Injectable nano-composite hydrogels based on hyaluronic acid-chitosan derivatives for simultaneous photothermal-chemo therapy of cancer with anti-inflammatory capacity.

Nowadays, the photothermal therapy (PTT) has received widespread attention and research by rapidly killing tumors with local high temperature. However, due to the irregular edges of tumor and the blurred boundary between normal and necrotic tissues, the desirable treatment cannot be achieved by the single PTT, and excessive heat will cause serious inflammation in local tissues. Herein, an injectable composite hydrogel is prepared by the oxidized hyaluronic acid (OHA) and hydroxypropyl chitosan (HPCS) via the imine bonds, which is employed as the delivery substrate for functional substances. In the gel medium, the mesoporous polydopamine (MPDA) nanoparticles are incorporated as the high efficiency photothermal agent and a reservoir of DOX, which can achieve the good photothermal conversion performance and pulsed drug release. Besides, the addition of the curcumin-cyclodextrin host-guest inclusion complex (CUR@NH2-CD) in the composite hydrogel could reduce the inflammation caused by PTT. The composite hydrogel shows favorable the Hepa1-6 tumor inhibition in vivo by virtue of the comprehensive effect of the admired photothermal efficacy of MPDA, chemotherapy of DOX and anti-inflammatory of CUR. It can be predicted that the composite hydrogel has a broad prospect in the field of comprehensive therapy for tumor.

Thermoacoustic Imaging-Guided Thermo-Chemotherapy for Hepatocellular Carcinoma Sensitized by a Microwave-Responsive Nitric Oxide Nanogenerator.

Imaging-guided percutaneous microwave thermotherapy has been regarded as an important alternative nonsurgical therapeutic strategy for hepatocellular carcinoma (HCC) that provides excellent local tumor control and favorable survival benefit. However, providing a high-resolution, real-time, and noninvasive imaging technique for intraoperative guidance and controlling postoperative residual tumor recurrence are urgent needs for the clinical setting. In this study, a cisplatin (CDDP)-loaded nanocapsule (NPs@CDDP) with microwave responsive property was prepared to simultaneously serve as a contrast agent of emerging thermoacoustic imaging and a sensitizing agent of microwave thermo-chemotherapy. Accompanying the enzymolysis in the tumor microenvironment, the NPs@CDDP responsively release l-arginine (l-Arg) and CDDP. l-Arg with excellent microwave-absorbing property allowed it to serve as a thermoacoustic imaging contrast agent for accurately delineating the tumor and remarkably increasing tumor temperature under ultralow power microwave irradiation. Apart from the chemotherapeutic effect, CDDP elevated the intracellular H2O2 level through cascade reactions and further accelerated the continuous transformation of l-Arg to nitric oxide (NO), which endowed the NPs@CDDP with NO-generation capability. Notably, the high concentration of intracellular NO was proved to aggravate lipid peroxidation and greatly improved the efficacy of microwave thermo-chemotherapy. Thereby, NPs@CDDP was expected to serve as a theranostic agent integrating the functions of tumor microenvironment-responsive drug delivery system, contrast agent of thermoacoustic imaging, thermal sensitizing agent, and NO nanogenerator, which was promising to provide a potential imaging-guided therapeutic strategy for HCC.

Rationally Driven Drug Nonradiative Decay via a Label-Free Polyprodrug Strategy to Renew Tumor Cascade Photothermal-Chemotherapy.

