Silica-based nanoparticles for biomedical applications

In this short review we highlight novel uses of silica-based nanoparticles (NPs) in the biomedical sector. Silica NPs are widely used in nanotechnology because they are easy to prepare and inexpensive to produce. Their specific surface characteristics, porosity and capacity for functionalization make them good tools for biomolecule detection and separation, providing solid media for drug delivery systems and acting as contrast agent protectors. In addition, they are used as safety and biocompatible pharmaceutical additives. Here, we focus on novel techniques based on silica NPs for the most important biomedical applications.     

Characterization and toxicology evaluation of zirconium oxide nanoparticles on the embryonic development of zebrafish,Danio rerio

Zirconia oxide nanoparticles (ZrO₂NPs) are known to be one of the neutral bioceramic metal compounds that has been widely used for their beneficial applications in many biomedical areas, in dental implants, bone joint replacements, drug delivery vehicles, and in various industrial applications. To study the effects of ZrO₂NPs on zebrafish model, we used early life stages of the zebrafish (Danio rerio) to examine such effects on embryonic development in this species. ZrO₂NPs were synthesized by the sol-gel method, size about 15–20?nm and characterized by SEM, EDX, XRD, FTIR, UV-Vis Spectra. In this study, zebrafish embryos were treated with ZrO₂NPs 0.5, 1, 2, 3, 4, or 5?μg of nanoparticles/ml during 24–96?hour post fertilization (hpf). The results showed that ≥0.5–1?μg/ml of ZrO₂NPs instigated developmental acute toxicity in these embryos, causing mortality, hatching delay, and malformation. ZrO₂NPs exposure induced axis bent, tail bent, spinal cord curvature, yolk-sac, and pericardial edema. A typical phenotype was observed as an unhatched dead embryo at ≥1?μg/ml of ZrO₂NPs exposure. This study is one of the first reports on developmental toxicity of zebrafish embryos caused by zirconium oxide nanoparticles in aquatic environments. Our results show that exposure of zirconium oxide nanoparticles is more toxic to embryonic zebrafish at lower concentrations. The results will contribute to the current understanding of the potential biomedical toxicological effects of nanoparticles and support the safety evaluation and synthesis of Zirconia oxide nanoparticles.     

Mechanism of anti-angiogenic property of gold nanoparticles: role of nanoparticle size and surface charge

Discovering therapeutic inorganic nanoparticles (NPs) is evolving as an important area of research in the emerging field of nanomedicine. Recently, we reported the anti-angiogenic property of gold nanoparticles (GNPs): It inhibits the function of pro-angiogenic heparin-binding growth factors (HB-GFs), such as vascular endothelial growth factor 165 (VEGF165) and basic fibroblast growth factor (bFGF), etc. However, the mechanism through which GNPs imparts such an effect remains to be investigated. Using GNPs of different sizes and surface charges, we demonstrate here that a naked GNP surface is required and core size plays an important role to inhibit the function of HB-GFs and subsequent intracellular signaling events. We also demonstrate that the inhibitory effect of GNPs is due to the change in HB-GFs conformation/configuration (denaturation) by the NPs, whereas the conformations of non-HB-GFs remain unaffected. We believe that this significant study will help structure-based design of therapeutic NPs to inhibit the functions of disease-causing proteins.

From the Clinical Editor

In this landmark paper by Arvizo and colleagues, the angiogenesis inhibitor effects of gold nanoparticles were investigated as the function of size and charge. This study will pave the way to the development of therapeutic NPs that inhibit the functions of pathogenic proteins.     

