Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, ...unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe
O
@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe
O
@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe
O
@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe
O
have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe
O
@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.
This paper investigates the problem of compensating miss-distance delay in opto-electronic platform tracking servo system. According to the characteristic of LOS (light-of-sight) motion, we setup the ...Markovian process model and compensate this unknown time-varying delay by feed-forward forecasting controller based on robust H∞ control. Finally, simulation based on double closed-loop PI (Proportion Integration) control system indicates that the proposed method is effective for compensating unknown time-varying delay. Tracking experiments on the opto-electronic platform indicate that RMS (root-mean-square) error is 1.253 mrad when tracking 10° 0.2 Hz signal.
Benign prostatic hyperplasia (BPH) is an age-related disease and characterized by nonmalignant enlargement of the prostate gland. Currently, it’s etiology remains unclear. A previous report showed ...that autophagy is decreased in the human BPH cell line (BPH-1) compared with the normal prostate cells (RWPE-1). The purpose of this study was to investigate whether cordycepin (3′-deoxyadenosine) could alleviate BPH through activating autophagy in BPH-1 cells. BPH-1 cells were treated 100 μM cordycepin for 48-h and BPH-related markers, such as androgen receptor (AR), 5-alpha reductase 2 (5AR-2), prostate-specific antigen (PSA), and apoptosis-related markers (Bax and BCL-2) were examined via RT-qPCR, cell proliferation rates were measured via MTT assay, cell cycle-related proteins (Cdk1 and Cyclin B1), pro-inflammatory cytokines (TNF-α and IL-1β), and autophagy flux were determined via immunoblot. Treatment with 100 μM of cordycepin significantly decreased on AR (~63%), 5AR-2 (~46%), and PSA (~68%) mRNA expression levels in BPH-1 cells (
p
< 0.05). Cordycepin significantly decreased cell proliferation rates (~29%), Cdk1 (~65%), Cyclin B1 (~43%), and both TNF-α (~55%) and IL-1β (~60%) protein levels in BPH-1 cells (
p
< 0.05). Cordycepin (100 μM) significantly enhanced autophagy flux in accordance with increased AMPK and decreased ribosomal protein S6 (mTOR substrate) phosphorylation. These positive effects of cordycepin appear to occur via AMPK-mTOR-dependent autophagy signaling mechanism. This study suggests that cordycepin is a potent autophagy activator and a promising agent for the treatment of BPH and other autophagy-impaired diseases.
A multifunctional CO/thermo/chemotherapy nanoplatform is here reported, which is composed of mesoporous carbon nanoparticles (MCN) as near infrared (NIR)-responsive drug carrier, doxorubicin (DOX) as ...chemotherapeutic drug and triiron dodecacarbonyl (FeCO) as thermosensitive CO prodrug. The nanoplatform could absorb near-infrared (NIR) light and convert it into ample heat to trigger CO release and could also release DOX in the acidic tumor microenvironment. More importantly, the generated CO molecules successfully increase cancer cell sensitivity to chemotherapeutics by the ferroptosis pathway. Subsequently, under the guidance of photoacoustic imaging, the FeCO-DOX@MCN nanoplatform demonstrates high treatment efficacies in vitro and in vivo by combination of chemotherapy, photothermal therapy and gas therapy. This multifunctional platform with excellent antitumor efficacy has great potential in precision cancer therapy.
The aim of this work is to introduce a simple and rapid method for characterizing the molecular weight parameters and other molecular structure parameters of natural rubber (NR) using a rubber ...process analyzer (RPA). In this work, NR of different molecular weights was prepared by milling. Molecular weight parameters were measured by gel permeation chromatography coupled with laser light scattering (GPC-LLS) for comparison with RPA results. It was verified that increasing of milling time leads to a decrease of the number-average molecular weight (M-n), weight-average molecular weight (M-w), and molecular weight distribution (MWD). The dynamic and rheological properties were evaluated on RPA by tests of strain sweep, frequency sweep, and stress relaxation. These results were used to characterize the average molecular weight, MWD, and viscosity of NR and were found to agree with those from GPC-LLS. This convenient and rapid technology for characterizing NR molecular weight parameters would be especially useful in the elastomer industry.
