ABSTRACT
Efficiently synergistic therapy of hepatocellular carcinoma (HCC) by chemotherapeutic drug and photothermal agent remains a considerable challenge. Here, we report a nanodrug that integrates specific hepatoma-targeted delivery, pH-triggered drug release, and cooperative photothermal-chemotherapy function. By grafting the easily self-assembled CuS@polydopamine (CuS@PDA) nanocapsulation with polyacrylic acid (PAA), an inorganic-organic-polymeric hybrid nanovehicle was developed as a dual photothermal agent and carrier for loading antitumor drug-doxorubicin (DOX) through electrostatic adsorption and chemical linking antibody against GPC3 commonly overexpressed in HCC, resulting in the nanodrug, CuS@PDA/PAA/DOX/GPC3. The multifunctional nanovehicle had excellent biocompatibility, stability, and high photothermal conversion efficiency, due to the rationally designed binary CuS@PDA photothermal agent. The 72-h accumulative drug release in pH 5.5 tumor microenvironment can reach up to 84%, far higher than 15% measured in pH 7.4 condition. Notably, in contrast to the merely 20% survival rate of H9c2 and HL-7702 cells exposed to free DOX, their viabilities in the nanodrug circumstance can maintain 54% and 66%, respectively, suggesting the abated toxicity to the normal cell lines. When exposed to the hepatoma-targeting nanodrug, the viability of HepG2 cells was found to be 36%, which further drastically declined to 10% plus 808-nm NIR irradiation. Moreover, the nanodrug is potent to cause tumor ablation in HCC-modeled mice, and the therapeutic efficacy can be greatly enhanced under NIR stimulus. Histology analyses reveal that the nanodrug can effectively alleviate the chemical damage to heart and liver, as compared to free DOX. This work thus offers a facile strategy for design of targeting anti-HCC nanodrug toward combined photothermal-chemotherapy.
Subject(s)
Carcinoma, Hepatocellular , Hyperthermia, Induced , Liver Neoplasms , Nanoparticles , Animals , Mice , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Doxorubicin , Hydrogen-Ion Concentration , Phototherapy , Drug Liberation , Tumor MicroenvironmentABSTRACT
OBJECTIVE: To study effects of Shenmai Injection on hypertensive heart failure and its mechanism for inhibiting myocardial fibrosis. METHODS: Salt-sensitive (Dahl/SS) rats were fed with normal diet (0.3% NaCl) and the high-salt diet (8% NaCl) to observe the changes in blood pressure and heart function, as the control group and the model group. Salt-insensitive rats (SS-13BN) were fed with the high-salt diet (8% NaCl) as the negative control group. After modeling, the model rats were randomly divided into heart failure (HF) group, Shenmai Injection (SMI) group and pirfenidone (PFD) group by a random number table, with 6 rats in each group. They were given sterilized water, SMI and pirfenidone, respectively. Blood pressure, cardiac function, fibrosis and related molecular expression were detected by sphygmomanometer, echocardiogram, enzyme linked immunosorbent assay (ELISA), hematoxylin-eosin staining, Masson staining, immunofluorescence and qPCR analysis. RESULTS: After high-salt feeding, compared with the control and negative control group, in the model group the blood pressure increased significantly, the left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) were significantly reduced, and the serum NT-proBNP concentration increased significantly (all P<0.05); furthermore, the arrangement of myocardial cells was disordered, the edema was severe, and the degree of myocardial fibrosis was also significantly increased (P<0.05); the protein and mRNA expressions of collagen type I (Col I) were up-regulated (P<0.05), and the mRNA expressions of transforming growth factor ß 1 (TGF- ß 1), Smad2 and Smad3 were significantly up-regulated (P<0.05). Compared with HF group, after intervention of Shenmai Injection, LVEF and LVFS increased, myocardial morphology was improved, collagen volume fraction decreased significantly (P<0.05), and the mRNA expressions of Col I, TGF- ß 1, Smad2 and Smad3, as well as Col I protein expression, were all significantly down-regulated (all P<0.05). CONCLUSION: Myocardial fibrosis is the main pathological manifestation of hypertensive heart failure, and Shenmai Injection could inhibit myocardial fibrosis and effectively improve heart failure by regulating TGF-ß 1/Smad signaling pathway.
