily distinguished by the naked eyes. Moreover, glutathione (GSH) and ascorbic acid (AA) could convert blue ox-TMB into colorless TMB due to the inhibitory effect of GSH/AA to the catalytic oxidation of TMB. Based on this phenomenon, a rapid and sensitive colorimetric method for the assay of H2O2, GSH, and AA was developed using Fe-POP as sensor. The detection limits of H2O2, GSH, and AA  were 1.37, 0.44, and 0.33 µM, respectively. Finally, the colorimetric method based on Fe-POP was used to evaluate the GSH and AA content in real samples, which provided the guidance for GSH and AA supplements in our daily diet, suggesting the significant potential of Fe-POP in practical applications.

Identification of Molecular Targets and Potential Mechanisms of Yinchen Wuling San Against Head and Neck Squamous Cell Carcinoma by Network Pharmacology and Molecular Docking.

Head and neck squamous cell carcinoma (HNSCC) represents one of the most malignant and heterogeneous tumors, and the patients have low 5-year survival. Traditional Chinese medicine (TCM) has been demonstrated as an effective complementary and/or alternative therapy for advanced malignancies including HNSCC. It has been noted that several herbs that are used for preparing Yinchen Wuling San (YWLS) have anti-tumor activities, whereas their mechanisms of action remain elusive. In this study, network pharmacology and molecular docking studies were employed to explore the underlying mechanisms of action of YWLS against HNSCC. The 58 active ingredients from six herbs used for YWLS and their 506 potential targets were screened from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. A total of 2,173 targets associated with HNSCC were mainly identified from the DisGeNET and GeneCards databases. An active components-targets-disease network was constructed in the Cytoscape. Top 20 hub targets, such as AKT1, EGFR, TNF, ESR1, SRC, HSP90AA1, MAPK3, ERBB2, and CCND1, were identified by a degree in the protein-protein interaction (PPI) network. Gene functional enrichment analysis showed that PI3K-AKT, MAPK, Ras, TNF, and EGFR were the main signaling pathways of YWLS in treating HNSCC. There were 48 intersected targets such as EGFR, AKT1, and TNF that were associated with patients' outcomes by the univariate Cox analysis, and most of them had increased expression in the tumor as compared to normal tissues. The area under curves of receiver operating characteristic indicated their diagnostic potential. Inhibition of these survival-related targets and/or combination with EGFR or AKT inhibitors were promising therapeutic options in HNSCC. The partial active components of YWLS exhibited good binding with the hub targets, and ADME analysis further evaluated the drug-likeness of the active components. These compounds and targets identified in this study might provide novel treatment strategies for HNSCC patients, and the subsequent work is essential to verify the underlying mechanisms of YWLS against HNSCC.

Self-assembled porphyrin polymer nanoparticles with NIR-II emission and highly efficient photothermal performance in cancer therapy.

The development of new organic nanoagents with extremely high photothermal conversion efficiency and good biocompatibility has gained considerable attention in the area of photothermal cancer therapy. In this work, we designed and synthesized a new porphyrin polymer (P-PPor) with donor-acceptor (D-A) structure. P-PPor displayed intense absorbance in the near-infrared (NIR) region with the maximum peak around at 850 â€‹nm. Under excitation of 808 â€‹nm, P-PPor demonstrated the significant fluorescence in the NIR-II region (λ max â€‹= â€‹1015 â€‹nm), with the fluorescence quantum yield of 2.19%. Due to the presence of hydrophilic PEG chains and hydrophobic alkyl chains in the conjugated skeleton, the amphiphilic P-PPor could self-assemble into the nanoparticles (P-PPor NPs) with good dispersibility in water and enhanced absorption in the NIR region. Moreover, P-PPor NPs exhibited quenched fluorescence because of the aggregation-caused quenching (ACQ) effect, resulting in the distinct photothermal effect. The photothermal conversion efficiency (PCE) of P-PPor NPs was measured as 66% under 808 â€‹nm laser irradiation, higher than most of PTT agents. The remarkable photothermal effect of P-PPor NPs was further demonstrated in vitro and in vivo using 4T1 tumor mode. Meanwhile, the NIR-II fluorescence imaging in vivo indicated the high distribution of P-PPor NPs in tumor site. These results suggested that P-PPor NPs could effectively damage the cancer cells in mice under 808 â€‹nm laser irradiation, and did not cause any obvious side effects after phototherapy. Thus, P-PPor NPs could be used as a potential agent in photothermal cancer therapy with high effectiveness and safety.

Triphenylamine-perylene diimide conjugate-based organic nanoparticles for photoacoustic imaging and cancer phototherapy.

