Showing papers in "Journal of Nanobiotechnology in 2018"

Nano based drug delivery systems: recent developments and future prospects

Abstract: Nanomedicine and nano delivery systems are a relatively new but rapidly developing science where materials in the nanoscale range are employed to serve as means of diagnostic tools or to deliver therapeutic agents to specific targeted sites in a controlled manner Nanotechnology offers multiple benefits in treating chronic human diseases by site-specific, and target-oriented delivery of precise medicines Recently, there are a number of outstanding applications of the nanomedicine (chemotherapeutic agents, biological agents, immunotherapeutic agents etc) in the treatment of various diseases The current review, presents an updated summary of recent advances in the field of nanomedicines and nano based drug delivery systems through comprehensive scrutiny of the discovery and application of nanomaterials in improving both the efficacy of novel and old drugs (eg, natural products) and selective diagnosis through disease marker molecules The opportunities and challenges of nanomedicines in drug delivery from synthetic/natural sources to their clinical applications are also discussed In addition, we have included information regarding the trends and perspectives in nanomedicine area

‘Green’ synthesis of metals and their oxide nanoparticles: applications for environmental remediation

Abstract: In materials science, “green” synthesis has gained extensive attention as a reliable, sustainable, and eco-friendly protocol for synthesizing a wide range of materials/nanomaterials including metal/metal oxides nanomaterials, hybrid materials, and bioinspired materials. As such, green synthesis is regarded as an important tool to reduce the destructive effects associated with the traditional methods of synthesis for nanoparticles commonly utilized in laboratory and industry. In this review, we summarized the fundamental processes and mechanisms of “green” synthesis approaches, especially for metal and metal oxide [e.g., gold (Au), silver (Ag), copper oxide (CuO), and zinc oxide (ZnO)] nanoparticles using natural extracts. Importantly, we explored the role of biological components, essential phytochemicals (e.g., flavonoids, alkaloids, terpenoids, amides, and aldehydes) as reducing agents and solvent systems. The stability/toxicity of nanoparticles and the associated surface engineering techniques for achieving biocompatibility are also discussed. Finally, we covered applications of such synthesized products to environmental remediation in terms of antimicrobial activity, catalytic activity, removal of pollutants dyes, and heavy metal ion sensing.

A review on biosynthesis of silver nanoparticles and their biocidal properties.

Abstract: Use of silver and silver salts is as old as human civilization but the fabrication of silver nanoparticles (Ag NPs) has only recently been recognized. They have been specifically used in agriculture and medicine as antibacterial, antifungal and antioxidants. It has been demonstrated that Ag NPs arrest the growth and multiplication of many bacteria such as Bacillus cereus, Staphylococcus aureus, Citrobacter koseri, Salmonella typhii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, Vibrio parahaemolyticus and fungus Candida albicans by binding Ag/Ag+ with the biomolecules present in the microbial cells. It has been suggested that Ag NPs produce reactive oxygen species and free radicals which cause apoptosis leading to cell death preventing their replication. Since Ag NPs are smaller than the microorganisms, they diffuse into cell and rupture the cell wall which has been shown from SEM and TEM images of the suspension containing nanoparticles and pathogens. It has also been shown that smaller nanoparticles are more toxic than the bigger ones. Ag NPs are also used in packaging to prevent damage of food products by pathogens. The toxicity of Ag NPs is dependent on the size, concentration, pH of the medium and exposure time to pathogens.

Recent advancements in the use of exosomes as drug delivery systems.

Abstract: Extracellular vesicles (EVs) are the substances that are released by most types of cells and have an important role in cell to cell communication. Among the most highly researched EVs are exosome. Recent studies show that exosomes derived from cells have different roles and targets. Many studies show that exosome can efficiently deliver many different kinds of cargo to the target cell. Therefore, they are often used to deliver therapeutic cargo for treatment. The exosomes that have been used include both natural ones and those that have been modified with other substances to increase the delivery ability. This article provides a review of both exosomes derived from various cells and modified exosome and their ability in delivering the many kinds of cargo to the target cell.

Recent advances in graphene-based biosensor technology with applications in life sciences

Abstract: Graphene’s unique physical structure, as well as its chemical and electrical properties, make it ideal for use in sensor technologies. In the past years, novel sensing platforms have been proposed with pristine and modified graphene with nanoparticles and polymers. Several of these platforms were used to immobilize biomolecules, such as antibodies, DNA, and enzymes to create highly sensitive and selective biosensors. Strategies to attach these biomolecules onto the surface of graphene have been employed based on its chemical composition. These methods include covalent bonding, such as the coupling of the biomolecules via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide reactions, and physisorption. In the literature, several detection methods are employed; however, the most common is electrochemical. The main reason for researchers to use this detection approach is because this method is simple, rapid and presents good sensitivity. These biosensors can be particularly useful in life sciences and medicine since in clinical practice, biosensors with high sensitivity and specificity can significantly enhance patient care, early diagnosis of diseases and pathogen detection. In this review, we will present the research conducted with antibodies, DNA molecules and, enzymes to develop biosensors that use graphene and its derivatives as scaffolds to produce effective biosensors able to detect and identify a variety of diseases, pathogens, and biomolecules linked to diseases.

Advances in redox-responsive drug delivery systems of tumor microenvironment.

