Moreover, TNF-α inhibition attenuated the Mn-induced activation of IKK-β and YY1. Taken together, Mn-induced oxidative stress and TNF-α mediates activation of NF-κB signaling and YY1 upregulation, leading to repression of EAAT2. Thus, targeting reactive oxygen species (ROS), TNF-α and IKK-β may attenuate Mn-induced YY1 activation and consequent EAAT2 repression.Cancer is the second leading cause of death in the world. Some of the usual cancer treatments include surgery, chemotherapy, and radiotherapy. However, due to low efficacy and side effects of these treatments, novel targeted therapeutic methods are needed. One of the common drawbacks of cancer chemotherapy is off-target toxicity. In order to overcome this problem, many investigations have been conducted. One of the new targeted therapy methods known as bacterial directed enzyme-prodrug therapy (BDEPT) employs bacteria as enzyme carriers to convert a pro-drug to a drug specifically within the tumor site. In the present study, we used Escherichia coli DH5α carrying luxCDABE gene cluster and overexpressing β-glucuronidase for luminescent emission and enzyme expression, respectively. Enzyme expression can lead to the conversion of glycyrrhizic acid as a prodrug to glycyrrhetinic acid, a potent anti-cancer agent. DH5α-lux/βG was characterized and its stability was also evaluated. Bacteria colonization in the tumor site was measured by tissue homogenate preparation and colony counting method. Histopathological studies on the liver, spleen, and tumor were also conducted. According to the results, co-treatment of 4T1, a highly metastatic mouse breast cancer cell line, with GL and DH5α-lux/βG could significantly decrease the IC50 values. Moreover, increased number of bacteria could lead to a dramatic drop in IC50 value. Specific colonization of DH5α-lux/βG was observed in the tumor site compared with other tissues (p less then 0.0001). Moreover, the biocompatibility evaluation proved that DH5α-lux/βG had no adverse effects on normal tissues. Furthermore, concurrent usage of GL and bacteria in the treatment of induced 4T1 tumors in BALB/c mice significantly delayed tumor growth (p less then 0.001) during 16 days of investigation. Based on these findings, BDEPT might be useful for targeted breast cancer therapy, although further investigations are required to confirm this.Intracellular ions played prominent part in cell function and behavior. Disrupting intracellular ions homeostasis might switch ions signal from „regulating“ to „destroying“. Inspired by this, we introduced the ions interference strategy for tumor therapy. Herein, curcumin (CUR) and transferrin (Tf) co-loaded calcium peroxide nanoparticles (CaO2 NPs) were formulated. With tumor targeting ability, CaO2/Tf/CUR pinpointed tumor cells and then instantaneously decomposed in acidic lysosomes, concurrently accompanying with the release of Ca2+ and CUR, as well as the production of H2O2. Then H2O2 not only damaged structure of Tf to release Fe3+, but also was converted to hydroxyl radicals via ferric ions mediated Fenton reaction for ferroptosis. In addition, the released Ca2+ and CUR induced Ca2+ overload via exogenous and endogenous calcium ions accumulation, respectively, further activating mitochondria apoptosis signaling pathway for cell injury. Therefore, based on calcium and ferric ions interference strategy, the cascade catalytic CaO2/Tf/CUR offered synergistic combination of ferroptosis, Ca2+ overload therapy and chemotherapy, which held a great promise in cancer treatment.The tissue-specific targeted delivery and efficient cellular uptake of siRNAs are the main obstacles to their clinical application. Antibody-siRNA-conjugates (ARCs) can deliver siRNA by exploiting the targeting property of antibodies like antibody-drug conjugates (ADCs). However, the effective conjugation of antibodies and siRNAs and the release of siRNAs specifically at target sites have posed challenges to the development of ARCs. In this study, the successful conjugation of antibodies and siRNAs was achieved using a multifunctional peptide as a linker, composed of a cell-penetrating peptide (CPP) and a substrate peptide (SP), which is highly expressed in solid tumors. The resulting antibody-multifunctional peptide (SP-CPP)-siRNA system delivered the siRNA to target tumor cells by the specific binding of the antibody. Once the enzymes on the tumor cell surface hydrolyzed the substrate peptide linker, siRNA-CPP was released from ARCs. The released siRNA-CPP entered the targeted cells via the cellular penetrating ability of CPP, resulting in improved siRNA-mediated gene silencing efficiency, verified both in vitro and in vivo. After intravenous administration, the designed ARCs achieved approximately 66.7% EGFP (Enhanced Green Fluorescent Protein) downregulation efficiency in nude mice xenografted with the HCT116-EGFP tumor model. The proposed system provides a prospective choice for ARC production and the safe and efficient delivery of siRNAs.

Targeted therapy exploits cancerous niches‘ properties including acidic extracellular environment, hypoxic tumor core, and over expression of tumor-specific surface antigens. The present study aims to develop and evaluate a sequential targeted core-shell nanoparticulate (NPs) system for treatment of breast cancer. Sequential (double-stage) targeting was achieved at the cellular-level through employing the selective CD44- receptor binding hyaluronic acid (HA), followed by subcellular mitochondrial drug-delivery using the mitotropic triphenylphosphonium-conjugated doxorubicin (DOX-TPP

).

