Separation, enrichment and cytoprotection of antioxidant peptides from Xuanwei ham using aqueous two-phase extraction.

An ethanol/(NH4)2SO4 biphasic (aqueous two-phase) system was designed to effectively separate antioxidant peptides from Xuanwei ham, and its potential to prevent ultraviolet A-induced damage to skin cells was explored. Optimization via single factor experiments and response surface methodology revealed that under 20 % ethanol aqueous solution (w/w), 25.5 % (NH4)2SO4 aqueous solution (w/w), and pH 8.80 conditions, the optimal extraction ratio was 59.0 ± 1.73 %. In vitro antioxidant activity and cellular assays showed that the peptide purified in the upper phase exhibited strong antioxidant activity, increasing the viability of HaCat cells damaged by UVA irradiation from 56.14 ± 1.05 % to 66.3 ± 1.76 %. We used an in silico peptide screening strategy and identified 10 with potential antioxidant activity, emphasizing the important role of amino acids Pro, Gly, and Ala in antioxidant activity.

Fractional extraction of lignin from coffee beans with low cytotoxicity, excellent anticancer and antioxidant activities.

Lignin, a biopolymer generated from renewable resources, is widely present in terrestrial plants and possesses notable biosafety characteristics. The objective of this work was to assess the edible safety, in vitro antioxidant, and anti-cancer properties of various lignin fractions isolated from commercially available coffee beans often used for coffee preparation. The findings suggest that the phenolic hydroxyl content increased from 3.26 mmol/g (ED70L) to 5.81 mmol/g (ED0L) with decreasing molecular weight, which resulted in more significant antioxidant properties of the low molecular weight lignin fraction. The findings of the study indicate that the viability of RAW 264.7 and HaCaT cells decreased as the quantity of lignin fractions increased. It was observed that concentrations below 200 µg/mL did not exhibit any harmful effects on normal cells. The results of the study demonstrated a significant reduction of cancer cell growth (specifically A375 cells) at a concentration of 800 µg/mL for all lignin fractions, with an observed inhibition rate of 95 %. The results of this study indicate that the lignin extracts derived from coffee beans exhibit significant potential in mitigating diseases resulting from excessive radical production. Furthermore, these extracts show promise as natural antioxidants and anti-cancer agents.

Transepithelial transport and cytoprotection of novel antioxidant peptides isolated from simulated gastrointestinal digestion of Xuanwei ham.

As a traditional fermented meat product, dry-cured Xuanwei ham could be a rich source of bioactive peptides. This study intended to investigate the transepithelial transport and cytoprotection of antioxidant peptides isolated from simulated gastrointestinal digestion of Xuanwei ham. Through ultrafiltration and gel filtration chromatography after simulated digestion, five new antioxidative cell-penetrating peptides (CPPs) with 16-27 amino acid residues were identified, and protective effects of the pretreatment with GHYTEGAELVDSVLDVVRK (GK-19) and TDEFQLHTNVNDGTEFGGSIYQK (TK-23) on H2O2-induced damaged HepG2 cells were investigated. The results showed that the peptide TK-23 at 0.5 mg mL-1 showed a good antioxidant activity through upregulating the activity of antioxidant enzymes (CAT, SOD and GR) and decreasing the MDA level in H2O2-induced damaged HepG2 cells with a better protective effect compared to GSH. Our observations of novel antioxidant CPPs with 16-27 amino acid residues could enrich the antioxidative CPP database, and these findings could provide data support for further study of CPPs.

Tumor-specific cyclic amplification of oxidative stress by disulfide-loaded fluoropolymer nanogels.

Amplification of intracellular oxidative stress has been found to be an effective strategy to induce cancer cell death. Herein, the effect of a disulfide, 2,2'-dithiobis(5-aminopyridine) (BAPS), is revealed on depleting glutathione (GSH) circularly and generating superoxide anion (O2•-) spontaneously to manipulate intracellular redox homeostasis. Thus, BAPS is able to work as an oxidative stress amplifier in cancer cells with high GSH concentrations and kill them efficiently. Moreover, leveraging a new class of water-soluble fluoropolymers poly(N-(2-((2,2,2-trifluoroethyl)sulfonyl)ethyl)acrylamide) (PFSNM), BAPS, together with oxygen, can be effectively delivered into hypoxic tumor cells through circulation and significantly inhibit the tumor growth. Therefore, BAPS-loaded PFSNM is an oxidative regulation nanosystem with remarkable therapeutic efficacy for chemodynamic therapy.

NIR Responsive Injectable Nanocomposite Thermogel System Against Osteosarcoma Recurrence.

