Toxicity of inorganic nanomaterials in biomedical imaging

Inorganic nanoparticles have shown promising potentials as novel biomedical imaging agents with high sensitivity, high spatial and temporal resolution. To translate the laboratory innovations into clinical applications, their potential toxicities are highly concerned and have to be evaluated comprehensively both in vitro and in vivo before their clinical applications. In this review, we first summarized the in vivo and in vitro toxicities of the representative inorganic nanoparticles used in biomedical imagings. Then we further discuss the origin of nanotoxicity of inorganic nanomaterials, including ROS generation and oxidative stress, chemical instability, chemical composition, the surface modification, dissolution of nanoparticles to release excess free ions of metals, metal redox state, and left-over chemicals from synthesis, etc. We intend to provide the readers a better understanding of the toxicology aspects of inorganic nanomaterials and knowledge for achieving optimized designs of safer inorganic nanomaterials for clinical applications.     

Quantum dots for tracking cellular transport of lectin-functionalized nanoparticles

Successful drug delivery by functionalized nanocarriers largely depends on their efficient intracellular transport which has not yet been fully understood. We developed a new tracking technique by encapsulating quantum dots into the core of wheat germ agglutinin-conjugated nanoparticles (WGA-NP) to track cellular transport of functionalized nanocarriers. The resulting nanoparticles showed no changes in particle size, zeta potential or biobinding activity, and the loaded probe presented excellent photostability and tracking ability. Taking advantage of these properties, cellular transport profiles of WGA-NP in Caco-2 cells was demonstrated. The cellular uptake begins with binding of WGA to its receptor at the cell surface. The subsequent endocytosis happened in a cytoskeleton-dependent manner and by means of clathrin and caveolae-mediated mechanisms. After endosome creating, transport occurs to both trans-Golgi and lysosome. Our study provides new evidences for quantum dots as a cellular tracking probe of nanocarriers and helps understand intracellular transport profile of lectin-functionalized nanoparticles.     

Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery

Abstract

Topical or transdermal drug delivery is challenging because the skin acts as a natural and protective barrier. Therefore, several methods have been examined to increase the permeation of therapeutic molecules into and through the skin. One approach is to use the nanoparticulate delivery system. Starting with liposomes and other vesicular systems, several other types of nanosized drug carriers have been developed such as solid lipid nanoparticles, nanostructured lipid carriers, polymer-based nanoparticles and magnetic nanoparticles for dermatological applications. This review article discusses how different particulate systems can interact and penetrate into the skin barrier. In this review, the effectiveness of nanoparticles, as well as possible mode of actions of nanoparticles, is presented. In addition to nanoparticles, cell-penetrating peptide (CPP)-mediated drug delivery into the skin and the possible mechanism of CPP-derived delivery into the skin is discussed. Lastly, the effectiveness and possible mechanism of CPP-modified nanocarriers into the skin are addressed.     

MNPs-IHSPN nanoparticles in multi-application with absorption of bio drugs in vitro

The aim of this project is to investigate the method of using a common buffer to determine the degree of stabilization and secretion of two drug molecules that have been analyzed in vitro. First, magnetic nanoparticles were synthesized and their structure was identified by instruments such as XPS (X-ray photoelectron spectroscopy) and FT-IR (Fourier transform infrared spectroscopy). The main purpose of this study was to investigate the stabilization and release of methotrexate on the surface of magnetic nanoparticles. The two temperatures were 37 and 25°, respectively. After reaction with the biomolecules, the adsorption rate for both drug molecules was about 60–80. PBS buffer was also used for diffusion of biomolecules and the results were analyzed by spectrophotometer analysis. With these results, the adsorption of cysteine and MTX was more than 60% and its release rate in MNPS-IHSPN was up to 90%, which means that high-strength stabilization and release by magnetic nanoparticles under external magnetic field and in vitro confirmed. The result of this project for the exchange of drugs by the surface of magnetic nanoparticles to repair damaged cells in the body of living organisms can be generalized.     

