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Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%-30% 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Cationic liposomes contained -[1-(2,3-dioleoyloxy)propyl]- , , -trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl- -glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine-methyl-poly(ethylene glycol) (DSPE-mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE-mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels. Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS.

ABSTRACT Purpose To employ Doxorubicin-loaded liposomes, modified with YSA-peptide to target EphA2, to reduce adverse effects against primary bone cells and maximize toxicity against Saos-2 osteosarcoma cells. Methods PEGylated liposomes were prepared by thin film method using Dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearylphosphatidylethanolamine-polyethyleneglycol conjugate (DSPE-mPEG) in 67.9:29.1:3 M ratios, and loaded with DOX (L-DOX) by pH-gradient method. Targeted liposomes (YSA-L-DOX), were prepared by conjugating YSA-peptide to DSPE-mPEG. Liposomes were physicochemically characterized and tested in cellular toxicity assays. Results YSA conjugation efficiency was >98%. Size and polydispersity index of both L-DOX and YSA-L-DOX were around 88 nm and 0.188, respectively. Both had similar zeta potential, and 85% DOX loading efficiencies. DOX release kinetics followed the Korsmeyer-Peppa model, and showed comparable release for both formulations from 1–8 h, and a plateau of 29% after 48 h. Both formulations could be stably stored for ≥6 months at 4°C in the dark. Toxicity assays showed a significant 1.91-fold higher cytotoxicity compared to free DOX in the Saos-2 cells, and 2-fold lesser toxicity in primary bone cells compared to the Saos-2 cells. Cellular uptake studies showed higher and more nuclear uptake in YSA-L-DOX compared to L-DOX treated cells. Conclusions YSA-L-DOX vesicles might be effective for targeted treatment of osteosarcoma.

In this paper, a label-free aptamer based detection system (apta-DS) was investigated for detecting colon cancer cells. For this purpose, we employed an aptamer specific to colon cancer cells like HCT116 expressing carcinoembryonic antigen (CEA) on their surfaces. Capture aptamers were covalently immobilized on the surface of gold nanoparticles (GNPs) through self-assembly monolayer of 11-mercaptoundecanoic acid (11-MUA) activated with EDC (1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide)/N-hydroxysuccinimide (NHS). The cyclic voltammetry (CV) and chronopotentiometry (CP) methods were used for electrodeposition of GNPs on the surface of indium tin oxide (ITO). In this work, the CV method was also used to demonstrate the conjugation of GNPs and aptamers and identify the cancer cell capturing events. Additionally, Field Emission Scanning Electron Microscopy (FE-SEM) confirmed the deposition of GNPs on ITO and the immobilization of aptamer on the apta-DS. The electrodeposited GNPs played the role of nanoprobes for cancer cell targeting without losing the optical transparency of the ITO substrate. A conventional optical microscope also verified the detection of captured cancer cells. Based on this study’s results relying on electrochemical and optical microscopic methods, the proposed apta-DS is reliable and high sensitive with a LOD equal to 6 cell/mL for colon cancer detection.

This study aimed to evaluate a co-encapsulated pegylated nano-liposome system based on two herbal anti-tumor drugs, silibinin and glycyrrhizic acid, for delivery to a hepatocellular carcinoma (HCC) cell line (HepG2). In this experimental study, co-encapsulated nano-liposomes by the thin layer film hydration method with HEPES buffer and sonication at 60% amplitude. Liposomes that co-encapsulated silibinin and glycyrrhizic acid were prepared with a specified molar ratio of dipalmitoylphosphatidylcholine (DPPC), cholesterol (CHOL), and methoxy-polyethylene glycol 2000 (PEG2000)-derived distearoyl phosphatidylethanolamine (mPEG2000-DSPE). We used the MTT technique to assess cytotoxicity for various concentrations of co-encapsulated nano-liposomes, free silibinin (25% w/v) and glycyrrhizic acid (75% w/v) on HepG2 and fibroblast cell lines over a 48-hour period. Formulation of pegylated nano-liposomes showed a narrow size distribution with an average diameter of 46.3 nm. The encapsulation efficiency (EE) for silibinin was 24.37%, whereas for glycyrrhizic acid it was 68.78%. Results of in vitro cytotoxicity showed significantly greater co-encapsulated nano-liposomes on the HepG2 cell line compared to the fibroblast cell line. The half maximal inhibitory concentration (IC50) for co-encapsulated pegylated nanoliposomal herbal drugs was 48.68 µg/ml and free silibinin with glycyrrhizic acid was 485.45 µg/ml on the HepG2 cell line. This in vitro study showed that nano-liposome encapsulation of silibinin with glycyrrhizic acid increased the biological activity of free drugs, increased the stability of silibinin, and synergized the therapeutic effect of silibinin with glycyrrhizic acid. The IC50 of the co-encapsulated nano-liposomes was lower than the combination of free silibinin and glycyrrhizic acid on the HepG2 cell line.

