Zinc nanoparticles coated with doxorubicin-conjugated alginate as a radiation sensitizer in triple-negative breast cancer cells.

The main treatment modalities for breast cancer include surgery, chemotherapy, and radiotherapy, and each treatment will bring different side effects. Design and synthesizing a novel nanostructure for chemo-radiotherapy has been proposed as an effective method in consideration to enhance the drug efficiency as well as improve the effect of radiotherapy. This study aimed to synthesize zinc nanoparticles (ZnNPs) coated with alginate conjugated with Doxorubicin (Dox) drug and investigate its effects along with X-irradiation on MDA-MB-231 triple-negative breast cancer cell line. ZnNPs coated with alginate were synthesized and conjugated to Dox by covalent bonding and characterized using various physicochemical tests. A hemolysis test was used to assess blood biocompatibility. The radiosensitization properties and anti-cancer effects of the synthesized nanostructures were tested by cell uptake, cell viability, apoptosis, cell cycle, and scratch assays with and without radiation exposure. The physicochemical characterization results showed that the synthesis of nanostructures was successfully carried out. The obtained results from the cell uptake assay showed the effective absorption of nanostructures by the cells. The Zn@Alg-Dox NPs significantly reduced cell growth, increased apoptosis, inhibited cell migration, and led to the arrest of different cell cycle phases in both conditions with and without X-ray exposure. Coating ZnNPs with alginate and Doxorubicin conjugation leads to an increase the radiation sensitivity in radiotherapy as well as therapeutic efficiency. Therefore, Zn@Alg-Dox NPs can be used as radiosensitizing nanomedicine for in vivo studies in the future.

Targeting c-Myc with decoy oligodeoxynucleotide-loaded polycationic nanoparticles inhibits cell growth and induces apoptosis in cancer stem-like cells (NTERA-2).

BACKGROUND: An increase in cancer stem cell (CSC) populations and their resistance to common treatments could be a result of c-Myc dysregulations in certain cancer cells. In the current study, we investigated anticancer effects of c-Myc decoy ODNs loaded-poly (methacrylic acid-co-diallyl dimethyl ammonium chloride) (PMA-DDA)-coated silica nanoparticles as carriers on cancer-like stem cells (NTERA-2). METHODS AND RESULTS: The physicochemical characteristics of the synthesized nanocomposites (SiO2@PMA-DDA-DEC) were analyzed using FT-IR, DLS, and SEM techniques. UV-Vis spectrophotometer was applied to analyze the release pattern of decoy ODNs from the nanocomposite. Furthermore, uptake, cell viability, apoptosis, and cell cycle assays were used to investigate the anticancer effects of nanocomposites loaded with c-Myc decoy ODNs on NTERA-2 cancer cells. The results of physicochemical analytics demonstrated that SiO2@PMA-DDA-DEC nanocomposites were successfully synthesized. The prepared nanocomposites were taken up by NTERA-2 cells with high efficiency, and could effectively inhibit cell growth and increase apoptosis rate in the treated cells compared to the control group. Moreover, SiO2@PMA-DDA nanocomposites loaded with c-Myc decoy ODNs induced cell cycle arrest at the G0/G1 phase in the treated cells. CONCLUSIONS: The conclusion drawn from this study is that c-Myc decoy ODN-loaded SiO2@PMA-DDA nanocomposites can effectively inhibit cell growth and induce apoptosis in NTERA-2 cancer cells. Moreover, given that a metal core is incorporated into this synthetic nanocomposite, it could potentially be used in conjunction with irradiation as part of a decoy-radiotherapy combinational therapy in future investigations.

Combinational therapy with Myc decoy oligodeoxynucleotides encapsulated in nanocarrier and X-irradiation on breast cancer cells.

The Myc gene is the essential oncogene in triple-negative breast cancer (TNBC). This study investigates the synergistic effects of combining Myc decoy oligodeoxynucleotides-encapsulated niosomes-selenium hybrid nanocarriers with X-irradiation exposure on the MDA-MB-468 cell line. Decoy and scramble ODNs for Myc transcription factor were designed and synthesized based on promoter sequences of the Bcl2 gene. The nanocarriers were synthesized by loading Myc ODNs and selenium into chitosan (Chi-Se-DEC), which was then encapsulated in niosome-nanocarriers (NISM@Chi-Se-DEC). FT-IR, DLS, FESEM, and hemolysis tests were applied to confirm its characterization and physicochemical properties. Moreover, cellular uptake, cellular toxicity, apoptosis, cell cycle, and scratch repair assays were performed to evaluate its anticancer effects on cancer cells. All anticancer assessments were repeated under X-ray irradiation conditions (fractionated 2Gy). Physicochemical characteristics of niosomes containing SeNPs and ODNs showed that it is synthesized appropriately. It revealed that the anticancer effect of NISM@Chi-Se-DEC can be significantly improved in combination with X-ray irradiation treatment. It can be concluded that NISM@Chi-Se-DEC nanocarriers have the potential as a therapeutic agent for cancer treatment, particularly in combination with radiation therapy and in-vivo experiments are necessary to confirm the efficacy of this nano-drug.