Carbon nanomaterials combined with metal nanoparticles for theranostic applications

Among targeted delivery systems, platforms with nanosize dimensions, such as carbon nanomaterials (CNMs) and metal nanoparticles (NPs), have shown great potential in biomedical applications. They have received considerable interest in recent years, especially with respect to their potential utilization in the field of cancer diagnosis and therapy. The many functions of nanomaterials provide opportunities to use them as multimodal agents for theranostics, a combination of therapy and diagnosis. Carbon nanotubes and graphene are some of the most widely used CNMs because of their unique structural and physicochemical properties. Their high specific surface area allows for efficient drug loading and the possibility of functionalization with various bioactive molecules. In addition, CNMs are ideal platforms for the attachment of NPs. In the biomedical field, NPs have also shown tremendous potential for use in drug delivery, non-invasive tumour imaging and early detection due to their optical and magnetic properties. NP/CNM hybrids not only combine the unique properties of the NPs and CNMs but they also exhibit new properties arising from interactions between the two entities. In this review, the preparation of CNMs conjugated to different types of metal NPs and their applications in diagnosis, imaging, therapy and theranostics are presented.     

Exploring gold nanoparticles interaction with mucins: A spectroscopic-based study

The interaction between two mucin types (mucin from porcine stomach – PGM and mucin from bovine submaxillary glands – BSM) and gold nanoparticles (GNPs) of various size (5, 20 and 40?nm) and functionalization (with cysteamine or thioglycolic acid) was studied under physiological conditions, in order to investigate the affinity of the nanoparticles to the proteins.Different methods are employed to monitor the interactions: UV–vis and fluorescence spectroscopy, fluorescence lifetime, circular dichroism and transmission electron microscopy. These studies have shown the formation of a complex between GNPs and both PGM and BSM.This aspect could be of great importance for the use of gold nanoparticles for biomedical purposes in those diseases where qualitative and quantitative mucin anomalies play an essential role in mucus composition and rheology.     

Applications of plant-based nanoparticles in nanomedicine: A review

Plants encompass numerous phytochemicals like flavonoids, alkaloids, tannins, saponins, and other metabolites that have a major impact on the generation of nanomaterials with chief implications in current therapeutic methods for a variety of diseases including cancers; herbal extracts serve as potential means for the generation of nanomaterial via safer pathways. Various secondary metabolites embodying the extracts function as stabilizing and or reducing agents to form nanoparticles (NPs) and such plant extract-derived NPs have diverse applications in assorted fields particularly in nanomedicine. Numerous groups have recently generated, green-synthesized metal nanoparticles deploying various bio-resources such as plant, bacteria, fungus, etc. Herein, prominent recent advancements for various biomedical applications of such nanomaterials, namely for cancer and other treatment of diseases are reviewed with discussions on in vivo and in vitro toxicity experiments pertaining to the potential intriguing pharmaceutical appliances.     

Modeling uptake of nanoparticles in multiple human cells using structure–activity relationships and intercellular uptake correlations

Biomedical applications of nanoparticles (NPs) are largely dependent on their cellular uptake potential that enables them to reach the specific targets in the body. Experimental determination of cellular uptake of diverse functionalized NPs in different human cell types is tedious, expensive and time intensive, hence compelling for alternative methods. We developed quantitative structure–activity relationship (QSAR) models for predicting uptake of functionalized NPs in multiple cell types in accordance with the OECD guidelines. The decision treeboost QSAR models precisely predicted uptake of 104 NPs in five different cell types yielding high R² between experimental and model predicted values in the respective training (>0.966) and test (>0.914) sets. The cross-validation Q² values ranged between 0.627 and 0.926. Low RMSE (<0.11) and MAE (<0.09) in test data emphasized for the usefulness of developed models for predicting new NPs, which outperformed the previous reports. Relevant structural features of NPs (modifier) that were responsible and influence the cellular permeability were identified. Here, we also attempted to develop intercellular uptake correlations based quantitative activity–activity relationship (QAAR) models for predicting cellular viability of NPs for all the cell types. The performances of all the 20 developed QAAR models were highly comparable with the QSAR models. The applicability domains of the developed models were defined using leverage method. The proposed QAAR models can be employed for extrapolating activity endpoints of NPs to either of the five cell types when the data for the other cell type are available. The developed models can be used as tools for screening new functionalized NPs for their cell-specific affinities prior to their biomedical applications.     

Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice

The current study aimed to develop gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) as drug carriers for temozolomide (TMZ) and investigate the possible therapeutic effects of intratracheal inhalation of nanoformulation of TMZ-loaded gold nanoparticles (TGNPs) and liposome-embedded TGNPs (LTGNPs) against urethane-induced lung cancer in BALB/c mice. Physicochemical characters and zeta potential studies for gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) were performed. The current study was conducted by inducing lung cancer chemically via repeated exposure to urethane in BALB/C mice. GNPs and LGNPs were exhibited in uniform spherical shape with adequate dispersion stability. GNPs and LGNPs showed no significant changes in comparison to control group with high safety profile, while TGNPs and LTGNPs succeed to improve all biochemical data and histological patterns. GNPs and LGNPs are promising drug carriers and succeeded in the delivery of small and efficient dose of temozolomide in treatment lung cancer. Antitumor activity was pronounced in animal-treated LTGNPs, these effects may be due to synergistic effects resulted from combination of temozolomide and gold nanoparticles and liposomes that may improve the drug distribution and penetration.     

The integrated biomarker response: a suitable tool to evaluate toxicity of metal-based nanoparticles

Nanotechnology is a much promising field of science and technology with applications in a wide range of areas such as electronics, biomedical applications, energy and cosmetics. Metal-based engineered nanoparticles (ENPs) are common in many technological applications; some of the most common nanoparticles available commercially are silver, gold, copper oxide (CuO), zinc oxide (ZnO) and cadmium sulphide (CdS). The toxicity of metal-based NPs may be either due to their specific physical characteristics as NPs or to the specific toxicity of metals released from NPs under environmental conditions. In this study we evaluated the toxicity effects of a range of ENPs (Ag, Au, CuO, CdS, ZnO) along with a control containing equivalent quantities of dissolved metal on two endobenthic species: the ragworm Hediste diversicolor and the bivalve Scrobicularia plana. A suite of complementary biomarkers was used to reveal toxicity effects. A common challenge in multibiomarkers studies is to go beyond an independent interpretation of each one, and to assess a global response of individuals. The Integrated Biomarker Response (IBR) was calculated for both species exposed to the different metal-based ENPs studied or to their dissolved metal counterpart to provide efficient and easy tools for environmental managers. We evidence that metal-based NPs lead to an overall difference in biological responses from that of their dissolved counterparts. The IBR could thus be considered as an efficient tool to transfer research results to stakeholders with possible implementation for regulatory purposes.     

Nanotoxicity of gold and gold-cobalt nanoalloy

Nanotoxicology test of gold nanoparticles (Au NPs) and gold-cobalt (Au-Co) nanoalloy is an important step in their safety evaluation for biomedical applications. The Au and Au-Co NPs were prepared by reducing the metal ions using sodium borohydride (NaBH(4)) in the presence of polyvinyl pyrrolidone (PVP) as a capping material. The average size and shape of the nanoparticles (NPs) were characterized using high resolution transmission electron microscopy (HRTEM). Cobalt presence in the nanoalloy was confirmed by energy dispersive X-ray spectroscopy (EDX) analysis, and the magnetic properties of these particles were determined using a vibrating sample magnetometer (VSM). The Gold and gold-cobalt NPs of average size 15 ± 1.5 nm were administered orally to mice with a dose of 80, 160, and 320 mg/kg per body weight (bw) using gavages. Samples were collected after 7 and 14 days of the treatment. The results indicated that the Au-Co NPs were able to induce significant alteration in the tumor-initiating genes associated with an increase of micronuclei (MNs) formation and generation of DNA adduct (8-hydroxy-2-deoxyguanosine, 8-OHdG) as well as a reduction in the glutathione peroxidase activity. This action of Au-Co NPs was observed using 160 and 320 mg/kg bw at both time intervals. However, Au NPs had much lower effects than Au-Co NPs on alteration in the tumor-initiating genes, frequency of MNs, and generation of 8-OHdG as well as glutathione peroxidase activity except with the highest dose of Au NPs. This study suggests that the potential to cause in vivo genetic and antioxidant enzyme alterations due to the treatment by Au-Co nanoalloy may be attributed to the increase in oxidative stress in mice.     