Abstract: With the improvement of nanotechnology and nanomaterials, redox-responsive delivery systems have been studied extensively in some critical areas, especially in the field of biomedicine The system constructed by redox-responsive delivery can be much stable when in circulation In addition, redox-responsive vectors can respond to the high intracellular level of glutathione and release the loaded cargoes rapidly, only if they reach the site of tumor tissue or targeted cells Moreover, redox-responsive delivery systems are often applied to significantly improve drug concentrations in targeted cells, increase the therapeutic efficiency and reduce side effects or toxicity of primary drugs In this review, we focused on the structures and types of current redox-responsive delivery systems and provided a comprehensive overview of relevant researches, in which the disulfide bond containing delivery systems are of the utmost discussion

Memantine loaded PLGA PEGylated nanoparticles for Alzheimer’s disease: in vitro and in vivo characterization

Abstract: Memantine, drug approved for moderate to severe Alzheimer’s disease, has not shown to be fully effective. In order to solve this issue, polylactic-co-glycolic (PLGA) nanoparticles could be a suitable solution to increase drug’s action on the target site as well as decrease adverse effects. For these reason, Memantine was loaded in biodegradable PLGA nanoparticles, produced by double emulsion method and surface-coated with polyethylene glycol. MEM–PEG–PLGA nanoparticles (NPs) were aimed to target the blood–brain barrier (BBB) upon oral administration for the treatment of Alzheimer’s disease. The production parameters were optimized by design of experiments. MEM–PEG–PLGA NPs showed a mean particle size below 200 nm (152.6 ± 0.5 nm), monomodal size distribution (polydispersity index, PI < 0.1) and negative surface charge (− 22.4 mV). Physicochemical characterization of NPs confirmed that the crystalline drug was dispersed inside the PLGA matrix. MEM–PEG–PLGA NPs were found to be non-cytotoxic on brain cell lines (bEnd.3 and astrocytes). Memantine followed a slower release profile from the NPs against the free drug solution, allowing to reduce drug administration frequency in vivo. Nanoparticles were able to cross BBB both in vitro and in vivo. Behavioral tests carried out on transgenic APPswe/PS1dE9 mice demonstrated to enhance the benefit of decreasing memory impairment when using MEM–PEG–PLGA NPs in comparison to the free drug solution. Histological studies confirmed that MEM–PEG–PLGA NPs reduced β-amyloid plaques and the associated inflammation characteristic of Alzheimer’s disease. Memantine NPs were suitable for Alzheimer’s disease and more effective than the free drug.

Critical review of the safety assessment of titanium dioxide additives in food.

Abstract: Nanomaterial engineering provides an important technological advance that offers substantial benefits for applications not only in the production and processing, but also in the packaging and storage of food. An expanding commercialization of nanomaterials as part of the modern diet will substantially increase their oral intake worldwide. While the risk of particle inhalation received much attention, gaps of knowledge exist regarding possible adverse health effects due to gastrointestinal exposure. This problem is highlighted by pigment-grade titanium dioxide (TiO2), which confers a white color and increased opacity with an optimal particle diameter of 200–300 nm. However, size distribution analyses showed that batches of food-grade TiO2 always comprise a nano-sized fraction as inevitable byproduct of the manufacturing processes. Submicron-sized TiO2 particles, in Europe listed as E 171, are widely used as a food additive although the relevant risk assessment has never been satisfactorily completed. For example, it is not possible to derive a safe daily intake of TiO2 from the available long-term feeding studies in rodents. Also, the use of TiO2 particles in the food sector leads to highest exposures in children, but only few studies address the vulnerability of this particular age group. Extrapolation of animal studies to humans is also problematic due to knowledge gaps as to local gastrointestinal effects of TiO2 particles, primarily on the mucosa and the gut-associated lymphoid system. Tissue distributions after oral administration of TiO2 differ from other exposure routes, thus limiting the relevance of data obtained from inhalation or parenteral injections. Such difficulties and uncertainties emerging in the retrospective assessment of TiO2 particles exemplify the need for a fit-to-purpose data requirement for the future evaluation of novel nano-sized or submicron-sized particles added deliberately to food.

Targeting extracellular vesicles to injured tissue using membrane cloaking and surface display.

Abstract: Extracellular vesicles (EVs) and exosomes are nano-sized, membrane-bound vesicles shed by most eukaryotic cells studied to date EVs play key signaling roles in cellular development, cancer metastasis, immune modulation and tissue regeneration Attempts to modify exosomes to increase their targeting efficiency to specific tissue types are still in their infancy Here we describe an EV membrane anchoring platform termed “cloaking” to directly embed tissue-specific antibodies or homing peptides on EV membrane surfaces ex vivo for enhanced vesicle uptake in cells of interest The cloaking system consists of three components: DMPE phospholipid membrane anchor, polyethylene glycol spacer and a conjugated streptavidin platform molecule, to which any biotinylated molecule can be coupled for EV decoration We demonstrate the utility of membrane surface engineering and biodistribution tracking with this technology along with targeting EVs for enhanced uptake in cardiac fibroblasts, myoblasts and ischemic myocardium using combinations of fluorescent tags, tissue-targeting antibodies and homing peptide surface cloaks We compare cloaking to a complementary approach, surface display, in which parental cells are engineered to secrete EVs with fusion surface targeting proteins EV targeting can be enhanced both by cloaking and by surface display; the former entails chemical modification of preformed EVs, while the latter requires genetic modification of the parent cells Reduction to practice of the cloaking approach, using several different EV surface modifications to target distinct cells and tissues, supports the notion of cloaking as a platform technology

Nanographene oxide-methylene blue as phototherapies platform for breast tumor ablation and metastasis prevention in a syngeneic orthotopic murine model.