Subject(s)
Heart Failure , Hypertension , Rats , Animals , Stroke Volume , Sodium Chloride , Rats, Inbred Dahl , Ventricular Function, Left , Transforming Growth Factor beta1/metabolism , Fibrosis , RNA, MessengerABSTRACT
Herein, we present the facile design and construction of a nanodrug system integrating targeted drug delivery and synergistic chemo-photothermal antitumor activity. MoS2 nanosheets were synthesized and modified by ανß3 integrin binding peptide (Arg-Gly-Asp, RGD) using lipoic acid functionalized polyethylene glycol (LA-PEG-COOH), forming a well dispersed and targeted delivery nanocarrier. Further, covalent coupling of antitumor drug, thiolated doxorubicin (DOX) via disulfide linkage resulted in a novel nanodrug, RGD/MoS2/DOX. The prepared nanocarrier showed favorable stability, biocompatibility and photothermal conversion efficiency. Fluorescence imaging revealed that Hela cells could endocytose far more nanodrug than H9c2 normal myocardial cells due to the targeted delivery characteristic. Particularly, GSH-induced disulfide bond cleavage facilitated the effective release of DOX from the nanodrug in the tumor microenvironment. The survival rate of Hela cells incubated with the nanodrug for 48 h was 22.2 ± 1.2%, which dramatically reduced to 8.9 ± 1.4% in combination with 808 nm NIR irradiation, demonstrating powerful photothermal induced tumor-killing efficacy. In contrast, the survival rates of H9c2 cells treated by the nanodrug and free DOX were 68.5 ± 2.6% and 6.7 ± 2.6%, respectively, an indication of the notably alleviated cardiotoxicity of the designed nanodrug. The cell apoptosis experiment further verified the synergistic chemo-photothermal effect, thus paving a way toward design of high-efficiency and low-toxicity antitumor nanodrug.
Subject(s)
Hyperthermia, Induced , Nanoparticles , Cell Line, Tumor , Disulfides/chemistry , Doxorubicin/chemistry , Drug Delivery Systems , Drug Liberation , HeLa Cells , Humans , Molybdenum/chemistry , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Oligopeptides , PhototherapyABSTRACT
OBJECTIVE: To investigate the utility of intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI) derived parameters in hypothalamus for monitoring the effect of Exendin-4 (Ex-4) intervention on the feeding behavior in obese diabetic rats within early feeding. METHODS: 21 obese and 19 non-obese rats which were treated with streptozotocin injections were initially divided into an obese diabetes group (OD, n = 10), a non-obese diabetes group (D, n = 8), an obese group (O, n = 9) and a non-obese group (N, n = 9). Then, the rats in the 4 groups received subcutaneous injections of Ex-4, and feeding behavior was examined at 5, 35, 65, 95, and 125 min. The hypothalamic function was evaluated by IVIM-DWI. Finally, the relationship between the hypothalamic function and the amount of food intake was analyzed. RESULTS: In comparison with the N group, the food intake significantly decreased in the O , OD, and D groups in response to Ex-4. Furthermore, a significant positive correlation was found between food intake and D values at different times from 5 to 125 min after Ex-4 intervention in all 4 groups. CONCLUSION: A direct correlation between the change of hypothalamic function and feeding behavior was detected in OD rats with Ex-4 intervention in the early feeding period. The hypothalamic D value derived from IVIM-DWI is promising to reflect the dynamic change of hypothalamic function due to intervention.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Exenatide/therapeutic use , Feeding Behavior/drug effects , Glucagon-Like Peptide-1 Receptor/agonists , Hypothalamus/drug effects , Obesity/drug therapy , Animals , Body Weight/drug effects , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Diffusion Magnetic Resonance Imaging , Eating/drug effects , Eating/physiology , Exenatide/pharmacology , Glucagon-Like Peptide-1 Receptor/metabolism , Male , Obesity/complications , Obesity/physiopathology , Rats , Rats, Sprague-DawleyABSTRACT
Nanochannels with functional elements have shown promise for DNA sequencing, single-molecule sensing, and ion gating. Ionic current measurement is currently a benchmark, but is focused solely on the contribution from nanochannels' inner-wall functional elements (NIWFE); the attributes of functional elements at nanochannels' outer surface (NOSFE) are nearly ignored, and remain elusive. Here we show that the role of NOSFE and NIWFE for ion gating can be distinguished by constructing DNA architectures using dual-current readout. The established molecular switches have continuously tunable and reversible ion-gating ability. We find that NOSFE exhibits negligible ion-gating behavior, but it can produce a synergistic effect in alliance with NIWFE. Moreover, the high-efficiency gating systems display more noticeable synergistic effect than the low-efficiency ones. We also reveal that the probe amount of NOSFE and NIWFE is almost equally distributed in our biomimetic nanochannels, which is potentially a premise for the synergistic ion-gating phenomena.