Electrospun nanofibers as versatile platform in antimicrobial delivery: current state and perspectives

Nanotechnology has attracted increasing interest in different aspects of biotechnology. The fabrication of electrospun nanofibers (NFs) containing antibacterial agents for antimicrobial applications has been significantly enhanced in recent years. In the current review, various electrospun NFs with antimicrobial properties were introduced and evaluated. The main focus was on the recent developments and applications of antimicrobial electrospun NFs incorporated with different antimicrobial agents, including metal nanoparticles (NPs), antibiotics, quaternized ammonium compounds, triclosan, herbal extracts, carbon nanomaterials, and antimicrobial biopolymers with inherent antimicrobial properties. The search results revealed that antimicrobial containing electrospun NFs had enhanced antimicrobial performance with various biomedical applications compared to the traditional antimicrobial materials. According to the reported results, most of the studies were of an investigative nature and were mostly based on in vitro tests. Hence, further examination on in vivo clinical performance of these antimicrobial NFs seems necessary. However, these antimicrobial NFs appear to have the potential to achieve clinical usefulness and commercial production in the near future.     

Interaction of gold nanoparticles and nickel(II) sulfate affects dendritic cell maturation

Despite many investigations have focused on the pristine toxicity of gold nanoparticles (GNPs), little is known about the outcome of co-exposure and interaction of GNPs with heavy metals which can possibly detoxify or potentiate them. Here, the combined exposure of nickel (II) sulfate (NiSO₄) and GNPs on the maturation response of dendritic cells (DCs) was explored. Exposure to GNPs or NiSO₄ separately induced cell activation. When cells were exposed to a mixture of both, however, the observed cell activation pattern indicated a competitive rather than an additive effect of both inducers with levels similar to those induced by NiSO₄ alone. Quantification of the GNP uptake by DCs demonstrated a significant decrease in intracellular gold content during co-incubation with NiSO₄. An extensive physiochemical characterization was performed to determine the interaction between GNPs and NiSO₄ in the complex physiological media using nanoparticle tracking analyses, disc centrifugation, UV–visible spectroscopy, ICP-MS analyses, zeta potential measurements, electron microscopy, and proteomics. Although GNPs and NiSO₄ did not directly interact with each other, the presence of NiSO₄ in the physiological media resulted in changes in GNPs' charge and their associated protein corona (content and composition), which may contribute to a decreased cellular uptake of GNPs and sustaining the nickel-induced DC maturation. The presented results provide new insights in the interaction of heavy metals and NPs in complex physiological media. Moreover, this study highlights the necessity of mixture toxicology, since these combined exposures are highly relevant for human subjection to NPs and risk assessment of nanomaterials.     

Hydrothermal combustion based ZnO nanoparticles from Croton bonplandianum: Characterization and evaluation of antibacterial and antioxidant potential

The present study reports facile phytomediated synthesis of ZnO nanoparticles (ZnO NPs) using hydrothermal combustion from Croton bonplandianum Bail. The characterization studies revealed that an average 44 nm size spherical ZnO NPs with high zinc composition having good crystalline nature. FTIR analysis confirmed the presence of functional groups O–H, sp3 C–H bend, and alkoxy C–O functional groups which might be involved in capping and reduction for ZnO NPs synthesis. The biosynthesized ZnO NPs exhibited potent antibacterial activity against Gram-positive and Gram-negative bacteria. The MIC results revealed that ZnO NPs were most effective against Bacillus cereus whereas least sensitive towards Pseudomonas aeruginosa and Vibrio parahaemolyticus. This investigation suggests that biosynthesized ZnO NPs are promising agents for antibacterial and antioxidant applications in the biomedical field.     