Abstract: In the photodynamic therapy (PDT), the photosensitizer absorbs light and transfers the energy of the excited state to the oxygen in the cell environment producing reactive oxygen species (ROS), that in its turn, may cause cell damage. In the photothermal therapy (PTT), light also is responsible for activating the photothermal agent, which converts the absorbed energy in heat. Graphene oxide is a carbon-based material that presents photothermal activity. Its physical properties allow the association with the photosensitizer methylene blue and consequently the production of ROS when submitted to light irradiation. Therefore, the association between nanographene oxide and methylene blue could represent a strategy to enhance therapeutic actions. In this work, we report the nanographene oxide-methylene blue platform (NanoGO-MB) used to promote tumor ablation in combination with photodynamic and photothermal therapies against a syngeneic orthotopic murine breast cancer model. In vitro, NanoGO-MB presented 50% of the reactive oxygen species production compared to the free MB after LED light irradiation, and a temperature increase of ~ 40 °C followed by laser irradiation. On cells, the ROS production by the nanoplatform displayed higher values in tumor than normal cells. In vivo assays demonstrated a synergistic effect obtained by the combined PDT/PTT therapies using NanoGO-MB, which promoted complete tumor ablation in 5/5 animals. Up to 30 days after the last treatment, there was no tumor regrowth compared with only PDT or PTT groups, which displayed tumoral bioluminescence 63-fold higher than the combined treatment group. Histological studies confirmed that the combined therapies were able to prevent tumor regrowth and liver, lung and spleen metastasis. In addition, low systemic toxicity was observed in pathologic examinations of liver, spleen, lungs, and kidneys. The treatment with combined PDT/PTT therapies using NanoGO-MB induced more toxicity on breast carcinoma cells than on normal cells. In vivo, the combined therapies promoted complete tumor ablation and metastasis prevention while only PDT or PTT were unable to stop tumor development. The results show the potential of NanoGO-MB in combination with the phototherapies in the treatment of the breast cancer and metastasis prevention.

Paclitaxel and curcumin coadministration in novel cationic PEGylated niosomal formulations exhibit enhanced synergistic antitumor efficacy

Abstract: The systemic administration of cytotoxic chemotherapeutic agents for cancer treatment often has toxic side effects, limiting the usage dose. To increase chemotherapeutic efficacy while reducing toxic effects, a rational design for synergy-based drug regimens is essential. This study investigated the augmentation of therapeutic effectiveness with the co-administration of paclitaxel (PTX; an effective chemotherapeutic drug for breast cancer) and curcumin (CUR; a chemosensitizer) in an MCF-7 cell line. We optimized niosome formulations in terms of surfactant and cholesterol content. Afterward, the novel cationic PEGylated niosomal formulations containing Tween-60: cholesterol:DOTAP:DSPE-mPEG (at 59.5:25.5:10:5) were designed and developed to serve as a model for better transfection efficiency and improved stability. The optimum formulations represented potential advantages, including extremely high entrapment efficiency (~ 100% for both therapeutic drug), spherical shape, smooth-surface morphology, suitable positive charge (zeta potential ~ + 15 mV for both CUR and PTX), sustained release, small diameter (~ 90 nm for both agents), desired stability, and augmented cellular uptake. Furthermore, the CUR and PTX kinetic release could be adequately fitted to the Higuchi model. A threefold and 3.6-fold reduction in CUR and PTX concentration was measured, respectively, when the CUR and PTX was administered in nano-niosome compared to free CUR and free PTX solutions in MCF-7 cells. When administered in nano-niosome formulations, the combination treatment of CUR and PTX was particularly effective in enhancing the cytotoxicity activity against MCF-7 cells. Most importantly, CUR and PTX, in both free form and niosomal forms, were determined to be less toxic on MCF-10A human normal cells in comparison to MCF-7 cells. The findings indicate that the combination therapy of PTX with CUR using the novel cationic PEGylated niosome delivery is a promising strategy for more effective breast cancer treatment.

Graphene oxide conjugated with polymers: a study of culture condition to determine whether a bacterial growth stimulant or an antimicrobial agent?

Abstract: The results showed that the deciding factor is the culture medium in which the bacteria and the graphene oxide (GO) are incubated at the initial manipulation step. These findings allow better use of GO and GO-based materials more and be able to clearly apply them in the field of biomedical nanotechnology. To study the use of GO sheets applied in the field of biomedical nanotechnology, this study determines whether GO-based materials [GO, GO-polyoxyalkyleneamine (POAA), and GO-chitosan] stimulate or inhibit bacterial growth in detail. It is found that it depends on whether the bacteria and GO-based materials are incubated with a nutrient at the initial step. This is a critical factor for the fortune of bacteria. GO stimulates bacterial growth and microbial proliferation for Gram-negative and Gram-positive bacteria and might also provide augmented surface attachment for both types of bacteria. When an external barrier that is composed of GO-based materials forms around the surface of the bacteria, it suppresses nutrients that are essential to microbial growth and simultaneously produces oxidative stress, which causes bacteria to die, regardless of whether they have an outer-membrane-Gram-negative-bacteria or lack an outer-membrane-Gram-positive-bacteria, even for high concentrations of biocompatible GO-POAA. The results also show that these GO-based materials are capable of inducing reactive oxygen species (ROS)-dependent oxidative stress on bacteria. Besides, GO-based materials may act as a biofilm, so it is hypothesized that they suppress the toxicity of low-dose chitosan. Graphene oxide is not an antimicrobial material but it is a general growth enhancer that can act as a biofilm to enhance bacterial attachment and proliferation. However, GO-based materials are capable of inducing ROS-dependent oxidative stress on bacteria. The applications of GO-based materials can clearly be used in antimicrobial surface coatings, surface-attached stem cells for orthopedics, antifouling for biocides and microbial fuel cells and microbial electro-synthesis.

