Simvastatin (SV) repurposing has emerged as an alternative approach for the treatment of cancer. In this study, SV chitosan nanoparticles co-crosslinked with tripolyphosphate and chondroitin sulfate (SVCSChSNPs) were developed in order to maximize SV therapeutic efficiency. The hepatic targeting was realized using N-acetylgalactosamine (GalNAc) residues of ChS, which can be identified by the ASGPR receptors specifically expressed in hepatocytes. SV was repurposed as an anticancer agent against hepatocellular carcinoma (HCC). NPs were fabricated by the ionic gelation method, and the formulation variables (CS concentration, CS:ChS ratio, and CS solution pH) were optimized using a three-factor, three-level Box-Behnken design. The optimized NPs were investigated for particle size, size distribution, zeta potential, morphology, in vitro cytotoxicity, apoptotic effects against human hepatocellular carcinoma HepG2 cells, and detection of intracellular localization. The NPs were further evaluated for in vitro release behavior of SV and pharmacokinetics using Wister albino rats. Transmission electron microscopy (TEM) imaging showed a spherical shape with regular surface NPs of < 100 nm diameter. In vitro cytotoxicity testing showed that the SVCSChSNPs exhibited greater inhibition of proliferation in HepG2 cells and high cellular uptake through ASGPR-mediated endocytosis. The in vitro dissolution profile was 2.1-fold greater than that of pure SV suspension. Furthermore, in vivo oral pharmacokinetics revealed that the obtained NPs enhanced the bioavailability of SV by up to 2- and 1.6-fold for SV and SVA, respectively, compared to the pure SV suspension. These findings demonstrated that hepatic-targeted CSChSNPs delivering SV could potentially serve as a promising platform for HCC and other liver-related diseases.

The study aimed to develop a new glutathione (GSH) oral formulation to enhance the delivery of GSH and counter the nephrotoxicity of the anticancer drug, cyclophosphamide (CP). A nanostructured lipid carrier glutathione formulation (GSH-NLCs) composed of glutathione (500 mg), stearic and oleic acid (300 mg, each), and Tween^® 80 (2%, w/v) was prepared through the emulsification-solvent-evaporation technique, which exhibited a 452.4 ± 33.19 nm spheroidal-sized particulate material with narrow particle size distributions, −38.5 ± 1.4 mV zeta potential, and an entrapment efficiency of 79.8 ± 1.9%. The GSH formulation was orally delivered, and biologically tested to ameliorate the CP-induced renal toxicity in a rat model. Detailed renal morphology, before and after the GSH-NLCs administration, including the histopathological examinations, confirmed the ameliorating effects of the prepared glutathione formulation together with its safe oral delivery. CP-induced oxidative stress, superoxide dismutase depletion, elevation of malondialdehyde levels, depletion of Bcl-2 concentration levels, and upregulated NF-KB levels were observed and were controlled within the recommended and near normal/control levels. Additionally, the inflammatory mediator marker, IL-1β, serum levels were marginally normalized by delivery of the GHS-NLCs formulation. Oral administration of the pure glutathione did not exhibit any ameliorating effects on the renal tissues, which suggested that the pure glutathione is reactive and is chemically transformed during the oral delivery, which affected its pharmacological action at the renal site. The protective effects of the GSH-NLCs formulation through its antioxidant and anti-inflammatory effects suggested its prominent role in containing CP-induced renal toxicity and renal tissue damage, together with the possibility of administrating higher doses of the anticancer drug, cyclophosphamide, to achieve higher and effective anticancer action in combination with the GSH-NLCs formulation.

Tumor necrosis factor (TNF‐α) and inflammatory cytokine (IL‐6) play a vital role in various cellular incidents such as the proliferation and death of cells during carcinogenesis. Hence, regulation of these biomarkers could be a promising tool for controlling tumor progression using nanoformulations. Silver nanoparticles‐poly (vinyl pyrrolidone) (AgNPs‐PVP) were prepared using the reduction of silver nitrate and stabilized with PVP. They are characterized through yield percentage, UV‐VIS, FT‐IR, size, charge, and morphology. The obtained AgNPs were tested for anticancer activity against prostate cancer (PC 3) and human skin fibroblast (HFS) cell lines. Moreover, biomarker‐based confirmations like TNF‐α and IL‐6 were estimated. The synthesized AgNPs‐PVP were stable, spherical in shape, with particle sizes of 122.33 ± 17.61 nm, a polydispersity index of 0.49 ± 0.07, and a negative surface charge of −19.23 ± 0.61 mV. In vitro cytotoxicity testing showed the AgNPs‐PVP exhibited antiproliferation properties in PC3 in a dose‐dependent manner. In addition, when compared to control cells, AgNPs‐PVP has lower TNF‐α with a significant value ( ^∗p < 0.05); the value reached 16.84 ± 0.71 pg/ml versus 20.81 ± 0.44 pg/ml, respectively. In addition, HSF cells showed a high level of reduction ( ^∗∗∗p < 0.001) in IL‐6 production. This study suggested that AgNPs‐PVP could be a possible therapeutic agent for human prostate cancer and anti‐IL‐6 in cancerous and noncancerous cells. Further studies will be performed to investigate the effect of AgNPs‐PVP in different types of cancer.