Compared to traditional postoperative radiation and chemotherapy, immune checkpoint blockade (ICB) therapy demonstrates superiority by provoking own immune system to cure cancer completely even for some terminally ill patients. However, systemic administration of ICB is liable to cause severe immunity inflammation or immune storm. Here, an injectable, near infrared (NIR) responsive, multifunctional nanocomposite thermogel as a local ICB delivery system for cancer postsurgical therapy is proposed. By copolymerization of thermosensitive and zwitterionic monomer, the injectable thermogel with adjustable sol-gel transition temperature is obtained. Afterward, combined with functional mesoporous nanoparticles, the platform can absorb NIR light and transfer it into heat. The generated heat will promote retro Diels-Alder (D-A) reaction to degrade coating layer on nanoparticle, achieving NIR controlled ICB release. Furthermore, the local ICB delivery system is applied on an osteosarcoma postsurgical recurrence model and results indicate the platform with favorable biocompatibility can avoid early leakage of cargos and greatly increase drug content at tumor site. Besides, long-term controlled ICB release of the system effectively improves the amount of active T cells, resulting in excellent antitumor recurrence effect. Overall, this work suggests the local injectable nanocomposite thermogel is expected to be a promising tool for cancer postoperative therapy.

Simvastatin induced ferroptosis for triple-negative breast cancer therapy.

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 (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@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 Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.

A phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug with a long circulation time and charged conversion for enhanced chemotherapy.

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.

Zwitterionic Polymer Coating of Sulfur Dioxide-Releasing Nanosystem Augments Tumor Accumulation and Treatment Efficacy.

Multiple drug resistance (MDR) exhibited by cancer cells and low intratumor accumulation of chemotherapeutics are the main obstacles in cancer chemotherapy. Herein, the preparation of a redox-responsive sulfur dioxide (SO2 )-releasing nanosystem, with high SO2 -loading capacity, aimed at improving the treatment efficacy of cancers exhibiting MDR is described. The multifunctional nanomedicine (MON-DN@PCBMA-DOX) is designed and constructed by coating mesoporous organosilica nanoparticles with a zwitterionic polymer, poly(carboxybetaine methacrylate) (PCBMA), which can concurrently load SO2 prodrug molecules (DN, 2,4-dinitrobenzenesulfonylchloride) and chemotherapeutics (DOX, doxorubicin). The generated SO2 molecules can sensitize cells to chemotherapy and overcome the MDR by downregulating the expression of P-glycoprotein. Furthermore, the PCBMA coating prolongs the blood circulation time of the inner core, leading to an increased intratumor accumulation of the nanomedicine. Owing to the prolonged blood circulation, enhanced tumor accumulation, and SO2 sensitization of cells to chemotherapy, the nanomedicine exhibits excellent tumor suppression with a tumor inhibition rate of 94.8%, and might provide a new platform for cancer therapy.

Biodegradable zwitterionic polymer membrane coating endowing nanoparticles with ultra-long circulation and enhanced tumor photothermal therapy.

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.

Multifunctional Mesoporous Polydopamine With Hydrophobic Paclitaxel For Photoacoustic Imaging-Guided Chemo-Photothermal Synergistic Therapy.

BACKGROUND: Chemo-photothermal therapy has attracted intensive attention because of its low side effects and better therapeutic efficiency. Although many photothermal agents have been loaded with chemotherapeutic drugs for chemo-photothermal therapy, their applications are limited by complex synthetic protocols and long-term safety. Therefore, there is significant clinical value in the development of a simple system of biocompatible and biodegradable photothermal nanomaterials with high payloads of chemotherapeutic drugs for chemo-photothermal synergistic therapy. MATERIALS AND METHODS: In this study, PEG-modified polydopamine nanoparticles with mesoporous structure (MPDA-PEG) were successfully obtained by an emulsion-induced interface assembly strategy. Subsequently, paclitaxel (PTX) dissolved in acetone was loaded into the mesoporous channels of MPDA-PEG nanoparticles by solution absorption method. A PTX-loaded MPDA-PEG (MPDA-PEG-PTX) nanoplatform for combination of photothermal therapy (PTT) and chemotherapy was developed. RESULTS: The synthesized MPDA-PEG nanoparticles had a great photothermal effect under near-infrared (NIR) laser irradiation and exhibited an enhanced photothermal effect with the increase of particle size. Meanwhile, MPDA-PEG nanoparticles also had a high payload of PTX, and the PTX release could be greatly accelerated by elevated temperature from photothermal effect. In MTT cytotoxicity assay, A549 cells incubated with MPDA-PEG-PTX under NIR laser irradiation (PTT + chemotherapy group) exhibited better therapeutic effect than single chemotherapy (MPDA-PEG-PTX group) and PTT (MPDA-PEG + Laser group). The synergistic therapeutic effect of MPDA-PEG-PTX with NIR laser irradiation in vivo was further investigated under the guidance of photoacoustic imaging (PAI), tumors of nude mice treated with MPDA-PEG-PTX with NIR laser irradiation were completely eliminated with minimal side effect. CONCLUSION: The MPDA-PEG-PTX nanoplatform is a simple and effective platform which can completely inhibit tumor growth with minimal side effects under NIR irradiation, and it exhibits better therapeutic effect than single chemotherapy and PTT.

Multifunctional nanoplatform for photoacoustic imaging-guided combined therapy enhanced by CO induced ferroptosis.

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.

Biodegradable phosphorylcholine-based zwitterionic polymer nanogels with smart charge-conversion ability for efficient inhibition of tumor cells.

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.

Compensating Unknown Time-Varying Delay in Opto-Electronic Platform Tracking Servo System.

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.