Nanomaterial enabled sensors for environmental contaminants

Abstract: The need and desire to understand the environment, especially the quality of one’s local water and air, has continued to expand with the emergence of the digital age. The bottleneck in understanding the environment has switched from being able to store all of the data collected to collecting enough data on a broad range of contaminants of environmental concern. Nanomaterial enabled sensors represent a suite of technologies developed over the last 15 years for the highly specific and sensitive detection of environmental contaminants. With the promise of facile, low cost, field-deployable technology, the ability to quantitatively understand nature in a systematic way will soon be a reality. In this review, we first introduce nanosensor design before exploring the application of nanosensors for the detection of three classes of environmental contaminants: pesticides, heavy metals, and pathogens.

Gold nanoparticles stabilize peptide-drug-conjugates for sustained targeted drug delivery to cancer cells.

Abstract: Peptide-drug-conjugates (PDCs) are being developed as an effective strategy to specifically deliver cytotoxic drugs to cancer cells. However one of the challenges to their successful application is the relatively low stability of peptides in the blood, liver and kidneys. Since AuNPs seem to have a longer plasma half-life than PDCs, one approach to overcoming this problem would be to conjugate the PDCs to gold nanoparticles (AuNPs), as these have demonstrated favorable physico-chemical and safety properties for drug delivery systems. We set out to test whether PEG coated-AuNPs could provide a suitable platform for the non-covalent loading of pre-formed PDCs and whether this modification would affect the bioavailability of the PDCs and their cytotoxicity toward target cancer cells. Peptides specifically internalized by A20 murine lymphoma cells were isolated from a phage library displaying 7mer linear peptides. Peptide specificity was validated by flow cytometry and confocal microscopy. PDCs were synthesized containing a selected peptide (P4) and either chlorambucil (Chlor), melphalan (Melph) or bendamustine (Bend). Gold nanoparticles were sequentially coated with citrate, PEG-6000 and then PDC (PDC-PEG-AuNP). The physico-chemical properties of the coated particles were analyzed by electrophoresis, TEM, UV–VIS and FTIR. Stability of free and PDC-coated AuNP was determined. Biopanning of the phage library resulted in discovery of several novel peptides that internalized into A20 cells. One of these (P4) was used to synthesize PDCs containing either Chlor, Melph or Bend. All three PDCs specifically killed A20 target cells, however they had short half-lives ranging from 10.6 to 15.4 min. When coated to PEG-AuNPs, the half-lives were extended to 21.0–22.3 h. The PDC-PEG-AuNPs retained cytotoxicity towards the target cells. Moreover, whereas pre-incubation for 24 h of free PDCs almost completely abolished their cytotoxic activity, the PDC-PEG-AuNPs were still active even after 72 h pre-incubation. Peptide-drug-conjugates hold potential for improving the target efficacy of chemotherapeutic drugs, however their short half-lives may limit their application. This hurdle can be overcome by easily conjugating them to gold nanoparticles. This conjugation also opens up the possibility of developing slow release formulations of targeted drug delivery systems containing PDCs.

Application of atomic force microscopy in cancer research

Abstract: Atomic force microscopy (AFM) allows for nanometer-scale investigation of cells and molecules. Recent advances have enabled its application in cancer research and diagnosis. The physicochemical properties of live cells undergo changes when their physiological conditions are altered. These physicochemical properties can therefore reflect complex physiological processes occurring in cells. When cells are in the process of carcinogenesis and stimulated by external stimuli, their morphology, elasticity, and adhesion properties may change. AFM can perform surface imaging and ultrastructural observation of live cells with atomic resolution under near-physiological conditions, collecting force spectroscopy information which allows for the study of the mechanical properties of cells. For this reason, AFM has potential to be used as a tool for high resolution research into the ultrastructure and mechanical properties of tumor cells. This review describes the working principle, working mode, and technical points of atomic force microscopy, and reviews the applications and prospects of atomic force microscopy in cancer research.

Gold nanoparticles improve metabolic profile of mice fed a high-fat diet

Abstract: Obesity is a high risk for multiple metabolic disorders due to excessive influx of energy, glucose and lipid, often from a western based diet Low-grade inflammation plays a key role in the progression of such metabolic disorders The anti-inflammatory property of gold compounds has been used in treating rheumatoid arthritis in the clinic Previously we found that pure gold nanoparticles (AuNPs, 21 nm) also possess anti-inflammatory effects on the retroperitoneal fat tissue following intraperitoneal injection, by downregulating tumor necrosis factor (TNF) α However, whether such an effect can change the risk of metabolic disorders in the obese has not been well studied The study employed C57BL/6 mice fed a pellet high fat diet (HFD, 43% as fat) that were treated daily with AuNPs [low (HFD-LAu) or high (HFD-HAu) dose] via intraperitoneal injection for 9 weeks In the in vitro study, RAW2647 macrophages and 3T3-L1 adipocytes were cultured with low and high concentrations of AuNPs alone or together The HFD-fed mice showed a significant increase in fat mass, glucose intolerance, dyslipidemia, and liver steatosis The HFD-LAu group showed an 8% reduction in body weight, ameliorated hyperlipidemia, and normal glucose tolerance; while the HFD-HAu group had a 5% reduction in body weight with significant improvement in their glucose intolerance and hyperlipidemia The underlying mechanism may be attributed to a reduction in adipose and hepatic local proinflammatory cytokine production, eg TNFα In vitro studies of co-cultured murine RAW2647 macrophage and 3T3-L1 adipocytes supported this proposed mechanism AuNPs demonstrate a promising profile for potential management of obesity related glucose and lipid disorders and are useful as a research tool for the study of biological mechanisms

