ICAM-1 targeted thermal-sensitive micelles loaded with tofacitinib for enhanced treatment of rheumatoid arthritis via microwave assistance.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease without effective treatment. Tofacitinib (TOF) is a JAK inhibitor that can be used for RA therapy, but it still faces the problems of nonspecific distribution and relatively low therapeutic effect. Herein, ICAM-1-modified TOF-loaded P(AN-co-AAm)-PEG micelles (AI-TM) were developed, which can result in an enhanced RA therapy when combining with microwave hyperthermia (MH). It was found that AI-TM could rapidly release the encapsulated TOF under a thermal condition of >43 °C, which was due to the fact that the polymeric micelles has an upper critical solution temperature (UCST) of 43 °C. AI-TM could specifically distribute into the inflamed joints of RA mice, which is associated with the high affinity between anti-ICAM-1 and overexpressed ICAM-1 receptors. Moreover, the combination of AI-TM and MH could result in a remarkably enhanced anti-rheumatic activity, which was related to the RA-targeted ability of AI-TM, the rapid TOF release under MH, and the combined effect between TOF and MH treatment. Our study definitely provides a novel strategy for effective treatment of RA.

Abscisic acid inhibited reactive oxygen species-mediated endoplasmic reticulum stress by regulating the PPAR-γ signaling pathway in ARDS mice.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of a respiratory disorder, and there are few effective therapies. Abscisic acid (ABA) has been proven to be effective in influenza and asthma. Herein, we explored the protective effect of ABA on the resolution of ARDS and the underlying mechanism. Mice were challenged with lipopolysaccharide (LPS) to establish an ARDS model. We found that ABA reduced pulmonary injury, with concomitant suppression of endoplasmic reticulum (ER) stress and reduction of reactive oxygen species (ROS) production. Furthermore, after the elimination of ROS by the specific inhibitor N-acetyl-L-cysteine (NAC), ABA did not further inhibit airway inflammation or ER stress in ARDS mice. In addition, ABA inhibited ROS production through nuclear factor erythroid 2-related factor 2 (Nrf2) activation in parallel with elevated levels of peroxisome proliferator activated receptor γ (PPAR-γ). Furthermore, the addition of a PPAR-γ antagonist abrogated the suppressive action of ABA on inflammation as well as on ER stress and oxidative stress, while NAC restored the protective effect of ABA in ARDS mice treated with a PPAR-γ antagonist. Collectively, ABA protects against LPS-induced lung injury through PPAR-γ signaling, and this effect may be associated with its inhibitory effect on ROS-mediated ER stress.

Microwave hyperthermia-responsible flexible liposomal gel as a novel transdermal delivery of methotrexate for enhanced rheumatoid arthritis therapy.

Methotrexate (MTX) as an anti-inflammatory drug for the treatment of rheumatoid arthritis (RA) through oral and injectable administration is still problematic in the clinic. Herein, a MTX-loaded thermal-responsible flexible liposome (MTFL) incorporated within a carbomer-based gel was prepared as a novel transdermal agent (MTFL/Gel) for effective treatment of RA. It was found that MTFL had an average size of approximately 90 nm, which could rapidly release the drug under thermal conditions. The prepared MTFL/Gel could remarkably increase the MTX skin permeation as compared with free MTX, which was possibly due to the deformable membrane of flexible liposomes. Moreover, the results suggested MTFL/Gel could lead to a remarkably enhanced RA treatment when in combination with microwave hyperthermia. The superior ability of MTFL/Gel to alleviate RA response was attributed to the excellent skin permeation, thermal-responsible drug release, and synergistic anti-arthritic effect of MTX chemotherapy and microwave-induced hyperthermia therapy. Overall, the MTFL/Gel with dual deformable and thermal-responsible performances could be used as a novel promising transdermal agent for enhanced treatment of RA.

NIR-Triggered Sequentially Responsive Nanocarriers Amplified Cascade Synergistic Effect of Chemo-Photodynamic Therapy with Inspired Antitumor Immunity.

A desirable cancer therapeutic strategy is supposed to have effective ability to not only exert maximum anticancer ability but also inspire antitumor immunity for preventing tumor relapse and metastasis. During this research, multifunctional upconversion nanoparticles (UCNPs) coated by ROS-responsive micelles are prepared for tumor targeting and near-infrared (NIR)-triggered photodynamic therapy (PDT)-combined synergistic effect of chemotherapy. Moreover, both PDT and chemotherapy agents could activate antitumor immunity via inducing immunogenic cell death with CD8+ and CD4+ T cells infiltrating in tumors. Through the experiments, intravenous administration of multifunctional nanocarriers with noninvasive NIR irradiation destroys the orthotopic tumors and efficiently suppresses lung metastasis in a metastatic triple-negative breast cancer model by cascade-amplifying chemo-PDT and systemic antitumor immunity. In conclusion, this study provides prospective chemo-PDT with inspired antitumor immunity for metastatic cancer treatment.

Sinomenine hydrochloride loaded thermosensitive liposomes combined with microwave hyperthermia for the treatment of rheumatoid arthritis.

The conventional medications are still facing a huge challenge for the treatment of rheumatoid arthritis (RA). Thus, looking for an effective therapy of RA has became an urgent issue nowadays. In this study, a novel thermosensitive liposome loaded with sinomenine hydrochloride (SIN-TSL) was developed by a pH gradient method. The SIN-TSL had a mean particle size of around 100 nm, and an high entrapment efficiency and drug loading capacity. The results also suggested that SIN-TSL had a thermosensitive drug release behaviour, with the drug release rate at 43 °C was much faster than the one at 37 °C. The SIN-TSL could be effectively taken up by lipopolysaccharide-activated HUVECs, without any cytotoxicity was observed. In addition, both in vitro and in vivo studies indicated that the SIN-TSL combined with microwave hyperthermia exhibited superior anti-rheumatoid arthritis effect. Overall, these results suggest that SIN-loaded thermosensitive liposomes combined with microwave hyperthermia could provide an optional strategy for alleviating the clinical symptoms of RA.