Aim: This study aimed to explore an affordable technique for the fabrication of Chitosan Nanoshuttles (CSNS) at the ultrafine nanoscale less than 100 nm with improved physicochemical properties, and cytotoxicity on the MCF-7 cell line. Background: Despite several studies reported that the antitumor effect of CS and CSNS could achieve intracellular compartment target ability, no enough information is available about this issue and further studies are required to address this assumption. Objectives: The objective of the current study was to investigate the potential processing variables for the production of ultrafine CSNS (less than; 100 nm) using Box-Behnken Design factorial design (BBD). This was achieved through a study of the effects of processing factors, such as CS concentration, CS/TPP ratio, and pH of the CS solution, on PS, PDI, and ZP. Moreover, the obtained CSNS was evaluated for physicochemical characteristics, morphology. In addition, hemocompatibility and cytotoxicity using Red Blood Cells (RBCs) and MCF-7 cell lines were investigated. Methods: Box-Behnken Design factorial design (BBD) was used in the analysis of different selected variables. The effects of CS concentration, sodium tripolyphosphate (TPP) ratio, and pH on particle size, Polydispersity Index (PDI), and Zeta Potential (ZP) were measured. Subsequently, the prepared CS nanoshuttles were exposed to stability studies, physicochemical characterization, hemocompatibility, and cytotoxicity using red blood cells and MCF-7 cell lines as surrogate models for in vivo study. Result: The present results revealed that the optimized CSNS has ultrafine nanosize, (78.3 ± 0.22 nm), homogenous with PDI (0.131 ± 0.11), and ZP (31.9 ± 0.25 mV). Moreover, CSNS has a spherical shape, amorphous in structure, and physically stable. Moreover, CSNS has biological safety as indicated by a gentle effect on red blood cell hemolysis, besides, the obtained nanoshuttles decrease MCF-7 viability. Conclusion: The present findings concluded that the developed ultrafine CSNS has unique properties with enhanced cytotoxicity, thus promising for use in intracellular organelles drug delivery.

Theophylline-loaded bovine serum albumin (BSA) microsphereswere prepared by an emulsion polymerization method usingglutaraldehyde as the crosslinking agent. The study was designedto evaluate the effects of different formulation parameters as BSAconcentration, surfactant concentration, hydrophilic lipophilicbalance (HLB), dispersion medium viscosity and glutaraldehydeconcentration on the extent of drug loading, size of microsphereand the in-vitro as well as the in-vivo release rates of theophyllinefrom such microspheres. Drug polymer ratios of 1:1, 1:2, 1:3, 1:4, 1:5 and 1:6 were investigated. Span 80 was used as a surfactant atdifferent concentrations. Moreover, Different span 80 / tween 80blend concentrations; 0.5, 1.0 and 2.0% w/v were used to study theeffect of HLB. Also different dispersion media; isooctane, lightparaffin oil, olive oil and Linseed oil were used for microspherespreparation. In addition, different glutaraldehyde concentrations;5, 10 and 25% v/v were used. It was found that all micro-sphereswere spherical with the mean particle size of 90-180 μm. Theresults revealed also that: as the concentration of BSA increases,the drug loading is increased. Increasing surfactant concentrationand viscosity of the dispersion medium has led to decrease theparticle size, while increasing glutaraldehyde concentration nearlyhad no effect. Furthermore, encapsulation efficiency was found tobe directly proprortional to albumin content, surfactantconcentration, viscosity of the dispersion medium andglutaraldehyde concentration. Drug release from the preparedmicrospheres displayed a biphasic pattern characterized by aninitial burst, followed by a slower release period, which may beattributed to the presence of theophylline material near to or ontothe microspheres surfaces. The bioavailability of theophylline fromthe prepared microspheres was evaluated in rabbits. The preparedmicrospheres were found to control theophylline release even up to10 hrs. The peak serum concentrations of such microspheres werewithin the therapeutic level. The results indicate also that theprevioiusly mentioned formulation parameters have a prnouncedimpact to control the release of the entrapped drug.