Biodegradable phosphorylcholine-based zwitterionic polymer nanogels with charge-conversion ability at tumor extracellular pH were fabricated by one-step reflux precipitation polymerization, leading ...to the enhanced tumor cellular uptake and controlled drug release.
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Zwitterionic polymer nanocarriers have attracted much attention in recent years due to their desirable biocompatibility and anti-fouling properties. However, the super-hydrophilic and neutral charge of zwitterionic polymer results in weak interactions with negatively charged cell membranes, which leads to suboptimal uptake by tumor cells. Herein, a series of biodegradable poly(2-methacryloyloxyethyl phosphorylcholine-s-s-vinylimidazole) (PMV) nanogels with uniform spherical shape was fabricated by one-step reflux precipitation polymerization, which was clean and efficient. The PMV nanogels remained in zwitterionic state at physiological pH (pH 7.4) and were converted rapidly to positive charged state at tumor extracellular pH (pH 6.5). Proton nuclear magnetic resonance spectra and acid-base titration experiment proved that the charge-conversion ability of PMV nanogels was attributed to protonation of the imidazole ring in an acidic environment. Protein stability experiment showed that PMV nanogels exhibited a protein-adsorption resistance at pH 7.4 for as long as 7 days while adsorbed protein rapidly at pH 6.5. Moreover, PMV nanogels showed a reducing-labile property, which was able to degrade into short linear polymer chains in the presence of reduction agents. Therefore, the doxorubicin (DOX) release profile was controlled finely with a low DOX leakage under physiological conditions (7.8% in 48 h) and a rapid DOX release in 10 mM glutathione at pH 7.4 (78.9% in 48 h). Confocal laser scanning microscope and flow cytometry showed that the PMV nanogels exhibit an enhanced cellular uptake by tumor cells at pH 6.5 compared with pH 7.4, which allows for a severe cytotoxic effect of DOX-loaded PMV nanogels against tumor cells.
Long blood circulation is the basic requirement of advanced drug delivery systems for tumor treatment, which leads to enhanced tumor therapeutic efficiency and reduced side effects. However, the ...pharmacokinetics of the current nanoparticles in vivo is still unsatisfactory, which leads to limited success to translate nanoparticles into clinical applications. Inspired by the natural cell membrane-coating strategy, a series of zwitterionic polymer membranes are firstly developed and coated onto different kinds of nanoparticles in this work. Intriguingly, the zwitterionic polymer membrane shows stronger protein adsorption resistance and reduced macrophage uptake compared with the corresponding zwitterionic polymer brush or the red blood cell (RBC) membrane, which results in longer blood circulation time and higher tumor accumulation of the coated nanoparticles. Combined with the photothermal effect of model nanoparticles, Fe3O4, zwitterionic polymer membrane-coated Fe3O4 shows enhanced photothermal therapy (PTT) efficacy on A549 tumors compared with the corresponding zwitterionic polymer brush or RBC membrane-coated Fe3O4. Notably, Fe3O4 coated by carboxybetaine-based biomimic membranes exhibits the ultra-long blood circulation (t1/2 = 96.0 h) and strongest PTT efficacy compared with those coated by phosphorylcholine-based or sulfobetaine-based biomimic membranes. In addition, the zwitterionic biomimic membrane exhibits rapid glutathione-triggered degradation with the products of low molecular weight (<2000 g mol−1). Therefore, the biodegradable zwitterionic biomimic membrane coating offers a universal platform for the design and application of long-circulating biomedical nanoparticles, which may pave the way for the clinical applications of biomedical nanoparticles in tumor therapy.
•Twelve different steel core structures are tested under drop-hammer impact tests.•Measured dynamic responses were observed to differ by type of sandwich structure.•Detailed FE models were developed ...and validated by the drop-hammer impact tests.•Sandwich structures with strong energy absorption stability were identified.•The results of multi-objective optimization show that the HT-F is most suitable for engineering applications.