Targeted anti-tumor synergistic effects of Myc decoy oligodeoxynucleotides-loaded selenium nanostructure combined with chemoradiotherapy on LNCaP prostate cancer cells.

In the present study, we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells. Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays. ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure. The physicochemical characteristics of nanostructures were determined by FTIR, DLS, UV-vis, TEM, EDX, in vitro release, and hemolysis tests. Subsequently, the cytotoxicity properties of them with and without X-irradiation were investigated by uptake, MTT, cell cycle, apoptosis, and scratch assays on the LNCaP cell line. The results of DLS and TEM showed negative charge (-9 mV) and nanometer size (40 nm) for Se@BSA@Chi-DEC-MTX NPs, respectively. The results of FTIR, UV-vis, and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles. The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL. The ODNs release from the nanostructures showed a pH-dependent manner, and the release rate was 15% higher in acidic pH. The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen (PSMA). The significant synergistic effects of nanostructure (containing MTX drug) treatment along with X-irradiation showed cell growth inhibition, apoptosis induction (~57%), cell cycle arrest (G2/M phase), and migration inhibition (up to 90%) compared to the control. The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells. This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

Biogenic and facile synthesis of selenium nanoparticles using Vaccinium arctostaphylos L. fruit extract and anticancer activity against in vitro model of breast cancer.

Biogenic synthesis of selenium nanoparticles (SeNPs) using plant extracts has emerged as a promising alternative approach to traditional chemical synthesis. The current study aims to introduce a safe, low-cost, and green synthesis of SeNPs using fresh fruit extract of Vaccinium arctostaphylos L. The biogenic synthesis of SeNPs was confirmed by different analyses including ultraviolet-visible spectrophotometry, Fourier transform infrared, and energy-dispersive X-ray. Also, the crystalline nature, size, and morphology of the obtained SeNPs were characterized by X-ray diffraction, dynamic light scattering, field emission scanning electron microscopy, and transmission electron microscopy techniques. The SeNPs were successfully synthesized with fruit extract of V. arctostaphylos L. in a regular spherical form and narrow size distribution with suitable zeta-potential values and exhibited appropriate biocompatibility. It revealed that the synthesized SeNPs can significantly inhibit the growth of 4T1 breast cancer cells with an IC50 of ∼84.19 ± 25.96 µg/ml after 72 h treatment. Overall, it can be concluded that the green synthesized SeNPs can be attractive, nontoxic, and eco-friendly candidates for drug delivery or medicinal applications.

Mitigated Oxidative Stress and Cognitive Impairments in Transient Global Ischemia using Niosomal Selegiline-NBP delivery.

Stroke is the most common reason for adult disabilities and the second ground for death worldwide. Our previous study revealed that selegiline serves as an alternative candidate in transient hypoxia-ischemia. However, aggressive and restless behavior was observed in stroke-induced rats receiving 4 mg/kg selegiline. In comparison, 1 mg/kg selegiline could induce negligible therapeutic effects on mitochondrial dysfunction and histopathological changes. Therefore, we designed oral noisome-based selegiline attached to 4-(4-nitrobenzyl) pyridine to improve transient global ischemia by attenuating cognitive impairments, oxidative stress, and histopathological injury. The investigation was performed in transient hypoxia-ischemia-induced rats by oral administration of nanoformulation containing selegiline (0.25-1 mg/kg) for 4 weeks (3 times a week). Novel object recognition (NOR) was considered to evaluate their cognitive dysfunction. Oxidative stress parameters and brain histopathological assessments were determined following the scarification of rats. Outstandingly, our data demonstrated slower selegiline release from niosomes relative to free drug, which was also in a controlled manner. Our data confirmed significant improvement in cognitive behavior in the NOR test, an increase in glutathione level and total antioxidant power, a decline in MDA and protein carbonyl level, as well as a decreased number of dead cells in histopathological assessment after being exposed to (0.5-1 mg/kg) selegiline-NBP nanoformulation. These data manifested that the selegiline-NBP nanoformulation (0.5-1 mg/kg) could significantly reduce oxidative damage, cognitive dysfunction, and histopathological damage compared to transient hypoxia-ischemia rats, which is 20 times lower than the therapeutic dose in humans. Therefore, the proposed nanoformulation would be capable as an alternative candidate without side effects in stroke.

