"Shell-Core" Bilayer Nanoparticle as Chemotherapeutic Drug Co-Delivery Platforms Render Synchronized Microenvironment Respond and Enhanced Antitumor Effects.

Background: Synergistic chemotherapy has been proved as an effective antitumor means in clinical practice. However, most co-administration treatment often lacks simultaneous control over the release of different chemotherapeutic agents. Materials and Methods: ß-cyclodextrin modified hyaluronic acid was the "shell", and the oxidized ferrocene-stearyl alcohol micelles served as the "core", where doxorubicin (DOX) and curcumin (CUR) were loaded in shell and core of the bilayer nanoparticles (BNs), respectively. The pH- and glutathione (GSH)-responsive synchronized release behavior was evaluated in different mediums, and the in vitro and in vivo synergistic antitumor effect and CD44-mediated tumor targeting efficiency were further investigated. Results: These BNs had a spherical structure with the particle size of 299 ± 15.17 nm, while the synchronized release behaviour of those two drugs was proved in the medium with the pH value of 5.5 and 20 mM GSH. The co-delivery of DOX and CUR reduced the IC50 value by 21% compared to DOX alone, with a further 54% reduction after these BNs delivery measurements. In tumor-bearing mouse models, these drug-loaded BNs showed significant tumor targeting, enhanced antitumor activity and reduced systemic toxicity. Conclusion: The designed bilayer nanoparticle could be considered as potential chemotherapeutic co-delivery platform for efficient synchronized microenvironment respond and drug release. Furthermore, the simultaneous and synergistic drug release guaranteed the enhanced antitumor effects during the co-administration treatment.

Nitrogen and bromine co-doped carbon dots with red fluorescence for sensing of Ag+ and visual monitoring of glutathione in cells.

Carbon dots (CDs) with red fluorescence emission have excellent advantages in cell imaging. Herein, novel nitrogen and bromine doped CDs (N,Br-CDs) were prepared with 4-bromo-1,2-phenylenediamine as precursor. The N, Br-CDs present the optimal emission wavelength at 582 nm (λex = 510 nm) at pH 7.0 and 648 nm (λex = 580 nm) at pH 3.0 âˆ¼ 5.0, respectively. The fluorescence intensity of N,Br-CDs at 648 nm versus Ag+ concentration shows a good relationship from 0 to 60 µM with the limit of detection (LOD) of 0.14 µM. Furthermore, the fluorescence of N,Br-CDs/Ag+ is efficiently restored via the combination of glutathione (GSH) and Ag+ and linearly changes with GSH concentration from 0 âˆ¼ 6.0 µM with LOD of 49 nM. This method has been successfully employed to monitor intracellular Ag+ and GSH with fluorescence imaging. The results suggest that the N,Br-CDs has application potential in the sensing of Ag+ and visual monitoring of GSH in cells.

BAO-Ag-NPs as Promising Suppressor of ET-1/ICAM-1/VCAM-1 Signaling Pathway in ISO-induced AMI in Rats.

OBJECTIVES: Acute myocardial infarction (AMI) is the most prevalent cause of myocardial fibrosis and the leading cause of mortality from cardiovascular disease. The goal of this work was to synthesize Balanites aegyptiaca oil-silver nanoparticles (BAO-Ag-NPs) and evaluate their cardioprotective effect against ISO-induced myocardial infarction in rats, as well as their mechanism. METHODS: BAO was isolated, and the unsaturated fatty acids were estimated. BAO-Ag-NPs was prepared, LD50 was calculated to evaluate its cardioprotective activity against ISO (85 mg/kg)- induced AMI. Different doses of BAO-Ag-NPs (1/50 LD50; 46.6 mg/kg.b.w and 1/20 LD50; 116.5 mg) were received to the rats. RESULTS: The total fatty acids and unsaturated fatty acids generated by BAO were 909.63 and 653.47 mg/100 g oil, respectively. Oleic acid methyl ester, 9-Octadecenoic acid methyl ester, and 9, 12-Octadecadienoic acid methyl ester were the predominant ingredients, with concentrations of 107.6, 243.42, and 256.77 mg/100 g oil, respectively. According to TEM and DLS examinations, BAO-Ag-NPs have a size of 38.20±2.5 nm and a negative zeta potential of -19.82 ± 0.30 mV, respectively. The LD50 of synthesized BAO-Ag-NPs is 2330 mg. On the other hand, BAO-Ag-NPs reduce myocardial necrosis by lowering increased BNP, cTnI, CK-MB, TC, TG, MDA, MMP2, TGF-ß1, PGE2, and IL-6 levels. Furthermore, BAO-Ag-NPs inhibit the expression of ET-1, ICAM-1, and VCAM-1 genes. BAO-Ag-NPs given to ISO-treated rats enhance HDL-C, CAT, and GSH levels when compared to the ISO-treated group of rats. Histopathological findings suggested that BAO-Ag-NPs enhance cardiac function by increasing posterior wall thickness in heart tissues. CONCLUSION: BAO-Ag-NPs protect against AMI in vivo by regulating inflammation, excessive autophagy, and oxidative stress, as well as lowering apoptosis via suppression of the ET-1, ICAM-1, and VCAM-1 signaling pathways.