Mesoporous silica templated-albumin nanoparticles with high doxorubicin payload for drug delivery assessed with a 3-D tumor cell model

Human serum albumin (HSA) nanoparticles emerge as promising carriers for drug delivery. Among challenges, one important issue is the design of HSA nanoparticles with a low mean size of ca. 50?nm and having a high drug payload. The original strategy developed here is to use sacrificial mesoporous nanosilica templates having a diameter close to 30?nm to drive the protein nanocapsule formation. This new approach ensures first an efficient high drug loading (ca. 30%) of Doxorubicin (DOX) in the porous silica by functionalizing silica with an aminosiloxane layer and then allows the one-step adsorption and the physical cross-linking of HSA by modifying the silica surface with isobutyramide (IBAM) groups. After silica template removal, homogenous DOX-loaded HSA nanocapsules (30–60?nm size) with high drug loading capacity (ca. 88%) are thus formed. Such nanocapsules are shown efficient in multicellular tumor spheroid models (MCTS) of human hepatocarcinoma cells by their significant growth inhibition with respect to controls. Such a new synthesis approach paves the way toward new protein based nanocarriers for drug delivery.     

Application of magnetic nanoparticles in smart enzyme immobilization

Immobilization of enzymes enhances their properties for efficient utilization in industrial processes. Magnetic nanoparticles, due to their high surface area, large surface-to-volume ratio and easy separation under external magnetic fields, are highly valued. Significant progress has been made to develop new catalytic systems that are immobilized onto magnetic nanocarriers. This review provides an overview of recent developments in enzyme immobilization and stabilization protocols using this technology. The current applications of immobilized enzymes based on magnetic nanoparticles are summarized and future growth prospects are discussed. Recommendations are also given for areas of future research.     

Detoxifying Antitumoral Drugs via Nanoconjugation: The Case of Gold Nanoparticles and Cisplatin

Nanoparticles (NPs) have emerged as a potential tool to improve cancer treatment. Among the proposed uses in imaging and therapy, their use as a drug delivery scaffold has been extensively highlighted. However, there are still some controversial points which need a deeper understanding before clinical application can occur. Here the use of gold nanoparticles (AuNPs) to detoxify the antitumoral agent cisplatin, linked to a nanoparticle via a pH-sensitive coordination bond for endosomal release, is presented. The NP conjugate design has important effects on pharmacokinetics, conjugate evolution and biodistribution and results in an absence of observed toxicity. Besides, AuNPs present unique opportunities as drug delivery scaffolds due to their size and surface tunability. Here we show that cisplatin-induced toxicity is clearly reduced without affecting the therapeutic benefits in mice models. The NPs not only act as carriers, but also protect the drug from deactivation by plasma proteins until conjugates are internalized in cells and cisplatin is released. Additionally, the possibility to track the drug (Pt) and vehicle (Au) separately as a function of organ and time enables a better understanding of how nanocarriers are processed by the organism.     

Metallic nanoparticles: microbial synthesis and unique properties for biotechnological applications,bioavailability and biotransformation

The impact of nanotechnology in all areas of science and technology is evident. The expanding availability of a variety of nanostructures with properties in the nanometer size range has sparked widespread interest in their use in biotechnological systems, including the field of environmental remediation. Nanomaterials can be used as catalysts, adsorbents, membranes, water disinfectants and additives to increase catalytic activity and capability due to their high specific surface areas and nanosize effects. Thus, nanomaterials appear promising for new effective environmental technologies. Definitely, nanotechnology applications for site remediation and wastewater treatment are currently in research and development stages, and new innovations are underway. The synthesis of metallic nanoparticles has been intensively developed not only due to its fundamental scientific interest but also for many technological applications. The use of microorganisms in the synthesis of nanoparticles is a relatively new eco-friendly and promising area of research with considerable potential for expansion. On the other hand, chemical synthesis occurs generally under extreme conditions (e.g. pH, temperature) and also chemicals used may have associated environmental and human health impacts. This review is an overview of current research worldwide on the use of microorganisms during the biosynthesis of metallic nanoparticles and their unique properties that make them good candidates for many applications, including in biotechnology.     

