ABSTRACT
Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca2+ under acidic conditions and self-assemble into an active mode to cleave heat shock protein (HSP) mRNA by consuming the oncogene miRNA-21. Silencing miRNA-21 enhances the expression of the tumor suppressor gene PTEN, leading to PTT sensitization. Meanwhile, curcumin maintains high intracellular Ca2+ to further suppress HSP-chaperone ATP by disrupting mitochondrial Ca2+ homeostasis. Therefore, pancreatic cancer is triple-sensitized to IR780-mediated PTT. The in vitro and in vivo results show that the MNAzyme-based nanomachine can strongly regulate HSP and PTEN expression and lead to significant pancreatic tumor inhibition under laser irradiation.
Subject(s)
Curcumin , DNA, Catalytic , MicroRNAs , Nanoparticles , Neoplasms , Pancreatic Neoplasms , Humans , Photothermal Therapy , Curcumin/pharmacology , Polyethylene Glycols/chemistry , Pancreatic Neoplasms/therapy , MicroRNAs/genetics , Oligopeptides , Cell Line, Tumor , Nanoparticles/chemistry , Phototherapy/methods , Pancreatic NeoplasmsABSTRACT
Di-(2-ethylhexyl)-phthalate (DEHP) is the most commonly used plasticizer and it has been a ubiquitous environmental contaminant which affects health. The purpose of this study was to investigate the protective effect of the Lycium barbarum polysaccharide (LBP) at dosages of 100, 200, and 300 mg/kg bw on DEHP-induced (3000 mg/kg) toxicity in rat liver through a 28-day animal experiment. The results showed that LBP attenuated oxidative stress slightly by lowering the production of ROS and improving the activity of SOD and GSH-Px in liver and serum of DEHP treatment rats. At the same time, the levels of PXR, CYP450, CYP2E1, CYP3A1, UGT1, and GST were reduced after LBP treatment. Moreover, LBP decreased the mRNA expression of PXR, UGT1, and GST significantly. These findings suggested that LBP might ameliorate DEHP-induced liver injury by down-regulating the expression of PXR in liver, further down-regulating the downstream phase I and II detoxification enzymes, thus reducing the damage caused by DEHP. Therefore, LBP may have the potential to become an auxiliary therapeutic agent as a natural ingredient of health food.
Subject(s)
Diethylhexyl Phthalate , Drugs, Chinese Herbal , Lycium , Phthalic Acids , Animals , Diethylhexyl Phthalate/metabolism , Diethylhexyl Phthalate/toxicity , Drugs, Chinese Herbal/pharmacology , Liver/metabolism , Oxidative Stress , Phthalic Acids/metabolism , RatsABSTRACT
Targeted theranostic platform that integrates multi-modal imaging and therapeutic function is emerging as a promising strategy for earlier detection and precise treatment of cancer. Herein, we designed targeted gold-nanoshelled poly (lactic-co-glycolic acid) (PLGA) magnetic hybrid nanoparticles carrying anti-human epidermal growth factor receptor 2 (Her2) antibodies (Her2-GPH NPs) for dual-modal ultrasound (US)/magnetic resonance (MR) imaging and photothermal therapy of breast cancer. The agent was fabricated by coating gold nanoshell around PLGA nanoparticles co-loaded with perfluorooctyl bromide (PFOB) and superparamagnetic iron oxide nanoparticles (SPIOs), followed by conjugating with anti-Her2 antibodies. Cell-targeting studies demonstrated receptor-mediated specific binding of the agent to Her2-positive human breast cancer SKBR3 cells, and its binding rate was significantly higher than that of Her2-negative cells (P < 0.001). In vitro, the agent had capabilities for contrast-enhanced US imaging as well as T2-weighted MR imaging with a relatively high relaxivity (r2 = 441.47 mM-1 s-1). Furthermore, the Her2 functionalization of the agent prominently enhanced the US/MR molecular imaging effect of targeted cells by cell-specific binding. Live/dead cell assay and targeted photothermal cytotoxicity experiments confirmed that Her2-GPH NPs could serve as effective photoabsorbers to specifically induce SKBR3 cell death upon near-infrared laser irradiation. In summary, Her2-GPH NPs were demonstrated to be novel targeted theranostic agents with great potential to facilitate early non-invasive diagnosis and adjuvant therapy of breast cancer.