Drugs are frequently used for only chemotherapy that ignores their photophysical properties that potentially endow them with other therapeutic potency. Additionally, current photothermal-chemotherapy replies on the codelivery of drugs and photothermal agents, but their spatiotemporal delivery and precise release is unsatisfactory. Herein, label-free doxorubicin (DOX) polyprodrug nanoparticles (DPNs) are formulated from disulfide bonds-tethered DOX polyprodrug amphiphiles (PDMA-b-PDOXM). Benefiting from boosted nonradiative decay of high-density DOX, significant fluorescence quenching and photothermal effects are observed for DPNs without common photothermal agents. Upon cellular uptake and laser irradiation, the heat can promote lysosomal escape of DPNs into reductive cytosol, whereupon free DOX is released to activate chemotherapy and fluorescence, achieving rational cascade photothermal-chemotherapy. The current label-free polyprodrug strategy can make full use of drugs; it provides an alternative insight to extend the therapeutic domain of drugs.

Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy.

Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.

Nicotinamide promotes cardiomyocyte derivation and survival through kinase inhibition in human pluripotent stem cells.

Nicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women.

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients' outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

Camellia nitidissima Chi Extract Potentiates the Sensitivity of Gastric Cancer Cells to Paclitaxel via the Induction of Autophagy and Apoptosis.

BACKGROUND: Camellia nitidissima Chi (CNC) has been applied as a traditional folk medicine for the effective treatment of various diseases. However, there is little research regarding the mechanism of CNC on pharmaceutical function including anticancer effect. MATERIALS AND METHODS: JHC-4 is a n-butanol extract from CNC. The anti-proliferation effect was evaluated by MTT assays. Monodansylcadaverine (MDC) staining, Western blotting and autophagy inhibitors (CQ and BafA1) were applied to determine whether JHC-4 induced autophagy. The synergistic anticancer effect was evaluated by MTT assays, flow cytometry, Western blotting and autophagy inhibitors. Western blotting was used to explore the influence of PI3K/Akt/mTOR signaling pathway induced by drug treatment. RESULTS: JHC-4 caused significant growth inhibition and induced autophagy in human gastric cancer cells. Moreover, JHC-4 as an autophagy agonist synergistically potentiated the sensitivity of gastric cancer cells to paclitaxel. Meanwhile, JHC-4 could significantly enhance the growth inhibition effect of paclitaxel by the induction of autophagy and apoptosis. Finally, we demonstrated that the PI3K/Akt/mTOR signaling pathway was involved in the synergistic anti-proliferation effect of JHC-4 and paclitaxel. CONCLUSION: All these data indicated that JHC-4 was a novel autophagy inducer when combination with paclitaxel for gastric cancer, which provided the scientific evidence for the use of this Chinese traditional medicine against cancer.

DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway.

BACKGROUND: Emerging hallmark of cancer is reprogrammed cellular metabolism, increased glycolytic metabolism is physiological characteristic of human malignant neoplasms. Saponin monomer 13 of the dwarf lilyturf tuber (DT-13) is the main steroidal saponin from Liriopes Radix, which has been reported to exert anti-inflammation and anti-tumor activities but low toxicity to normal tissue. However, the effect of DT-13 on metabolism process is still unclear. PURPOSE: This study aims to characterize the role of DT-13 in glucose metabolism in colorectal cancer cells, and investigate whether the metabolism process is involved in the anti-cancer response of DT-13. METHODS: Colony formation assay was employed to determine anti-proliferative effect induced by DT-13 at 2.5, 5, 10 µM. Apoptosis and cell cycle arrest were detected by Annexin V/PI staining and PI staining, respectively. Genetic inhibition of glycolytic metabolism was carried out by knockdown of GLUT1. Orthotopic implantation mouse model of colorectal cancer was used to assess in vivo antitumor effect of DT-13 (0.625, 1.25, 2.5 mg/kg). The chemoprevention effect of DT-13 (10mg/kg) was evaluated by using C57BL/6J APCmin mice model. Glycolytic-related key enzymes and AMPK pathway were detected by using quantitative real-time PCR, western blotting, and immunohistochemical staining. RESULTS: Our results showed that cell proliferation was significantly inhibited by DT-13 in a dose-dependent manner. DT-13 inhibited glucose uptake, ATP generation, and reduced lactate production. Furthermore, DT-13 remarkably inhibited GLUT1 expression in both mRNA and protein levels. Knocking down of GLUT1 led to reduced inhibition of glucose uptake after DT-13 treatment. Moreover, deletion of GLUT1 decreased inhibitory ratio of DT-13 on cancer growth. Orthotopic implantation mouse model of colorectal cancer further confirmed that DT-13 inhibited colorectal cancer growth via blocking GLUT1 in vivo. In addition, C57BL/6J APCmin mice model revealed that DT-13 dramatically reduced the total number of spontaneous adenomas in intestinal, which further confirmed the anti-tumor activity of DT-13 in colorectal cancer. Furthermore, the mechanistically investigation showed DT-13 activated AMPK and inhibited m-TOR to block cancer growth in vitro. CONCLUSION: DT-13 is a potent anticancer agent for colorectal cancer.