Magnetic Nanoparticles for the Delivery of Dapagliflozin to Hypoxic Tumors: Physicochemical Characterization and Cell Studies

In solid tumors, hypoxia (lack of oxygen) is developed, which leads to the development of resistance of tumor cells to chemotherapy and radiotherapy through various mechanisms. Nevertheless, hypoxic cells are particularly vulnerable when glycolysis is inhibited. For this reason, in this study, the development of magnetically targetable nanocarriers of the sodium-glucose transporter protein (SGLT2) inhibitor dapagliflozin (DAPA) was developed for the selective delivery of DAPA in tumors. This nanomedicine in combination with radiotherapy or chemotherapy should be useful for effective treatment of hypoxic tumors. The magnetic nanoparticles consisted of a magnetic iron oxide core and a poly(methacrylic acid)-graft-poly(ethyleneglycol methacrylate) (PMAA-g-PEGMA) polymeric shell. The drug (dapagliflozin) molecules were conjugated on the surface of these nanoparticles via in vivo hydrolysable ester bonds. The nanoparticles had an average size of ~ 70 nm and exhibited a DAPA loading capacity 10.75% (w/w) for a theoretical loading 21.68% (w/w). The magnetic responsiveness of the nanoparticles was confirmed with magnetophoresis experiments. The dapagliflozin-loaded magnetic nanoparticles exhibited excellent colloidal stability in aqueous and biological media. Minimal (less than 15% in 24 h) drug release from the nanoparticles occurred in physiological pH 7.4; however, drug release was significantly accelerated in pH 5.5. Drug release was also accelerated (triggered) under the influence of an alternating magnetic field. The DAPA-loaded nanoparticles exhibited higher in vitro anticancer activity (cytotoxicity) against A549 human lung cancer cells than free DAPA. The application of an external magnetic field gradient increased the uptake of nanoparticles by cells, leading to increased cytotoxicity. The results justify further in vivo studies of the suitability of DAPA-loaded magnetic nanoparticles for the treatment of hypoxic tumors.     

无机纳米粒子作为基因载体的研究进展

转染是将具生物功能的核酸转移、运送到细胞内,并使其在细胞内维持生物功能的过程。作为现代生物化学和分子生物学中的一种主要技术手段,转染对于基因治疗有重要的意义。无机纳米粒子作为基因载体受到人们日益广泛的关注,其具有易于制备,可进行多样化的表面修饰等多种优势。本文将概述无机纳米粒子作为基因载体的现状及其对基因表达的影响。     

Nanostructured Antimicrobials in Food Packaging—Recent Advances

Active food packaging systems promote better food quality and/or stability, such as by releasing antimicrobial agents into food. Advantages of adding antimicrobials to the packaging material instead of into the bulk food include controlled diffusion, reduced antimicrobial contents, and improved cost effectiveness. Nanostructured antimicrobials are especially effective due to their high specific surface area. The present review is focused on recent advances and findings on the main nanostructured antimicrobial packaging systems for food packaging purposes. Several kinds of nanostructures, including both inorganic particles and organic structures, have been proven effective antimicrobials by different mechanisms of action and with different application scopes. Moreover, there are systems containing nanocarriers to protect antimicrobials and deliver them in a controlled fashion. On the other hand, scientific data about migration of nanostructures onto food and their toxicity are still limited, requiring special attention from researchers and regulation sectors.     

Nanosilver—The burgeoning therapeutic molecule and its green synthesis

Nanotechnology is a field that is burgeoning day by day, making an impact in all spheres of human life. Biological methods of synthesis have paved way for the “greener synthesis” of nanoparticles and these have proven to be better methods due to slower kinetics, they offer better manipulation and control over crystal growth and their stabilization. This has motivated an upsurge in research on the synthesis routes that allow better control of shape and size for various nanotechnological applications. Nanosilver has developed as a potent antibacterial, antifungal, anti-viral and anti-inflammatory agent. The recent advancement in the field includes the enzymatic method of synthesis suggesting enzymes to be responsible for the nanoparticle formation. The biomedical applications of silver nanoparticle can be effective by the use of biologically synthesized nanoparticles which minimize the factors such as toxicity and cost and are found to be exceptionally stable. The targeting of cancer cells using silver nanoparticles has proven to be effective, but neither the exact mechanism of action nor the modes of activation of the downstream signaling molecules have been revealed yet. The review illustrates a probable signaling pathway and mechanism by which silver nanoparticles target the cancer cells. The current review also examines the historical background of nanoparticles, role of silver nanoparticles in various biomedical applications and also focusing on better methods of the synthesis of nanoparticles.     