Phototherapy has gained great attention in the past decade owing to the advantages of high selectivity and low toxicity. However, it's still a challenge to develop a single photosensitizer that can achieve both photothermal and photodynamic effects. Herein, we design and synthesize a new organic compound (PIT) with a typical D-A-D structure through the covalent conjugation of perylene diimides (PDI) and triphenylamine (TPA). The amphiphilic PIT could be transformed to the nanoparticles (PIT NPs) through nanoprecipitation method. PIT NPs exhibit good water dispersibility with particle size around 70 nm. Because of the efficient NIR absorption, PIT NPs display high photothermal conversion efficiency (PCE) (η = 46.1 %) and strong photoacoustic signal under irradiation of 635 nm laser. Moreover, under the same laser irradiation, significant reactive oxygen species can be induced by PIT NPs both in aqueous solution and cancer cells. The MTT assay demonstrate the good biocompatibility and outstanding photocytotoxicity of PIT NPs. Thus, the as-prepared PIT NPs could be used as excellent candidates for photoacoustic imaging and photodynamic/photothermal therapy.

Self-Assembled Naphthalimide Conjugated Porphyrin Nanomaterials with D-A Structure for PDT/PTT Synergistic Therapy.

Light-activated phototherapy, including photothermal and photodynamic therapy, has become a new way for spatiotemporal control and noninvasive treatment of cancer. In this study, two new organic porphyrin molecules (NI-Por and NI-ZnPor) with donor (D)-acceptor (A) structure were designed and synthesized. The donor-acceptor pairs facilitated the intermolecular electron transfer, resulting in the enhancement of near-infrared (NIR) absorbance and nonradiative heat generation. After self-assembling, the nanoparticles were formed with the size around 60 nm. Relative to that of organic molecules, the absorption of NI-Por NPs and NI-ZnPor NPs broadened and red-shifted to the near-infrared region. Moreover, the porphyrin-containing nanoparticles can generate heat and reactive oxygen species (ROS) simultaneously induced by a single laser (635 nm). The intracellular reactive oxygen species production of NI-Por NPs and NI-ZnPor NPs was confirmed using DCFH-DA as an indicator. Furthermore, the localization of NI-Por NP and NI-ZnPor NP in HeLa cells was verified by fluorescence confocal laser microscopy. The photocytoxicity of two nanoparticles against HeLa cells was evaluated through the CCK-8 method. The IC50 of NI-Por NPs and NI-ZnPor NPs upon 635 nm laser irradiation was calculated to be 6.92 µg/mL and 5.86 µg/mL, respectively. Furthermore, the PDT/PTT synergistic effect of NPs under a 635 nm laser was verified through different treatment groups in vitro. All these results demonstrated that the as-prepared porphyrin-based nanoparticles are promising nanoagents for PDT/PTT in clinic.

Organic small molecular nanoparticles based on self-assembly of amphiphilic fluoroporphyrins for photodynamic and photothermal synergistic cancer therapy.

Two new porphyrin-based organic compounds (Por and ZnPor) were synthesized by introducing hydrophilic polyethylene glycol chains and pentafluorobenzene moieties onto the parent porphyrin structure. After self-assembling into nanoparticles, the absorption spectrum of (Zn)Por NPs broadened and red-shifted to some extent, relative to that of organic molecules. Meanwhile, the fluorescence of organic molecule nanoparticles was quenched significantly, which facilitated the nonradiative thermal generation for potential applications in photothermal cancer therapy. Por NPs and ZnPor NPs presented spherical structure with average diameter about 100 nm, endowing them with tumor targeting properties based on the enhanced permeability and retention (EPR) effect. Due to the heavy atom effect, ZnPor NPs presented the higher efficiency of ROS generation than that of Por NPs. In contrast, Por NPs exhibited the better photothermal effect relative to that of ZnPor NPs under irradiation of a 635-nm laser. The photothermal conversion efficiency of Por NPs was calculated to be 16.34%. The in vitro experiments suggested that Por NPs and ZnPor NPs could enter tumor cells efficiently with good biocompatibility and exhibited high photocytotoxicity with IC50 of 7.3 µg/mL and 3.0 µg/mL, respectively. Thus, the as-prepared porphyrin nanomaterials can be used as potential photosensitizers for cancer photodynamic/photothermal synergistic therapy in vivo, benefiting from their good biocompatibility, strong near-infrared absorption, and high photodynamic and photothermal effects.

Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma.

BACKGROUND: Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance. METHODS: Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR. GST-pull down and LC-MS/MS was used to detect the interaction of PXR and Sorafenib. To test the properties of HCC tumor growth and metastasis, in vivo tumor explant model, FACS, trans-well assay, cell-survival inhibitory assay and Western blot were performed. In terms of mechanistic study, additional assays such as ChIP and luciferase reporter gene assay were applied. RESULTS: In the present work, we found high PXR level in clinical specimens is related to the poor prognosis of Sorafenib treated patients. By the mechanistic studies, we show that sorafenib binds to PXR and activates PXR pathway, and by which HCC cells develop sorafenib-resistance via activating. Moreover, PXR overexpression helps HCC cells to persist to sorafenib treatment. CONCLUSION: This study reports the endogenous sorafenib-resistance mechanism in HCC cells, which offers an opportunity to design new therapeutic approaches for HCC treatment. GENERAL SIGNIFICANCE: PXR mediates sorafenib-resistance in HCC cells and targeting PXR can be a useful approach to facilitate HCC treatment.