Nanomaterials as Smart Immunomodulator Delivery System for Enhanced Cancer Therapy.

Immunomodulatory therapeutics, which is conducive to overcoming tumor tolerance and restoring normal immune responses, has been proposed as a promising approach for enhanced cancer therapy and clinical advancement. However, issues including cytokine syndrome, inefficient delivery, hepatic dysfunction, and severe adverse reactions remain to be resolved. It is particularly critical to develop delivery technologies to overcome these limitations and further improve antitumor efficacy. With the continuous development of materials science, biomaterials have been widely used in the field of cancer treatment and have also provided exciting solutions to overcome the bottleneck of immunomodulatory therapeutics. A range of biomaterials, especially nanomaterials, has been developed as a local immunomodulatory platform to enhance targeted delivery, maintain drug stability, and reduce toxicity and side effects. In addition to single immunomodulatory therapeutics, nanomaterials have been demonstrated to possess significant potential in immunomodulatory therapeutics-based synergistic therapies, especially in combination with phototherapy, radiotherapy, chemotherapy, and immune checkpoint blockade. In this review, as background to the discussion of immunomodulatory therapeutics, we first described the mechanisms of action of multiple immunomodulators and discussed their current targeting agents. On this basis, we highlighted the latest advances in the use of nanomaterials-assisted immunomodulatory therapeutics and combination therapy to enhance anticancer immunity. In addition, current challenges and further promises for immunomodulatory therapeutics were also presented.

Gastric environment-stable oral nanocarriers for in situ colorectal cancer therapy.

Colorectal cancer (CRC) is a prevalent and fatal cancer. Oral administration provided the potential for in situ treatment of the colorectal cancer. However, drugs couldn't be well-absorbed mainly due to its degradation in the gastric area and poor intestinal permeability. In this study, we synthesized deoxycholic acid and hydroxybutyl decorated chitosan nanoparticles (DAHBC NPs) as oral curcumin (CUR) delivery system for colorectal cancer treatment. DAHBC with lower critical solution temperature (LCST) below 37 °C (27-33 °C) was obtained. DAHBC NPs were correspondingly stable in simulated gastric conditions (pH 1.2, 37 °C), due to the offset of size change between pH-responsive expansion and thermo-responsive shrinkage. In simulated intestinal tract (pH 7.0-7.4, 37 °C), DAHBC NPs exhibited burst release of CUR owing to the onefold effect of thermo-responsive shrinkage. DAHBC27 NPs showed the minimum CUR leakage (~10%) in simulated gastric conditions, because a furthest temperature-sensitive shrinkage caused by the lowest LCST offset the expansion in acid environment. DAHBC27 NPs induced ~10-fold increased (P < 0.05) CUR absorption by paracellular transport pathway, compared to the free CUR. Thus, DAHBC NPs stabilized in the gastric environment may be a promising oral drugs delivery system for effective in situ colorectal cancer therapy.

Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET.

Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFκB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.

Effect of cornuside on experimental sepsis.

This study was conducted to investigate the efficacy of cornuside, a secoiridoid glucoside compound, in cultured macrophages as well as in an experimental model of sepsis induced by cecal ligation and puncture (CLP) in rats. Cornuside was added to cultured macrophages at different concentrations, and all CLP rats were randomized to receive an intravenous injection of the corresponding drug followed by observation of its antisepsis effect. Our results showed that cornuside downregulated the levels of TNF- alpha, IL-6, and NO production in a dose-dependent manner in activated macrophages, while it upregulated the level of IL-10. Intravenous injection of cornuside or imipenem alone or in combination reduced CLP-induced lethality in rats after CLP. In addition, serum levels of TNF- alpha, IL-6, triggering receptor expressed on myeloid cells, and endotoxin were downregulated. On the other hand, the serum levels of IL-10 were upregulated. Decreased bacterial counts in blood, peritoneum, spleen, liver, and mesenteric lymph nodes and decreased myeloperoxidase in lung, liver, and small intestine also were found after cornuside injection. These data indicate that the antisepsis therapeutic effect of cornuside is mediated by decreased local and systemic levels of a wide spectrum of inflammatory mediators. This work provides first evidence for the clinic use of cornuside as a new immunomodulatory drug that has the capacity to inhibit the inflammatory response in sepsis.

Effects of scorpion venom bioactive polypolypeptides on platelet aggregation and thrombosis and plasma 6-keto-PG F1alpha and TXB2 in rabbits and rats.

Effects of scorpion venom active polypeptide (SVAP) from scorpion venom of Buthus Martensii Karsch of Chinese on platelet aggregation in ex vivo and vitro in rabbits, thrombosis in carotid artery of rats and plasma 6-keto-PG F1alpha and TXB2 in rats were studied by the turbidimetry, the duplicated thrombosis model by electrostimulation and RIA, respectively. The results showed that SVAP 0.125, 0.25, 0.5 mg/ml inhibited significantly the rabbit platelet aggregation triggered by 0.3 U/ml thrombin, 10 microM ADP in vitro (P<0.05 or 0.01) and SVAP at the dose of 0.32, 0.64 mg/kg iv prolonged distinctively the occlusion time of thrombosis that were induced by electrical stimulation. Increased% of 0.16, 0.32 and 0.64 mg/kg were 30.16, 71.74, 98.27%, respectively, which showed a good dose-effect relationship. SVAP 0.22 mg/ml (in vitro) or 0.2, 0.4 mg/kg (in ex vivo) could obviously increase the plasma concentration of 6-keto-PG F1alpha, but slightly effect rats plasma concentration of TXB2 in vitro and in ex vivo and significantly increase of value of PG I2/TXA2, which suggested that the mechanism of the antithrombotic action of SVAP is related to the resistance against platelet aggregation, increase of the concentration of PG I2 in plasma.