Objective: In this study, we aimed to develop new Lipo-niosomes based nanoparticles loaded with Amphotericin B (AmB) and Thymus Essential Oil (TEO) and test their effectiveness in the treatment of fungal-infected human adipose stem cells (hASCs). Materials and Methods: In this experimental study, optimal formulation of AmB and TEO loaded lipo-niosome (based on lipid-surfactant thin-film hydration method) was chemically, and biologically characterized. Therefore, encapsulation capacity, drug release, size, and the survival rate of cells with different concentrations of free and encapsulated AmB/ TEO were evaluated using the MTT method, and its antifungal activity was compared with conventional AmB. Results: Lipo-Niosome containing Tween 60 surfactant: cholesterol: Dipalmitoyl phosphatidylcholine (DPPC): Polyethylene glycol (PEG) with a ratio of 20:40:60:3 were chosen as optimal formulation. Lipo-Niosomes entrapment efficiency was %94.15. The drug release rate after 24 hours was %52, %54, and %48 for Lipo-AmB, Lipo-TEO, and Lipo-AmB/TEO, respectively. Physical and chemical characteristics of the Lipo-Niosomes particles indicated size of 200 nm and a dispersion index of 0.32 with a Zeta potential of -24.56 mv. Furthermore, no chemical interaction between drugs and nano-carriers was observed. The cell viability of adipose mesenchymal stem cells exposed to 50 μg/ml of free AmB, free TEO, and free AmB/TEO was %13.4, %58, and %36.9, respectively. Whereas the toxicity of the encapsulated formulas of these drugs was %48.9, %70.8, and %58.3 respectively. The toxicity of nanoparticles was very low (%8.5) at this concentration. Fluorescence microscopic images showed that the antifungal activity of Lipo- AmB/TEO was significantly higher than free formulas of AmB, TEO, and AmB/TEO. Conclusion:In this study, we investigated the efficacy of the TEO/AmB combination, in both free and encapsulatedniosomal form, on the growth of fungal infected-hASCs. The results showed that the AmB/TEO-loaded Lipo-Niosomes can be suggested as a new efficient anti-fungal nano-system for patients treated with hASCs.

This paper reports the design and implementation of an aptasensor using a modified KCHA10a aptamer. This aptasensor consists of a functionalized electrodes using various materials including 11-mercaptoandecanoic acid (11-MUA) and modified KCHA10a aptamer. The HCT 116, HT 29 and HEp-2 cell lines are used in this study to demonstrate the functionality of aptasensor for colon cancer detection purposes. Flow cytometry, fluorescence microscopy and electrochemical cyclic voltammetry are used to verify the binding between the target cells and aptamer. The limit of detection (LOD) of this aptasensor is equal to seven cancer cells. Based on the experimental results, the proposed sensor can be employed for point-of-care cancer disease diagnostics.