Albumin-binding prodrugs via reversible iminoboronate forming nanoparticles for cancer drug delivery.

Albumin-based nanomedicines are important nanoplatforms for cancer drug delivery. The drugs are either physically encapsulated or covalently conjugated to albumin or albumin-based nanosystems. Physical encapsulation is advantageous due to requiring no chemical modification of drug molecules, but many drugs, for instance, camptothecin (CPT) and curcumin (CCM), though very hydrophobic, can't be loaded in or form nanoformulations with albumin. Herein, we demonstrate prodrugs readily binding to proteins via iminoboronates and forming nanoparticles for cancer drug delivery. CPT and CCM were functionalized with 2-acetylphenylboronic acid (2-APBA) to produce prodrugs CPT-SS-APBA and CCM- APBA. The prodrugs bound to bovine serum albumin (BSA) via formation of iminoboronates and the produced BSA/prodrug readily self-assembled into well-defined nanoparticles with high loading efficiency, improved colloidal stability, and much-improved pharmacokinetics. The nanoparticles effectively released drugs in the intracellular acidic environment or the cytosol rich in glutathione (GSH). In vivo, the nanoparticles showed enhanced anticancer efficacy compared with clinically used irinotecan or sorafenib in subcutaneous 4 T1 or HepG2 tumor models. This work demonstrates a versatile protein-binding prodrug platform applicable to protein-based drug formulations and even antibody-drug conjugates.

Casein kinase 2 inhibition attenuates cholesterol oxidation product-induced apoptosis by suppressing the activation of the mitochondrial pathway and the caspase-8- and bid-dependent pathways.

Protein casein kinase 2 is involved in signal transduction, cell growth and apoptosis. However, it is unclear whether the cholesterol oxidation product-induced cell death is regulated by casein kinase 2. Therefore, in the respect of the cell death process, we assessed the regulatory effect of the casein kinase 2 on the cholesterol oxidation product-induced apoptosis in neuronal cells using differentiated PC12 cells. Casein kinase 2 inhibitors (4,5,6,7-tetrabromobezotriazole (TBB) and apigenin) which do not have toxic effects, reduced the 7-ketocholesterol or 25-hydroxycholesterol-induced cell death and nuclear damage in PC12 cells. Treatment with TBB inhibited the 7-ketocholesterol-induced decrease in Bid, Bcl-2 and survivin protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), cleavage of PARP-1, and increase in the tumor suppressor p53 levels. The results showed that the casein kinase 2 inhibitor at the concentrations tested which does not induce toxic effects, may attenuate the cholesterol oxidation product-induced apoptosis in differentiated PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect appears to be ascribed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH.

A study on the antioxidant effect of Coriolus versicolor polysaccharide in rat brain tissues.

The objective of the study was to investigate the antioxidant effect of Chinese medicine Coriolus versicolor polysaccharide on brain tissue and its mechanism in rats. SOD, MDA and GSH-Px levels in rat brain tissues were determined with SD rats as the animal model. The results showed that Coriolus versicolor polysaccharide can reduce the lipid peroxidation level in brain tissues during exhaustive exercise in rats, and can accelerate the removal of free radicals. The study concluded that its antioxidant effect is relatively apparent.

Refolding of the recombinant protein Sm29, a step toward the production of the vaccine candidate against schistosomiasis.

Schistosomiasis is an important parasitic disease, with about 240 million people infected worldwide. Humans and animals can be infected, imposing an enormous social and economic burden. The only drug available for chemotherapy, praziquantel, does not control reinfections, and an efficient vaccine for prophylaxis is still missing. However, the tegumental protein Sm29 of Schistosoma mansoni was shown to be a promising antigen to compose an anti-schistosomiasis vaccine. Though, recombinant Sm29 is expressed in Escherichia coli as insoluble inclusion bodies requiring an efficient process of refolding, thus, hampering its production in large scale. We present in this work studies to refold the recombinant Sm29 using high hydrostatic pressure, a mild condition to dissociate aggregated proteins, leading to refolding on a soluble conformation. Our studies resulted in high yield of rSm29 (73%) as a stably soluble and structured protein. The refolded antigen presented protective effect against S. mansoni development in immunized mice. We concluded that the refolding process by application of high hydrostatic pressure succeeded, and the procedure can be scaled-up, allowing industrial production of Sm29.