Anticancer evaluation of methotrexate and curcumin-coencapsulated niosomes against colorectal cancer cell lines.

Aim: The aim of the present investigation was to develop niosomes containing both curcumin (CUR) and methotrexate (MTX). Also, the combinational effect of CUR and MTX in both free and niosomal forms on growth inhibition potential and induction of apoptosis in the HCT-116 cell line were exploited. Materials & methods: Niosomes were prepared by the thin-film hydration method and their physicochemical properties were determined by various techniques. Cellular uptake, cell apoptosis, wound healing and MTT assay were conducted to ascertain niosomes' feasibility for cancer therapy. Results: The combination of CUR and MTX in niosomal formulation showed more toxicity than their combination in free form. Conclusion: The nanocarrier-based approach was effective for the codelivery of CUR and MTX against cancer cells in vitro.

Immuno-informatics analysis and expression of a novel multi-domain antigen as a vaccine candidate against glioblastoma.

Glioblastoma multiform is the most common of primary malignant brain tumors in adults. Currently, surgical resection of the tumor mass, followed by adjuvant radiotherapy and chemotherapy are standard treatments for glioblastoma multiform but so far are not effective treatments. Thus, the development of a vaccine, as a safe and efficient strategy for prophylactic or therapeutic purposes against glioblastoma multiform is very necessary. The present study aimed to design the multi-domain vaccine for glioblastoma multiform. An in silico approach was used to select the most potent domains of proteins to induce the host's B- and T-cell immune response against glioblastoma multiform. IL-13Rα-2 (amino acid positions 27-144), TNC (amino acid positions 1900-2100), and PTPRZ-1(amino acid positions 731-884) were found to have potent inducible immune responses. So, we considered them for fusing with a linker A(EAAAK)3A to construct the multi-domain recombinant vaccine. The immuno-informatics analysis of the designed recombinant vaccine construct was performed to evaluate its efficacy. Although the designed recombinant vaccine construct did not show allergen property, its antigenicity was estimated at 0.78. The Physico-chemical properties of the recombinant vaccine construct were characterized and revealed the potency of the vaccine candidate. Then its secondary and tertiary structures, mRNA structure, molecular docking, and immune simulation were predicted using bioinformatics tools. Next, the designed recombinant vaccine construct was synthesized, and cloned into the pET28a vector and expressed in E. coli BL21. Besides, the circular dichroism spectroscopy was utilized for the investigation of the secondary structure changes of the recombinant vaccine construct. The results of the verification assessment of the recombinant vaccine construct expression indicated that in silico analysis was relatively accurate, and relatively change occurred on the protein secondary structure. In our future plan, the vaccine candidate that was confirmed by in silico tools should be validated by further in vitro and in vivo experimental studies.

NANOG Decoy Oligodeoxynucleotide-Encapsulated Niosomes Nanocarriers: A Promising Approach to Suppress the Metastatic Properties of U87 Human Glioblastoma Multiforme Cells.

Recently, advances in the synthesis and development of multifunctional nanoparticle platforms have opened up great opportunities and advantages for specifically targeted delivery of genes of interest. BSA-coated niosome structures (NISM@B) can potentially improve the efficiency in vitro delivery of nucleic acid molecules and the transfection of genes. Few studies have reported the combined use of niosomes with nucleic acid as therapeutic agents or decoy oligodeoxynucleotides (ODNs). Herein, we synthesized NISM@B to encapsulate NANOG decoy ODN (NISM@B-DEC), after which the physicochemical characteristics and in vitro and in vivo properties of NISM@B-DEC were investigated. Our results regarding physicochemical characteristics revealed that the stable niosome nanocarrier system was successfully synthesized with a regular spherical shape and narrow size distribution with proper zeta-potential values and had an appropriate biocompatibility. The ODN release from the niosome nanocarrier system exhibited controlled and pH-dependent behavior as the best models to explain the ODN release profile. NISM@B-DEC was efficiently taken up by human glioblastoma cells (U87) and significantly inhibited cell growth. Finally, blockage of the NANOG pathway by NISM@B-DEC resulted in G1 cell cycle arrest, apoptosis, and cell death. In addition, NISM@B-DEC caused a significant decrease in tumor formation and improved wound-healing efficiency of the U87 cells. These findings confirm that NISM@B-DEC could potentially suppress the metastatic ability of these cells. It can be concluded that the presented nanocarrier system can be a promising approach for targeted gene delivery in cancer therapy.

