Hyaluronic Acid Hydrogels Hybridized With Au-Triptolide Nanoparticles for Intraarticular Targeted Multi-Therapy of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by synovial inflammation in multiple joints. Triptolide (TP) is a disease-modifying anti-rheumatic drug (DMARD) highly effective in patients with RA and has anti-inflammatory properties. However, its clinical application has been limited owing to practical disadvantages. In the present study, hyaluronic acid (HA) hydrogel-loaded RGD-attached gold nanoparticles (AuNPs) containing TP were synthesized to alleviate the toxicity and increase therapeutic specificity. The hydrogels can be applied for targeted photothermal-chemo treatment and in vivo imaging of RA. Hydrogel systems with tyramine-modified HA (TA-HA) conjugates have been applied to artificial tissue models as surrogates of cartilage to investigate drug transport and release properties. After degradation of HA chains, heat was locally generated at the inflammation region site due to near-infrared resonance (NIR) irradiation of AuNPs, and TP was released from nanoparticles, delivering heat and drug to the inflamed joints simultaneously. RA can be penetrated with NIR light. Intraarticular administration of the hydrogels containing low dosage of TP with NIR irradiation improved the inflamed conditions in mice with collagen-induced arthritis (CIA). Additionally, in vitro experiments were applied to deeply verify the antirheumatic mechanisms of TP-PLGA-Au@RGD/HA hydrogels. TP-PLGA-Au@RGD/HA hydrogel treatment significantly reduced the migratory and invasive capacities of RA fibroblast-like synoviocytes (RA-FLS) in vitro, through the decrease of phosphorylation of mTOR and its substrates, p70S6K1, thus inhibiting the mTOR pathway.

The naturally occurring flavonoid nobiletin reverses methotrexate resistance via inhibition of P-glycoprotein synthesis.

Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp-mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp-induced drug efflux.

The endoplasmic reticulum participated in drug metabolic toxicity.

Covalent binding of reactive metabolites formed by drug metabolic activation with biological macromolecules is considered to be an important mechanism of drug metabolic toxicity. Recent studies indicate that the endoplasmic reticulum (ER) could play an important role in drug toxicity by participating in the metabolic activation of drugs and could be a primarily attacked target by reactive metabolites. In this article, we summarize the generation and mechanism of reactive metabolites in ER stress and their associated cell death and inflammatory cascade, as well as the systematic modulation of unfolded protein response (UPR)-mediated adaptive pathways.

Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator.

Paclitaxel is a widely used anti-tumor chemotherapeutic drug. Solvent-based paclitaxel causes bone marrow suppression, allergic reactions, neurotoxicity and systemic toxicity, which are associated with non-specific cytotoxicity and side effects of fat-soluble solvents. Studies have explored various new nano-drug strategies of paclitaxel, including nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to improve the water solubility and safety of paclitaxel. Nab-paclitaxel is a targeted solvent-free formulation that inhibits microtubule depolymerization to anticancer. It is easily taken up by tumor and immune cells owing to the nano-scaled size and superior biocompatibility. The internalized nab-paclitaxel exhibits significant immunostimulatory activities to promote cancer-immunity cycle. The aim of this study was to explore the synergistic effect of nab-paclitaxel in tumor antigen presentation, T cell activation, reversing the immunosuppressive pattern of tumor microenvironment (TME), and the synergistic effect with cytotoxic lymphocytes (CTLs) in clearance of tumor cells. The effects of nab-paclitaxel on modulation of cancer-immunity cycle, provides potential avenues for combined therapeutic rationale to improve efficacy of immunotherapy.

Arsenic compounds: The wide application and mechanisms applied in acute promyelocytic leukemia and carcinogenic toxicology.

Arsenic (As), as well as its various compounds have been widely used for nearly 4000 years either as drugs or poisons. These compounds are valuable in the treatment of various diseases ranging from dermatosis to cancer, thereby emphasizing their important roles as therapeutic agents. The ability of As compounds, especially arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL), has fundamentally altered people's understanding of the poison, and has become a major factor in the re-emergence of Western medicine candidates to treat leukemia and other solid tumors. However, long-term exposure to As has been correlated with numerous disadvantageous influences on health, particularly carcinogenesis. Importantly, accumulating evidence suggests that biotransformation of As, as a step to eliminate As from the human body, can induce alterations at the genetic and epigenetic levels, resulting in therapeutic effects or carcinogenesis. In this article, we aimed to provide a systematic overview of the primary contributions associated with As and its compounds, as well as the detailed mechanisms applied in APL cells and carcinogenic toxicology. This review may help to understand the underlying mechanisms and safe wide clinical applications of medicinal As along with its compounds.

Hierarchical drug release designed Au @PDA-PEG-MTX NPs for targeted delivery to breast cancer with combined photothermal-chemotherapy.

Breast cancer (BC) is the most frequently diagnosed cancer with a low survival rate and one of the major causes of cancer-related death. Methotrexate (MTX) is an anti-tumor drug used in the treatment of BC. Poor dispersion in water and toxic side effects limit its clinical application. Gold nanoparticles (AuNPs), owing to their specific structures and unique biological and physiochemical properties, have emerged as potential vehicles for tumor targeting, bioimaging and cancer therapy. An innovative nano drug-loading system (Au @PDA-PEG-MTX NPs) was prepared for targeted treatment of BC. Au @PDA-PEG-MTX NPs under near infra-red region (NIR) irradiation showed effective photothermal therapy against MDA-MB-231 human BC cells growth in vitro by inducing apoptosis through triggering reactive oxygen species (ROS) overproduction and generating excessive heat. In vivo studies revealed deep penetration ability of Au @PDA-PEG-MTX NPs under NIR irradiation to find application in cancer-targeted fluorescence imaging, and exhibited effective photothermal therapy against BC xenograft growth by inducing apoptosis. Histopathological analysis, cellular uptake, cytotoxicity assay, and apoptosis experiments indicated that Au @PDA-PEG-MTX NPs possessed a good therapeutic effect with high biocompatibility and fewer side effects. This Au NPs drug-loading system achieved specific targeting of MTX to BC cells by surface functionalisation, fluorescence imaging under laser irradiation, combined photothermal-chemotherapy, and pH- and NIR- triggered hierarchical drug release.

The Role of miRNA in Tumor Immune Escape and miRNA-Based Therapeutic Strategies.

Tumor immune escape is a critical step in the malignant progression of tumors and one of the major barriers to immunotherapy, making immunotherapy the most promising therapeutic approach against tumors today. Tumor cells evade immune surveillance by altering the structure of their own, or by causing abnormal gene and protein expression, allowing for unrestricted development and invasion. These genetic or epigenetic changes have been linked to microRNAs (miRNAs), which are important determinants of post-transcriptional regulation. Tumor cells perform tumor immune escape by abnormally expressing related miRNAs, which reduce the killing effect of immune cells, disrupt the immune response, and disrupt apoptotic pathways. Consequently, there is a strong trend toward thoroughly investigating the role of miRNAs in tumor immune escape and utilizing them in tumor treatment. However, because of the properties of miRNAs, there is an urgent need for a safe, targeted and easily crossed biofilm vehicle to protect and deliver them in vivo, and exosomes, with their excellent biological properties, have successfully beaten traditional vehicles to provide strong support for miRNA therapy. This review summarizes the multiple roles of miRNAs in tumor immune escape and discusses their potential applications as an anti-tumor therapy. Also, this work proposes exosomes as a new opportunity for miRNA therapy, to provide novel ideas for the development of more effective tumor-fighting therapeutic approaches based on miRNAs.