Nanotechnology: a promising method for oral cancer detection and diagnosis

Abstract: Oral cancer is a common and aggressive cancer with high morbidity, mortality, and recurrence rate globally. Early detection is of utmost importance for cancer prevention and disease management. Currently, tissue biopsy remains the gold standard for oral cancer diagnosis, but it is invasive, which may cause patient discomfort. The application of traditional noninvasive methods-such as vital staining, exfoliative cytology, and molecular imaging-is limited by insufficient sensitivity and specificity. Thus, there is an urgent need for exploring noninvasive, highly sensitive, and specific diagnostic techniques. Nano detection systems are known as new emerging noninvasive strategies that bring the detection sensitivity of biomarkers to nano-scale. Moreover, compared to current imaging contrast agents, nanoparticles are more biocompatible, easier to synthesize, and able to target specific surface molecules. Nanoparticles generate localized surface plasmon resonances at near-infrared wavelengths, providing higher image contrast and resolution. Therefore, using nano-based techniques can help clinicians to detect and better monitor diseases during different phases of oral malignancy. Here, we review the progress of nanotechnology-based methods in oral cancer detection and diagnosis.

Nanostructured surface topographies have an effect on bactericidal activity

Abstract: Due to the increased emergence of antimicrobial resistance, alternatives to minimize the usage of antibiotics become attractive solutions. Biophysical manipulation of material surface topography to prevent bacterial adhesion is one promising approach. To this end, it is essential to understand the relationship between surface topographical features and bactericidal properties in order to develop antibacterial surfaces. In this work a systematic study of topographical effects on bactericidal activity of nanostructured surfaces is presented. Nanostructured Ormostamp polymer surfaces are fabricated by nano-replication technology using nanoporous templates resulting in 80-nm diameter nanopillars. Six Ormostamp surfaces with nanopillar arrays of various nanopillar densities and heights are obtained by modifying the nanoporous template. The surface roughness ranges from 3.1 to 39.1 nm for the different pillar area parameters. A Gram-positive bacterium, Staphylococcus aureus, is used as the model bacterial strain. An average pillar density at ~ 40 pillars μm−2 with surface roughness of 39.1 nm possesses the highest bactericidal efficiency being close to 100% compared with 20% of the flat control samples. High density structures at ~ 70 pillars μm−2 and low density structures at < 20 pillars μm−2 with surface roughness smaller than 20 nm reduce the bactericidal efficiency to almost the level of the control samples. The results obtained here suggests that the topographical effects including pillar density and pillar height inhomogeneity may have significant impacts on adhering pattern and stretching degree of bacterial cell membrane. A biophysical model is prepared to interpret the morphological changes of bacteria on these nanostructures.

ROS responsive resveratrol delivery from LDLR peptide conjugated PLA-coated mesoporous silica nanoparticles across the blood-brain barrier.

Abstract: Oxidative stress acts as a trigger in the course of neurodegenerative diseases and neural injuries. An antioxidant-based therapy can be effective to ameliorate the deleterious effects of oxidative stress. Resveratrol (RSV) has been shown to be effective at removing excess reactive oxygen species (ROS) or reactive nitrogen species generation in the central nervous system (CNS), but the delivery of RSV into the brain through systemic administration is inefficient. Here, we have developed a RSV delivery vehicle based on polylactic acid (PLA)-coated mesoporous silica nanoparticles (MSNPs), conjugated with a ligand peptide of low-density lipoprotein receptor (LDLR) to enhance their transcytosis across the blood–brain barrier (BBB). Resveratrol was loaded into MSNPs (average diameter 200 nm, pore size 4 nm) at 16 μg/mg (w/w). As a gatekeeper, the PLA coating prevented the RSV burst release, while ROS was shown to trigger the drug release by accelerating PLA degradation. An in vitro BBB model with a co-culture of rat brain microvascular endothelial cells (RBECs) and microglia cells using Transwell chambers was established to assess the RSV delivery across BBB. The conjugation of LDLR ligand peptides markedly enhanced the migration of MSNPs across the RBECs monolayer. RSV could be released and effectively reduce the activation of the microglia cells stimulated by phorbol-myristate-acetate or lipopolysaccharide. These ROS responsive LDLR peptides conjugated PLA-coated MSNPs have great potential for oxidative stress therapy in CNS.

Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma

Abstract: Sorafenib is an effective clinical drug in therapy of hepatocellular carcinoma, having led to improved prognosis in hepatocellular carcinoma patients. However acquired resistance is still being encountered. So, it is urgently to develop alternative strategies to overcome drug resistance. Exosomes can be modified with a variety of molecules, thereby acting as a vehicle for the delivery of therapeutic agents. The GRP78 is overexpressed in Sorafenib resistant cancer cells compared to Sorafenib sensitive cancer cells and thus is able to act as a target for therapy of hepatocellular carcinoma. In this study, we modified BM-MSCs to express the exosomal siGRP78. And we show that siGRP78 modified exosomes combined with Sorafenib is able to target GRP78 in hepatocellular carcinoma cells and inhibit the growth and invasion of the cancer cells in vitro. Further, siGRP78 modified exosomes combined with Sorafenib also inhibit the growth and metastasis of the cancer cells in vivo. siGRP78 modified exosomes could sensitize Sorafenib resistant cancer cells to Sorafenib and reverse the drug resistance.

An efficient antimicrobial depot for infectious site-targeted chemo-photothermal therapy

Abstract: Silver and photothermal therapy (PTT) have been widely used for eradicating the drug-resistant bacteria. However, the risks of excess of silver for humans and the low efficiency of PTT still limit their in vivo therapeutic application. Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. In this study, a chemo-photothermal therapeutic platform based on polydopamine (PDA)-coated gold nanorods (GNRs) was developed. The PDA coating acquired high Ag+ ions loading efficiency and Cy5-SE fluorescent agent labeled glycol chitosan (GCS) conjugation (Ag+-GCS-PDA@GNRs). This platform became positively charged in the low pH environment of the abscess, allowing their accumulation in local infection site as revealed by thermal/florescence imaging. The loaded Ag+ ions was released in a pH-sensitive manner, resulting in selective Ag+ ions delivery to the abscess environment (pH ~ 6.3). More importantly, the ultralow dose of Ag+ ions could effectively damage the bacterial membrane, causing the permeability increase and the heat resistance reduction of the cell membrane, leading to the large improvement on bactericidal efficiency of PTT. On the other hand, the hyperthermia could trigger more Ag+ ions release, resulting in further improvement on bactericidal efficiency of chemotherapy. Combinational chemo-hyperthermia therapy of Ag+-GCS-PDA@GNRs could thoroughly ablate abscess and accelerate wound healing via a synergistic antibacterial effect. Our studies demonstrate that Ag+-GCS-PDA@GNRs is a robust and practical platform for use in chemo-thermal focal infection therapy with outstanding synergistic bacteria ablating.

Combination of NF-kB targeted siRNA and methotrexate in a hybrid nanocarrier towards the effective treatment in rheumatoid arthritis

Abstract: The transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA). Effective treatment of RA is hindered due to the lack of specificity of small molecules in the inflamed joints. In this study, we aimed to develop a unique hybrid-nanoparticles system comprised of calcium phosphate/liposome to deliver NF-kB-targeted siRNA and methotrexate (MTX) to diseased site. We have successfully demonstrated that the combination of siRNA and MTX in a calcium phosphate/liposome-based hybrid nanocarrier could effectively treat the RA. We have showed that folate receptor-targeted nanocarrier system significantly suppression the arthritis progression in mice model. Substantial accumulation of F-siRML was observed in LPS-activated macrophages. These kind of activated macrophages are generally present in the RA and osteoarthritis and folate-targeted nanoparticle enables the effective accumulation of therapeutics in the diseased site. The combinational nanoparticles effectively blocked the NF-kB signaling pathways and reduced the expression of pro-inflammatory cytokines. Furthermore, siRML and F-siRML did not show any decrease in the lymphocyte count indicating that it can avoid the adverse effect of MTX. Therefore, siRML and F-siRML provides unique benefits of excellent therapeutic efficacy with excellent safety profile in the arthritic mice and could be an promising approach in the treatment of rheumatoid arthritis.

Development of keratin nanoparticles for controlled gastric mucoadhesion and drug release

Abstract: Nanotechnology-based drug delivery systems have been widely used for oral and systemic dosage forms delivery depending on the mucoadhesive interaction, and keratin has been applied for biomedical applications and drug delivery. However, few reports have focused on the keratin-based mucoadhesive drug delivery system and their mechanisms of mucoadhesion. Thus, the mucoadhesion controlled kerateine (reduced keratin, KTN)/keratose (oxidized keratin, KOS) composite nanoparticles were prepared via adjusting the proportion of KTN and KOS to achieve controlled gastric mucoadhesion and drug release based on their different mucoadhesive abilities and pH-sensitive properties. Furthermore, the mechanisms of mucoadhesion for KTN and KOS were also investigated in the present study. The composite keratin nanoparticles (KNPs) with different mass ratio of KTN to KOS, including 100/0 (KNP-1), 75/25 (KNP-2), 50/50 (KNP-3), and 25/75 (KNP-4), displayed different drug release rates and gastric mucoadhesion capacities, and then altered the drug pharmacokinetic performances. The stronger mucoadhesive ability of nanoparticle could supply longer gastric retention time, indicating that KTN displayed a stronger mucoadhesion than that of KOS. Furthermore, the mechanisms of mucoadhesion for KTN and KOS at different pH conditions were also investigated. The binding between KTN and porcine gastric mucin (PGM) is dominated by electrostatic attractions and hydrogen bondings at pH 4.5, and disulfide bonds also plays a key role in the interaction at pH 7.4. While, the main mechanisms of KOS and PGM interactions are hydrogen bondings and hydrophobic interactions in pH 7.4 condition and were hydrogen bondings at pH 4.5. The resulting knowledge offer an efficient strategy to control the gastric mucoadhesion and drug release of nano drug delivery systems, and the elaboration of mucoadhesive mechanism of keratins will enable the rational design of nanocarriers for specific mucoadhesive drug delivery.