Cholesterol-conjugated bovine serum albumin nanoparticles as a tamoxifen tumor-targeted delivery system.

In the present study, we introduced cholesterol (CLO)-conjugated bovine serum albumin nanoparticles (BSA NPs) as a new system for indirect targeting drug delivery. Tamoxifen, as an anticancer drug, was loaded on BSA NPs (BSA-TAX NPs); CLO was then conjugated to the BSA-TAX NPs surface for the targeted delivery of NPs system, by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy succinimide carbodiimide chemistry (CLO-BSA-TAX NPs). The physicochemical properties, toxicity, in vitro, and in vivo biocompatibility of the BSA NPs system were characterized on cancer cell lines (4T1). The results revealed that the BSA NPs system has a regular spherical shape and negative zeta-potential values. The drug release of BSA NPs system has shown controlled and pH-dependent drug release behavior. BSA NPs system was biocompatible but it was potentially toxic on the cancer cell line. The CLO-BSA-TAX NPs exhibited higher toxicity against cancer cell lines than other NPs formulation (BSA NPs and BSA-TAX NPs). It can be concluded that the CLO, as an indirect targeting agent, enhances the toxicity and specificity of NPs system on cancer cell lines. It could potentially be suitable approaches to targeting the tumors in clinical cancer therapy.

Hybrid of niosomes and bio-synthesized selenium nanoparticles as a novel approach in drug delivery for cancer treatment.

The current study intends to investigate a novel drug delivery system (DDS) based on niosomes structure (NISM) and bovine serum albumin (BSA) which was formulated to BSA coated NISM (NISM-B). Also, selenium nanoparticles (SeNPs) have been prepared by BSA mediated biosynthesis. Finally, the NISM-B was hybridized with SeNPs and was formulated as NISM-B@SeNPs for drug delivery applications. Physicochemical properties of all samples were characterized by UV-Vis spectroscopy, FT-IR, DLS, FESEM, and EDX techniques. The cytotoxicity of all samples against A549 cell line was assessed by cell viability analysis and flow cytometry for apoptotic cells as well as RT-PCR for the expression of MDR-1, Bax, and Bcl-2 genes. Besides, in vivo biocompatibility was performed by LD50 assay to evaluate the acute toxicity. The proposed formulation has a regular spherical shape and approximately narrow size distribution with proper zeta-potential values; the proposed DDS revealed a good biocompatibility. The compound showed a significant cytotoxic effect against A549 cell line. Although the Bax/Bcl-2 expression ratio was significantly in NISM-B@SeNPs- treated cancer cells, the expression of MDR-1 was non-significantly lower in NISM-B@SeNPs-treated cancer cells. The obtained results suggest that the proposed DDS presents a promising approach for drug delivery, co-delivery and multifunctional biomedicine applications.

Selegiline (L-Deprenyl) Mitigated Oxidative Stress, Cognitive Abnormalities, and Histopathological Change in Rats: Alternative Therapy in Transient Global Ischemia.

Selegiline (L-deprenyl) is the major drug which is used in the treatment of Parkinson's disease because of its neurotrophic and antiapoptotic properties. Previous studies suggested that low dose of L-methamphetamine (L-METH) caused lower mortality rate in patients with severe traumatic brain injury. As L-methamphetamine is one of the metabolites of selegiline, the present study aims to examine whether L-deprenyl can improve cognitive, biochemical, and histopathological injury in animal model of transient global ischemia. The animals were randomized in ten groups orally gavaged three times a week for 28 days. Then, novel object recognition (NOR) was conducted to assess their behavioral abnormality. After scarification of the rats, their brains were divided into two sections to measure oxidative stress parameters and perform pathological evaluations in rats. Our data revealed the involvement of oxidative stress, behavioral despair, and pathological data in transient global ischemia rats. Significant recovery in cognitive behavior, oxidative stress biomarker, and number of dead cell in histopathological assay was observed in rats treated with 1,2 and 4 mg/kg of selegiline. So, selegiline appears to be useful in alternative therapy of transient global ischemia.