Subject(s)
Biomimetic Materials , Ion Channel Gating , Ion Transport , Nanostructures , Aluminum Oxide , Patch-Clamp TechniquesABSTRACT
Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and is able to stabilize the conformation of some ubiquitin E3 ligases. However, the role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is lacking. Here we showed that Skp1 was overexpressed in 36/64 (56.3%) of non-small cell lung cancers, and elevated Skp1 was associated with poor prognosis. By structure-based high-throughput virtual screening, we found some Skp1-targeting molecules including a natural compound 6-O-angeloylplenolin (6-OAP). 6-OAP bound Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and ß-TRCP, and accumulation of their substrates Cyclin B1, P27 and E-Cadherin. 6-OAP induced prometaphase arrest and exerted potent anti-lung cancer activity in two murine models and showed low adverse effect. These results indicate that Skp1 is critical to lung cancer pathogenesis, and Skp1 inhibitor inactivates crucial oncogenic E3 ligases and exhibits significant therapeutic potentials.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Lactones/pharmacology , Lung Neoplasms/metabolism , S-Phase Kinase-Associated Proteins/biosynthesis , Sesquiterpenes/pharmacology , Aged , Animals , Antineoplastic Agents/chemistry , Blotting, Western , Cell Survival/drug effects , Female , Flow Cytometry , Fluorescent Antibody Technique , High-Throughput Screening Assays , Humans , Immunoprecipitation , Lactones/chemistry , Male , Mice , Mice, Nude , Middle Aged , RNA, Small Interfering , S-Phase Kinase-Associated Proteins/analysis , S-Phase Kinase-Associated Proteins/antagonists & inhibitors , Sesquiterpenes/chemistry , Transfection , Xenograft Model Antitumor AssaysABSTRACT
The nematode Caenorhabditis elegans is a useful model host for pathogenesis research that can be infected by a large number of human pathogens. Conventionally, nematode-pathogen infection assays are mainly performed on agar medium which are labor-intensive and time-consuming. To overcome these challenges, we develop for the first time an integrated microfluidic device for evaluating in vivo antimicrobial activity of natural compounds, which allows infection and anti-infection assays to be sequentially and automatically carried out in liquid medium. The device consists of a worm dispenser with 32 trap-construction chambers and concentration gradient generators, in which the processes of introduction, dispensation, confinement of worms in the chamber and drug delivery to the chamber can be integrated into a single device. In addition, the operation of the device is simple and does not require any expensive robotic fluid handling systems to dispense samples. To demonstrate the ability of this device, we devise an on-line screening experiment using a Caenorhabditis elegans-Staphylococcus aureus infection model and characterize the survival rate of the infected worms treated with antibiotics. Then, we applied the system to evaluate the antibacterial activity of several components of rhubarb: aloe-emodin, rhein and emodin at various concentrations. The device is able to load uniform worms into each chamber within 10 min and then generate various chemical concentrations automatically and simultaneously. Furthermore, the on-chip method only requires 6 h to establish the infection model and 48 h to perform the subsequent treatments. Based on the excellent advantages and scalable properties of microfluidics, the microfluidic platform holds a great potential in high-throughput screening for antimicrobials.