Nanosensors based on polymer vesicles and planar membranes: a short review

Abstract: This review aims to summarize the advance in the field of nanosensors based on two particular materials: polymer vesicles (polymersomes) and polymer planar membranes. These two types of polymer-based structural arrangements have been shown to be efficient in the production of sensors as their features allow to adapt to different environment but also to increase the sensitivity and the selectivity of the sensing device. Polymersomes and planar polymer membranes offer a platform of choice for a wide range of chemical functionalization and characteristic structural organization which allows a convenient usage in numerous sensing applications. These materials appear as great candidates for such nanosensors considering the broad variety of polymers. They also enable the confection of robust nanosized architectures providing interesting properties for numerous applications in many domains ranging from pollution to drug monitoring. This report gives an overview of these different sensing strategies whether the nanosensors aim to detect chemicals, biological or physical signals.

Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma

Abstract: Multidrug resistance-associated protein 1 (MRP1) overexpression plays a major role in chemoresistance in glioblastoma multiforme (GBM) contributing to its notorious deadly nature. Although MRP1-siRNA transfection to GBM in vitro has been shown to sensitise the cells to drug, MRP1 silencing in vivo and the phenotypic influence on the tumour and normal tissues upon MRP1 down-regulation have not been established. Here, porous silicon nanoparticles (pSiNPs) that enable high-capacity loading and delivery of siRNA are applied in vitro and in vivo. We established pSiNPs with polyethyleneimine (PEI) capping that enables high-capacity loading of siRNA (92 µg of siRNA/mg PEI-pSiNPs), and optimised release profile (70% released between 24 and 48 h). These pSiNPs are biocompatible, and demonstrate cellular uptake and effective knockdown of MRP1 expression in GBM by 30%. Also, siRNA delivery was found to significantly reduce GBM proliferation as an associated effect. This effect is likely mediated by the attenuation of MRP1 transmembrane transport, followed by cell cycle arrest. MRP1 silencing in GBM tumour using MRP1-siRNA loaded pSiNPs was demonstrated in mice (82% reduction at the protein level 48 h post-injection), and it also produced antiproliferative effect in GBM by reducing the population of proliferative cells. These results indicate that in vitro observations are translatable in vivo. No histopathological signs of acute damage were observed in other MRP1-expressing organs despite collateral downregulations. This study proposes the potential of efficient MRP1-siRNA delivery by using PEI-capped pSiNPs in achieving a dual therapeutic role of directly attenuating the growth of GBM while sensitising residual tumour cells to the effects of chemotherapy post-resection.

Impact of nanoparticle surface functionalization on the protein corona and cellular adhesion, uptake and transport

Abstract: Upon ingestion, nanoparticles can interact with the intestinal epithelial barrier potentially resulting in systemic uptake of nanoparticles Nanoparticle properties have been described to influence the protein corona formation and subsequent cellular adhesion, uptake and transport Here, we aimed to study the effects of nanoparticle size and surface chemistry on the protein corona formation and subsequent cellular adhesion, uptake and transport Caco-2 intestinal cells, were exposed to negatively charged polystyrene nanoparticles (PSNPs) (50 and 200 nm), functionalized with sulfone or carboxyl groups, at nine nominal concentrations (15–250 μg/ml) for 10 up to 120 min The protein coronas were analysed by LC–MS/MS Subtle differences in the protein composition of the two PSNPs with different surface chemistry were noted High-content imaging analysis demonstrated that sulfone PSNPs were associated with the cells to a significantly higher extent than the other PSNPs The apparent cellular adhesion and uptake of 200 nm PSNPs was not significantly increased compared to 50 nm PSNPs with the same surface charge and chemistry Surface chemistry outweighs the impact of size on the observed PSNP cellular associations Also transport of the sulfone PSNPs through the monolayer of cells was significantly higher than that of carboxyl PSNPs The results suggest that the composition of the protein corona and the PSNP surface chemistry influences cellular adhesion, uptake and monolayer transport, which might be predictive of the intestinal transport potency of NPs

Immunoassays for scarce tumour-antigens in exosomes: detection of the human NKG2D-Ligand, MICA, in tetraspanin-containing nanovesicles from melanoma

Abstract: Tumour-derived exosomes can be released to serum and provide information on the features of the malignancy, however, in order to perform systematic studies in biological samples, faster diagnostic techniques are needed, especially for detection of low abundance proteins. Most human cancer cells are positive for at least one ligand for the activating immune receptor NKG2D and the presence in plasma of NKG2D-ligands can be associated with prognosis. Using MICA as example of a tumour-derived antigen, endogenously expressed in metastatic melanoma and recruited to exosomes, we have developed two immunocapture-based assays for detection of different epitopes in nanovesicles. Although both techniques, enzyme-linked immunosorbent assay (ELISA) and Lateral flow immunoassays (LFIA) have the same theoretical basis, that is, using capture and detection antibodies for a colorimetric read-out, analysis of exosome-bound proteins poses methodological problems that do not occur when these techniques are used for detection of soluble molecules, due to the presence of multiple epitopes on the vesicle. Here we demonstrate that, in ELISA, the signal obtained was directly proportional to the amount of epitopes per exosome. In LFIA, the amount of detection antibody immobilized in Au-nanoparticles needs to be low for efficient detection, otherwise steric hindrance results in lower signal. We describe the conditions for detection of MICA in exosomes and prove, for the first time using both techniques, the co-existence in one vesicle of exosomal markers (the tetraspanins CD9, CD63 and CD81) and an endogenously expressed tumour-derived antigen. The study also reveals that scarce proteins can be used as targets for detection antibody in LFIA with a better result than very abundant proteins and that the conditions can be optimized for detection of the protein in plasma. These results open the possibility of analyzing biological samples for the presence of tumour-derived exosomes using high throughput techniques.