Silver nanoparticles as a new generation of antimicrobials

Silver has been in use since time immemorial in the form of metallic silver, silver nitrate, silver sulfadiazine for the treatment of burns, wounds and several bacterial infections. But due to the emergence of several antibiotics the use of these silver compounds has been declined remarkably. Nanotechnology is gaining tremendous impetus in the present century due to its capability of modulating metals into their nanosize, which drastically changes the chemical, physical and optical properties of metals. Metallic silver in the form of silver nanoparticles has made a remarkable comeback as a potential antimicrobial agent. The use of silver nanoparticles is also important, as several pathogenic bacteria have developed resistance against various antibiotics. Hence, silver nanoparticles have emerged up with diverse medical applications ranging from silver based dressings, silver coated medicinal devices, such as nanogels, nanolotions, etc.     

Magnetic nanoparticle-based hyperthermia for cancer treatment

Nanotechnology involves the study of nature at a very small scale, searching new properties and applications. The development of this area of knowledge affects greatly both biotechnology and medicine disciplines. The use of materials at the nanoscale, in particular magnetic nanoparticles, is currently a prominent topic in healthcare and life science. Due to their size-tunable physical and chemical properties, magnetic nanoparticles have demonstrated a wide range of applications ranging from medical diagnosis to treatment. Combining a high saturation magnetization with a properly functionalized surface, magnetic nanoparticles are provided with enhanced functionality that allows them to selectively attach to target cells or tissues and play their therapeutic role in them. In particular, iron oxide nanoparticles are being actively investigated to achieve highly efficient carcinogenic cell destruction through magnetic hyperthermia treatments. Hyperthermia in different approaches has been used combined with radiotherapy during the last decades, however, serious harmful secondary effects have been found in healthy tissues to be associated with these treatments. In this framework, nanotechnology provides a novel and original solution with magnetic hyperthermia, which is based on the use of magnetic nanoparticles to remotely induce local heat when a radiofrequency magnetic field is applied, provoking a temperature increase in those tissues and organs where the tumoral cells are present. Therefore, one important factor that determines the efficiency of this technique is the ability of magnetic nanoparticles to be driven and accumulated in the desired area inside the body. With this aim, magnetic nanoparticles must be strategically surface functionalized to selectively target the injured cells and tissues.     

Hazard Reduction in Nanotechnology

The release of hazardous substances is a matter of concern for nanotechnology. This may include some nanoparticles, reactants, by‐products, and solvents. The use of low‐hazard solvents may reduce the hazards from nanoparticle production and nanomaterial processing. The hazards of inorganic nanoparticles may be reduced by modifying their chemical composition, surface characteristics, or structure. In nanomedicine, optimizing the balance between persistence and excretion and preventing the release of toxic degradation products may reduce hazard. In applications of fixed inorganic nanoparticles, the focus should be on preventing the release of such particles and of hazardous compounds during the product life cycle. When, after exhaustion of known hazard reduction options, significant hazard remains, other approaches merit consideration.     

Nanomaterials for cancer therapy and imaging

A variety of organic and inorganic nanomaterials with dimensions below several hundred nanometers are recently emerging as promising tools for cancer therapeutic and diagnostic applications due to their unique characteristics of passive tumor targeting. A wide range of nanomedicine platforms such as polymeric micelles, liposomes, dendrimers, and polymeric nanoparticles have been extensively explored for targeted delivery of anti-cancer agents, because they can accumulate in the solid tumor site via leaky tumor vascular structures, thereby selectively delivering therapeutic payloads into the desired tumor tissue. In recent years, nanoscale delivery vehicles for small interfering RNA (siRNA) have been also developed as effective therapeutic approaches to treat cancer. Furthermore, rationally designed multi-functional surface modification of these nanomaterials with cancer targeting moieties, protective polymers, and imaging agents can lead to fabrication versatile theragnostic nanosystems that allow simultaneous cancer therapy and diagnosis. This review highlights the current state and future prospects of diverse biomedical nanomaterials for cancer therapy and imaging.     

Development of peptide and protein nanotherapeutics by nanoencapsulation and nanobioconjugation

The targeted delivery of therapeutic peptide by nanocarriers systems requires the knowledge of interactions of nanomaterials with the biological environment, peptide release, and stability of therapeutic peptides. Therapeutic application of nanoencapsulated peptides are increasing exponentially and >1000 peptides in nanoencapsulated form are in different clinical/trial phase. This review covers current scenario of therapeutic protein and peptides encapsulation on polymer to metallic nanocarriers including methods of protein encapsulation, peptide bioconjugation on nanoparticles, stability enhancement of encapsulated proteins and its biomedical applications.     