The relationship of kinase insert domain receptor gene polymorphisms and clinical outcome in advanced hepatocellular carcinoma patients treated with sorafenib.

Kinase insert domain receptor (KDR) is the principal receptor that promotes the pro-angiogenic action of vascular endothelial growth factor and has been the principal target of anti-angiogenic therapies. Our aim was to determine whether single-nucleotide polymorphisms (SNPs) in KDR gene are associated with clinical outcomes after first-line sorafenib therapy in advanced hepatocellular carcinoma (HCC). The SNPs in KDR were tested in 78 advanced HCC patients receiving first-line sorafenib. Correlations with clinicopathological features and survival were analyzed. Patients with AA genotype of rs1870377 and AA genotype of rs2305948 were significantly associated with a better response and longer time to progression (TTP) (5.8 vs 4.0 months, P=0.001; 5.8 vs 4.5 months, P=0.016, respectively). Patients harboring AA genotype in rs1870377 and TT/TC genotype in rs2071559 had a longer overall survival (OS) (15.0 vs 9.6 months, P=0.001; 13.0 vs 9.0 months, P=0.007, respectively). At multivariate analysis, major vascular invasion and rs1870377 were independent factors in TTP and performance status, rs1870377, and rs2071559 were independent factors in OS. Our results suggest that SNPs in KDR gene can predict clinical outcome in advanced HCC patients receiving first-line sorafenib.

Sorafenib continuation after first disease progression could reduce disease flares and provide survival benefits in patients with hepatocellular carcinoma: a pilot retrospective study.

BACKGROUND: Sorafenib is a promising drug for advanced hepatocellular carcinoma (HCC); however, treatment may be discontinued for multiple reasons, such as progressive disease, adverse events, or the cost of treatment. The consequences of sorafenib discontinuation and continuation are uncertain. MATERIALS AND METHODS: We retrospectively analyzed 88 HCC patients treated with sorafenib from July 2007 to January 2013. Overall survival (OS), post-disease progression overall survival (pOS), and time to disease progression (TTP) were compared for survival analysis. Cox proportional hazard regression was performed to assess the effect of important factors on OS in the overall patient population and on pOS in patients who continued sorafenib treatment. RESULTS: Sorafenib was discontinued and continued in 24 and 64 patients, respectively. The median OS (355 vs 517 days respectively; p=0.015) and median post-PD OS (260 vs 317 days, respectively; p=0.020) were statistically different between the discontinuation and continuation groups. Neither the median time to first PD nor the time to second PD were significantly different between the 2 groups. In the discontinuation group, 3 of the 24 patients (12.5%) suffered disease outbreaks. In Cox proportional hazard regression analysis after correction for confounding factors, BCLC stage (p=0.002) and PD site (p=0.024) were significantly correlated with pOS in patients who continued sorafenib treatment. CONCLUSIONS: Sorafenib discontinuation may cause HCC flares or outbreaks. It is advisable to continue sorafenib treatment after first PD, particularly in patients with Barcelona Clinic Liver Cancer stage B disease or only intrahepatic PD.