Mesenchymal Stem Cells: A New Generation of Therapeutic Agents as Vehicles in Gene Therapy.

In recent years, mesenchymal stem cells (MSCs) as a new tool for therapeutic gene delivery in clinics have attracted much attention. Their advantages cover longer lifespan, better isolation, and higher transfection efficiency and proliferation rate. MSCs are the preferred approach for cell-based therapies because of their in vitro self-renewal capacity, migrating especially to tumor tissues, as well as anti-inflammatory and immunomodulatory properties. Therefore, they have considerable efficiency in genetic engineering for future clinical applications in cancer gene therapy and other diseases. For improving therapeutic efficiency, targeted therapy of cancers can be achieved through the sustained release of therapeutic agents and functional gene expression induction to the intended tissues. The development of a new vector in gene therapy can improve the durability of a transgene expression. Also, the safety of the vector, if administered systemically, may resolve several problems, such as durability of expression and the host immune response. Currently, MSCs are prominent candidates as cell vehicles for both preclinical and clinical trials due to the secretion of therapeutic agents in several cancers. In the present study, we discuss the status of gene therapy in both viral and non-viral vectors along with their limitations. Throughout this study, the use of several nano-carriers for gene therapy is also investigated. Finally, we critically discuss the promising advantages of MSCs in targeted gene delivery, tumor inhibition and their utilization as the gene carriers in clinical situations.

Microemulsion and bovine serum albumin nanoparticles as a novel hybrid nanocarrier system for efficient multifunctional drug delivery.

The present study aims to: (a) design the versatile microemulsions (MEs) system for drug delivery; (b) use the bovine serum albumin nanoparticles for MEs system development; (c) characterize the physicochemical properties, cytotoxicity, and biocompatibility of the modified MEs (MMEs) system; (d) load of paclitaxel (PTX) and folate conjugate of MEs system; and (e) assess the potential of anticancer activity of MEs system. The physicochemical possessions, in vitro and in vivo cytotoxicity, and stability of MMEs system were characterized. The results of our study show that the MEs system was stable, having narrow particle size distribution, nontoxic, biocompatible, and not active for leukocyte proliferation. So it can be concluded that the MMEs system as a promising candidate for a targeted multifunctional drug delivery system (PTX and folate) that is called a smart MEs system.

In vivo and in vitro biocompatibility study of novel microemulsion hybridized with bovine serum albumin as nanocarrier for drug delivery.

The present study aimed to synthesize triacetin-microemulsion (T-ME) and T-ME hybridized with bovine serum albumin nanoparticles (T-BSA-ME) having narrow particle size distribution and versatile carrier systems as a novel microemulsion system. The suggested ME system was characterized by Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Atomic Force Microscopy (AFM). The physicochemical properties of microemulsion system including particle size, PDI and ζ-potential, refractive index, Conductivity, %Transmittance, pH, and rheological behavior were also evaluated. In vivo biocompatibility was done using Median Lethal Dose (LD 50) calculated and trialed to evaluate the acute toxicity. In Addition, hemolysis and leukocyte proliferation assay were characterized to evaluate in-vitro biocompatibility of the suggested MEs systems. Moreover, cytotoxicity of MEs systems was also investigated on HFF-2 and HEK-293 cells. The presence of BSA NPs as a macromolecular biomaterial hybridized with T-ME reduced the cytotoxicity. The properties of the suggested MEs system proposed the T-ME hybridized with BSA-NPs as a promising candidate for co-delivery and multifunctional biomedicine applications.

Niosome: A Promising Nanocarrier for Natural Drug Delivery through Blood-Brain Barrier.

Niosomes (the nonionic surfactant vesicles), considered as novel drug delivery systems, can improve the solubility and stability of natural pharmaceutical molecules. They are established to provide targeting and controlled release of natural pharmaceutical compounds. Many factors can influence on niosome construction such as the preparation method, type and amount of surfactant, drug entrapment, temperature of lipids hydration, and the packing factor. The present review discusses about the most important features of niosomes such as their diverse structures, the different preparation approaches, characterization techniques, factors that affect their stability, their use by various routes of administration, their therapeutic applications in comparison with natural drugs, and specially the brain targeting with niosomes-ligand conjugation. It also provides recent data about the various types of ligand agents which make available active targeting drug delivery to the central neuron system. This system has an optimistic upcoming in pharmaceutical uses, mostly with the improving availability of innovative schemes to overcome blood-brain barrier and targeting the niosomes to the brain.