Facile assembly of upconversion nanoparticle-based micelles for active targeted dual-mode imaging in pancreatic cancer.

Abstract: Pancreatic cancer remains the leading cause of cancer-related deaths, the existence of cancer stem cells and lack of highly efficient early detection may account for the poor survival rate. Gadolinium ion-doped upconversion nanoparticles (UCNPs) provide opportunities for combining fluorescent with magnetic resonance imaging, and they can improve the diagnostic efficacy of early pancreatic cancer. In addition, as one transmembrane glycoprotein overexpressed on the pancreatic cancer stem cells, CD326 may act as a promising target. In this study, we developed a facile strategy for developing anti-human CD326-grafted UCNPs-based micelles and performed the corresponding characterizations. After conducting in vitro and vivo toxicology experiments, we also examined the active targeting capability of the micelles upon dual-mode imaging in vivo. We found that the micelles owned superior imaging properties and long-time stability based on multiple characterizations. By performing in vitro and vivo toxicology assay, the micelles had good biocompatibility. We observed more cellular uptake of the micelles with the help of anti-human CD326 grafted onto the micelles. Furthermore, we successfully concluded that CD326-conjugated micelles endowed promising active targeting ability by conducting dual-mode imaging in human pancreatic cancer xenograft mouse model. With good biocompatibility and excellent imaging properties of the micelles, our results uncover efficient active homing of those micelles after intravenous injection, and undoubtedly demonstrate the as-obtained micelles holds great potential for early pancreatic cancer diagnosis in the future and would pave the way for the following biomedical applications.

Chiral polymer modified nanoparticles selectively induce autophagy of cancer cells for tumor ablation.

Abstract: Autophagy regulation through exogenous materials has aroused intensive attention to develop treatment protocols according to diverse human diseases. However, to the best of our knowledge, few examples have been reported to selectively control autophagy process and ultimately achieve efficient therapeutic potential. In this study, monolayers of poly (acryloyl-l, d and racemic valine) (l-PAV-AuNPs, d-PAV-AuNPs and l/d-PAV-AuNPs) chiral molecules were anchored on the surfaces of gold nanoparticles (PAV-AuNPs), and the subsequent chirality-selective effects on autophagy activation were thoroughly studied. The cytotoxicity induced by PAV-AuNPs towards MDA-MB-231 cells (Breast cancer cells) was achieved mainly through autophagy and showed chirality-dependent, with d-PAV-AuNPs exhibiting high autophagy-inducing activity in vitro and in vivo. In contrast, the PAV-AuNPs exhibited autophagy inactivation for normal cells, e.g., 3T3 fibroblasts and HBL-100 cells. The chirality-selective autophagy activation effect in MDA-MB-231 cells was likely attributed to the chirality-variant ROS generation, cellular uptake and their continuous autophagy stimulus. Furthermore, the intratumoral injection of d-PAV-AuNPs could largely suppress the tumor growth but exhibit negligible toxicity in vivo. As the first exploration on stereospecific NPs for autophagy induction, this work not only substantiates that chiral polymer coated NPs can selective induce autophagy-specific in cancer cells and achieve a high tumor eradication efficiency in vivo, but also opens up a new direction in discovering unprecedented stereospecific nanoagents for autophagy-associated tumor treatment.

Oligohistidine and targeting peptide functionalized TAT-NLS for enhancing cellular uptake and promoting angiogenesis in vivo

Abstract: Gene therapy has been developed and used in medical treatment for many years, especially for the enhancement of endothelialization and angiogenesis. But slow endosomal escape rate is still one of the major barriers to successful gene delivery. In order to evaluate whether introducing oligohistidine (Hn) sequence into gene carriers can promote endosomal escape and gene transfection or not, we designed and synthesized Arg-Glu-Asp-Val (REDV) peptide functionalized TAT-NLS-Hn (TAT: typical cell-penetrating peptide, NLS: nuclear localization signals, Hn: oligohistidine sequence, n: 4, 8 and 12) peptides with different Hn sequence lengths. pEGFP-ZNF580 (pZNF580) was condensed by these peptides to form gene complexes, which were used to transfect human umbilical vein endothelial cells (HUVECs). MTT assay showed that the gene complexes exhibited low cytotoxicity for HUVECs. The results of cellular uptake and co-localization ratio demonstrated that the gene complexes prepared from TAT-NLS-Hn with long Hn sequence (n = 12) benefited for high internalization efficiency of pZNF580. In addition, the results of western blot analysis and PCR assay of REDV-TAT-NLS-H12/pZNF580 complexes showed significantly enhanced gene expression at protein and mRNA level. Wound healing assay and transwell migration assay also confirmed the improved proliferation and migration ability of the transfected HUVECs by these complexes. Furthermore, the in vitro and in vivo angiogenesis assay illustrated that these complexes could promote the tube formation ability of HUVECs. The above results indicated that the delivery efficiency of pZNF580 and its expression could be enhanced by introducing Hn sequence into gene carriers. The Hn sequence in REDV-TAT-NLS-Hn is beneficial for high gene transfection. These REDV and Hn functionalized TAT-NLS peptides are promising gene carriers in gene therapy.