Generic delivery of payload of nanoparticles intracellularly via hybrid polymer capsules for bioimaging applications

Towards the goal of development of a generic nanomaterial delivery system and delivery of the 'as prepared' nanoparticles without 'further surface modification' in a generic way, we have fabricated a hybrid polymer capsule as a delivery vehicle in which nanoparticles are loaded within their cavity. To this end, a generic approach to prepare nanomaterials-loaded polyelectrolyte multilayered (PEM) capsules has been reported, where polystyrene sulfonate (PSS)/polyallylamine hydrochloride (PAH) polymer capsules were employed as nano/microreactors to synthesize variety of nanomaterials (metal nanoparticles; lanthanide doped inorganic nanoparticles; gadolinium based nanoparticles, cadmium based nanoparticles; different shapes of nanoparticles; co-loading of two types of nanoparticles) in their hollow cavity. These nanoparticles-loaded capsules were employed to demonstrate generic delivery of payload of nanoparticles intracellularly (HeLa cells), without the need of individual nanoparticle surface modification. Validation of intracellular internalization of nanoparticles-loaded capsules by HeLa cells was ascertained by confocal laser scanning microscopy. The green emission from Tb(3+) was observed after internalization of LaF(3):Tb(3+)(5%) nanoparticles-loaded capsules by HeLa cells, which suggests that nanoparticles in hybrid capsules retain their functionality within the cells. In vitro cytotoxicity studies of these nanoparticles-loaded capsules showed less/no cytotoxicity in comparison to blank capsules or untreated cells, thus offering a way of evading direct contact of nanoparticles with cells because of the presence of biocompatible polymeric shell of capsules. The proposed hybrid delivery system can be potentially developed to avoid a series of biological barriers and deliver multiple cargoes (both simultaneous and individual delivery) without the need of individual cargo design/modification.     

Preparation and characterization of chitosan and trimethyl-chitosanmodified poly-(ε-caprolactone) nanoparticles as DNA carriers

The purpose of this research was to prepare poly-(ε-caprolactone) (PCL) particles by an emulsion-diffusion-evaporation method using a blend of poly-(vinyl alcohol) and chitosan derivatives as stabilizers. The chitosan derivatives used were chitosan hydrochloride and trimethyl chitosans (TMC) with varying degrees of quaternization. Particle characteristics-size, zeta potential, surface morphology, cytotoxicity, and transfection efficiency-were investigated. The developed method yields PCL nanoparticles in the size range of 250 to 300 nm with a positive surface charge (2.5 to 6.8 mV). The cytotoxicity was found to be moderate and virtually independent of the stabilizers' concentration with the exception of the highly quaternized TMC (degree of substitution 66%) being significantly more toxic. In immobilization experiments with gel electrophoresis, it could be shown that these cationic nanoparticles (NP) form stable complexes with DNA at a NP:DNA ratio of 3:1. These nanoplexes showed a significantly higher transfection efficiency on COS-1 cells than naked DNA. Published: August 10, 2005     

Fabrication and Intracellular Delivery of Doxorubicin/Carbonate Apatite Nanocomposites: Effect on Growth Retardation of Established Colon Tumor

In continuing search for effective treatments of cancer, the emerging model aims at efficient intracellular delivery of therapeutics into tumor cells in order to increase the drug concentration. However, the implementation of this strategy suffers from inefficient cellular uptake and drug resistance. Therefore, pH-sensitive nanosystems have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms in endosomal or lysosomal acidic pH along with endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. Here, novel pH sensitive carbonate apatite has been fabricated to efficiently deliver anticancer drug Doxorubicin (DOX) to cancer cells, by virtue of its pH sensitivity being quite unstable under an acidic condition in endosomes and the desirable size of the resulting apatite-DOX for efficient cellular uptake as revealed by scanning electron microscopy. Florescence microscopy and flow cytometry analyses demonstrated significant uptake of drug (92%) when complexed with apatite nanoparticles. In vitro chemosensitivity assay revealed that apatite-DOX nanoparticles executed high cytotoxicity in several human cancer cell lines compared to free drugs and consequently apatite-DOX-facilitated enhanced tumor inhibitory effect was observed in colorectal tumor model within BALB/cA nude mice, thereby shedding light on their potential applications in cancer therapy.