In this study we prepared a novel formulation of liposomal doxorubicin (L- DOX). The drug dose was optimized by analyses of cellular uptake and cell viability of osteosarcoma (OS) cell lines upon exposure to nanoliposomes that contained varying DOX concentrations. We intended to reduce the cytotoxicity of DOX and improve characteristics of the nanosystems. In this experimental study, we prepared liposomes by the pH gradient hydration method. Various characterization tests that included dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo-TEM) imaging, and UV- Vis spectrophotometry were employed to evaluate the quality of the nanocarriers. In addition, the CyQUANT® assay and fluorescence microscope imaging were used on various OS cell lines (MG-63, U2-OS, SaOS-2, SaOS-LM7) and Human primary osteoblasts cells, as novel methods to determine cell viability and transfection efficacy. We observed an entrapment efficiency of 84% for DOX within the optimized liposomal formulation (L-DOX) that had a liposomal diameter of 96 nm. Less than 37% of DOX released after 48 hours and L-DOX could be stored stably for 14 days. L-DOX increased DOX toxicity by 1.8-4.6 times for the OS cell lines and only 1.3 times for Human primary osteoblasts cells compared to free DOX, which confirmed a higher sensitivity of the OS cell lines versus Human primary osteoblasts cells for L-DOX. We deduced that L- DOX passed more freely through the cell membrane compared to free DOX. We successfully synthesized a stealth L-DOX that contained natural phospholipid by the pH gradient method, which could encapsulate DOX with 84% efficiency. The resulting nanoparticles were round, with a suitable particle size, and stable for 14 days. These nanoparticles allowed for adequately controlled DOX release, increased cell permeability compared to free DOX, and increased tumor cell death. L-DOX provided a novel, more effective therapy for OS treatment.

Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%-30% 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Materials and methods: Cationic liposomes contained iV-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-xn-glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine--methyl-poly(ethylene glycol) (DSPE--mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE--mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels. Conclusion: Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS. Keywords: MAP kinase 8 interacting protein 1, MAPK8IP1, functionalization, cationic liposome, intracellular targeting, extracellular targeting

Improving production of bacteriorhodopsin in the culture medium of Halobacterium salinarum confronts indeterminacy related to culture conditions. Several studies have revealed that high oxygen content increases the growth of Halobacterium salinarum whereas it down-regulates the expression of genes responsible for bacteriorhodopsin production. The focus of this study was to clarify this contradictory role of oxygen in bacteriorhodopsin production and to indirectly regulate the oxygen content of the culture medium at a level that would increase the final concentration of bacteriorhodopsin. Oxygen consumption evaluation showed tha in a typical growth of Halobacterium salinarum at aerobic condition, the decrease in oxygen demand was concurrent with a sharp increase in bacteriorhodopsin production. Further investigation on culture conditions revealed that agitation rate and filling volume had a linear correlation with the cell growth and bacteriorhodopsin production by each cell, however, a two-factor interaction model described the relationship between the culture condition and overall bacteriorhodopsin concentration. It was concluded that although each cell of Halobacterium salinarum produced high amount of bacteriorhodopsin at low turbulence condition, the low yield of biomass production at this condition caused a low overall bacteriorhodopsin concentration. The highest overall bacteriorhodopsin concentration was obtained from high turbulence condition, in which cell numbers were high enough to compensate for low production of bacteriorhodopsin by each cell.

Essential oil (EO) of Zataria multiflora Bioss., contains components with antibacterial and antifungal properties that can be used as substitutes for synthetic drugs and food preservatives. These applications require appropriate carriers like nanoliposome. The purpose of this study was to encapsulate this EO into nanoliposomes. The EO was encapsulated into nanoliposomes by three different methods including thin film evaporation, ethanol injection and sonication methods. Formation of liposomes and their physical properties was studied by means of particle size, polydispersity index, zeta potential and encapsulation efficiency. In addition the changes in EO retention and mean size distribution were studied during one month of storage at 4±1 degrees Celsius. Liposomal systems prepared by sonication method with about 99 nm displayed the smallest mean size and better dispersivity. The encapsulation efficiency of nanoliposomes containing EO was in the following rank order: thin film evaporation > Ethanol Injection > sonication. Moreover, multilamellar vesicles liposomes prepared by the thin layer evaporation method showed better stability during storage.