This study aims to explore the dynamic crushing behaviors of a series of sandwich structures with varying configurations, which are composed of ultra-high performance fiber reinforced concrete (UHPFRC) face sheets and cores of steel and polyurethane (PU) foam. Drop-hammer impact tests were performed on 12 sandwich structure specimens, including four types (traditional frame (TF), ectopic frame (EF), corrugated plate (CP), and horizontal tube (HT)). The force profiles of EF type and HT type, compared with the other types, possessed low peak impact force (PIF) and high plateau force under the same impact energy. Test results indicated that the polyurea sprayed on the UHPFRC face did not affect the crashworthiness. Increases in core thickness can improve mean crushing force (MCF). The crashworthiness of the sandwich structure without the UHPFRC face sheet was weakened. The values of peak crushing force (PCF), MCF, energy absorption (EA), and specific energy absorption (SEA) under dynamic loading were greater than those in quasi-static loading. Finite element (FE) models were developed, validated, used to explore the energy absorption behavior in detail, and proved that EF-type and HT-type structures possess strong energy absorption stability. The multi-objective optimization showed that the HT-F structure is more suitable for practical applications.
In recent years, zeolitic imidazolate framework-8 (ZIF-8) has become an attractive metal organic framework (MOF) material in drug delivery for cancer chemotherapy. However, as a drug delivery system, ...ZIF-8 still shows some disadvantages, such as short blood circulation time and poor tumor targeting, leading to reduced drug delivery efficiency and unsatisfactory treatment. Herein, we developed a phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug (DOX@ZIF-8@P(MPC-co-C7A)), and the obtained nanodrug was prepared via a charge-conversional zwitterionic copolymer coating on DOX@ZIF-8 composites. In this system, DOX was encapsulated in the framework of ZIF-8, which could reduce the drug leakage in the bloodstream. The phosphorylcholine-based zwitterionic copolymer effectively extended the blood circulation time, resulting in enhanced tumor accumulation of the nanodrug. Once the nanodrug reached the tumor site, the surface charge of the system could rapidly convert to positive, resulting in an enhanced tumor cellular uptake. Finally, in the acidic environment inside intracellular organelles, DOX will be released rapidly for chemotherapy owing to the fast disintegration of ZIF-8 frameworks. Therefore, the obtained nanodrug could effectively inhibit the growth of A549-bearing tumors (93.2% tumor inhibition rate) with negligible side effects. Overall, this work significantly improved the drug delivery efficiency of ZIF-8, which may pave the way for the biomedical applications of ZIF-8 crystals in anti-tumor drug delivery.
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•A self-association zwitterionic hydrogel was prepared by simple copolymerization.•The hydrogel had suitable elasticity and electrical excellent ionic conductivity.•The hydrogel ...enhanced the maturation and functionalization of cardiomyocytes.•The hydrogel promoted electrical signal transfer and cell synchronous contraction.•The hydrogel derived cardiac patches improved the restoration of cardiac function.
In recent years, engineered cardiac patch (ECP) with electrical conductivity has been developed for cardiac repair after injury or infarction. However, the application of traditional conductive polymers in ECP is still limited due to their toxicity and difficulty in dispersing and degradation. Herein, a self-association crosslinked conductive zwitterionic hydrogel was developed by simple copolymerization of zwitterionic monomer carboxybetaine methacrylate (CBMA) and a biocompatible monomer hydroxyethyl methacrylate (HEMA). The fabricated p(CBMA-co-HEMA) hydrogel possessed excellent ionic conductivity, suitable compressive and stretchable properties, self-healing and mechanical sensory capability. In vitro, the zwitterionic hydrogel significantly enhanced the functionalization of the cardiomyocytes, resulting in excellent synchronous contraction by increasing the expression of cardiac-related factor α-actinin and transmission electrical signal-relevant Connexin-43 (CX-43). In vivo, the hydrogel-derived functional patch effectively promoted the transmission of electrophysiological signals, improved revascularization in infarcted area and then remarkably restored the cardiac function. These data indicated that our developed conductive zwitterionic hydrogel has good promise in repairing myocardial tissue injury.
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