NPs were prepared through incorporation of the electrostatic-complexes of DOX.HCl/DOX-TPP

with tripolyphosphate (STPP

) into chitosan (CS) forming the core that was further coated with HA shell. Physicochemical characterization techniques namely; FTIR, DSC, DLS, morphological evaluation and spectroscopic assessments were implemented. Moreover, the drug entrapment efficiency (EE%), loading capacity (LC%), drug release prSolid Ehrlich carcinoma (SEC)-bearing mice confirmed the efficient anticancer activity of the mitotropic DOX-TPP+-loaded NPs. Conclusively, the developed core-shell NPs proved efficient in sequential targeting of DOX to breast cancer.This paper presents a comprehensive assessment of the most widely used tablet compaction models in a continuous wet granulation tableting process. The porosity models, tensile strength models and lubricant models are reviewed from the literature and classified based on their formulations i.e. empirical or theoretical and applications, i.e. batch or continuous. The majority of these models are empirical and were initially developed for batch tabletting process. To ascertain their effectiveness and serviceability in the continuous tableting process, a continuous powder processing line of Diamond Pilot Plant (DiPP) installed at The University of Sheffield was used to provide the quantitative data for tablet model assessment. Magnesium stearate (MgSt) is used as a lubricant to investigate its influence on the tensile strength. Whilst satisfactory predictions from the tablet models can be produced, a compromise between the model fidelity and model simplicity needs to be made for a suitable model selection. The Sonnergaard model outperforms amongst the porosity models whilst the Reynolds model produces the best goodness of fitting for two parameters fitting porosity models. An improved tensile strength model is proposed to consider the influence of powder size and porosity in the continuous tableting process.The use of inorganic nanoparticles (NPs) gains interest for pharmaceutical applications, e.g. Veliparib ic50 as adjuvants or drug delivery vehicles. Colloidal stability of NPs in aqueous suspensions is a major development challenge. Both frozen and lyophilized liquids are alternative presentations to liquid dispersion. To improve the basic understanding, we investigated the freeze-thawing stability of model α-Al2O3 NPs. Freeze-thawing was conducted in three different buffer types at pH5 and 8 without and with additives to determine fundamental formulation principles. Before freeze-thawing, α-Al2O3 NPs could be stabilized in sodium citrate buffer at pH5 and 8, and in sodium or potassium phosphate at pH8. Particles revealed low zeta potential values in phosphate buffers at pH5 indicating insufficient electrostatic stabilization. After freeze-thawing, an increase in NP size was strongly reduced in potassium phosphate and sodium citrate buffers. Subsequent pH measurements upon freezing revealed a drastic acidic pH shift in sodium phosphate which was further demonstrated to destabilize NPs. The ionic stabilizers gelatin A/B, Na-CMC, and SDS, were suitable to improve colloidal stability in phosphate buffers at pH5 highlighting the importance of charge stabilization. Freeze-thawing stability was best in presence of gelatin A/B, followed by PVA, mannitol, or sucrose. Depletion and steric stabilization were insufficient using PEG and surfactants respectively. Thus, we could identify the fundamental formulation principles to preserve inorganic NPs upon freezing i) sufficient charge stabilization, ii) a maintained pH during freezing, and iii) the addition of a suitable stabilizer, preferably gelatin, not necessarily surfactants. This forms the basis for future studies, e.g. on lyophilization.The injectable hydrogel is an ideal reservoir for drug delivery. In this study, a new injectable DNA hydrogel was fabricated. Firstly, the DNA pre-gel was obtained by heat-cool treatments to induce cross-linkage through base-paring. Then, the pre-gel was cross-linked with chitosan (CS) through electrostatic interaction, which was confirmed by ATR-FTIR and XPS analysis. The DNA-CS hybrid gel showed finely tunable various properties such as porosity and viscosity. To simulate the biomedical application, the dexamethasone (Dex) was loaded into the gel and coated onto titanium implant surface to induce macrophages M2 polarization. Due to the excellent biocompatibility and Dex delivery, the decorated implant surface was favorable for RAW264.7 cells growth and showed powerful effects of inducing M2 polarization both in vitro and in vivo. In conclusion, it is the first report of DNA hydrogel synthesis via CS cross-linkage and the injectable DNA-CS hybrid gel was superb for therapeutic delivery.Inflammatory bowel disease (IBD) is a chronic and idiopathic inflammatory disorder affecting the gastrointestinal tract. The pharmacological treatments used currently for its treatment lack efficacy, so new therapeutic strategies should be developed. In this context, flavonoids loaded in biopolymeric nanoparticles can be considered as novel promising candidates. The aim of the present study was to evaluate the intestinal anti-inflammatory effects of quercetin when is administered loaded in silk fibroin nanoparticles (QSFN) in the dextran sulphate sodium experimental model of mouse colitis, which displays some similarities to human IBD. Previously characterized quercetin-loaded silk fibroin nanoparticles (QSFN). QSFN showed a reversible aggregation profile induced by the acidification of the solution but did not affect the loaded quercetin. Daily administration of QSFN significantly reduced disease activity index values compared to the control colitic group. This beneficial effect was not only corroborated by the histological examination of the colonic specimens but also the improvement of the colonic expression of the different proinflammatory cytokines (Tnf-α, Il-1β, Il-6, Mcp-1, Icam-1, Nlrp3 and iNOS).