Next‐Generation Magnetic Nanocomposites: Cytotoxic and Genotoxic Effects of Coated and Uncoated Ferric Cobalt Boron (FeCoB) Nanoparticles In Vitro

Metal nanoparticles (NPs) have unique physicochemical properties and a widespread application scope depending on their composition and surface characteristics. Potential biomedical applications and the growing diversity of novel nanocomposites highlight the need for toxicological hazard assessment of next‐generation magnetic nanomaterials. Our study aimed to evaluate the cytotoxic and genotoxic properties of coated and uncoated ferric cobalt boron (FeCoB) NPs (5–15 nm particle size) in cultured normal human dermal fibroblasts. Cell proliferation was assessed via ATP bioluminescence kit, and DNA breakage and chromosomal damage were measured by alkaline comet assay and micronucleus test. Polyacryl acid‐coated FeCoB NPs [polyacrylic acid (PAA)‐FeCoB NPs) and uncoated FeCoB NPs inhibited cell proliferation at 10 μg/ml. DNA strand breaks were significantly increased by PAA‐coated FeCoB NPs, uncoated FeCoB NPs and l ‐cysteine‐coated FeCoB NPs (Cys‐FeCoB NPs), although high concentrations (10 μg/ml) of coated NPs (Cys‐ and PAA‐FeCoB NPs) showed significantly more DNA breakage when compared to uncoated ones. Uncoated FeCoB NPs and coated NPs (PAA‐FeCoB NPs) also induced the formation of micronuclei. Additionally, PAA‐coated NPs and uncoated FeCoB NPs showed a negative correlation between cell proliferation and DNA strand breaks, suggesting a common pathomechanism, possibly by oxidation‐induced DNA damage. We conclude that uncoated FeCoB NPs are cytotoxic and genotoxic at in vitro conditions. Surface coating of FeCoB NPs with Cys and PAA does not prevent but rather aggravates DNA damage. Further safety assessment and a well‐considered choice of surface coating are needed prior to application of FeCoB nanocomposites in biomedicine.     

Cancer-targeting multifunctionalized gold nanoparticles in imaging and therapy

Nanotechnology has provided many promising nanoplatforms for targeted cancer imaging and therapy. Among these platforms, gold nanoparticles (GNPs) play a unique role in medicine because of their excellent physical and chemical properties. To expand the applications of GNPs in medicine, amounts of targeting moieties, imaging labels, and therapeutic agents have been integrated into these particles to form multifunctionalized GNPs. In this review, we highlight recent advances of the fabrication of cancer-targeting multifunctionalized GNPs and their applications in imaging and therapy.     

Antibacterial activity, inflammatory response, coagulation and cytotoxicity effects of silver nanoparticles

The incorporation of nanoparticles (NPs) in industrial and biomedical applications has increased significantly in recent years, yet their hazardous and toxic effects have not been studied extensively. Here, we studied the effects of 24 nm silver NPs (AgNPs) on a panel of bacteria isolated from medical devices used in a hospital intensive care unit. The cytotoxic effects were evaluated in macrophages and the expression of the inflammatory cytokines IL-6, IL-10 and TNF-α were quantified. The effects of NPs on coagulation were tested in vitro in plasma-based assays. We demonstrated that 24 nm AgNPs were effective in suppressing the growth of clinically relevant bacteria with moderate to high levels of antibiotic resistance. The NPs had a moderate inhibitory effect when coagulation was initiated through the intrinsic pathway. However, these NPs are cytotoxic to macrophages and are able to elicit an inflammatory response. Thus, beneficial and potential harmful effects of 24 nm AgNPs on biomedical devices must be weighed in further studies in vivo. From the Clinical Editor: The authors of this study demonstrate that gallic acid reduced 24 nm Ag NPs are effective in suppressing growth of clinically relevant antibiotic resistant bacteria. However, these NPs also exhibit cytotoxic properties to macrophages and may trigger an inflammatory response. Thus, the balance of beneficial and potential harmful effects must be weighed carefully in further studies.     

Poly-(ethylene glycol) modified gelatin nanoparticles for sustained delivery of the anti-inflammatory drug Ibuprofen-Sodium: An in vitro and in vivo analysis

The limited bioavailability and rapid clearance of the anti-inflammatory drug Ibuprofen Sodium (IbS) necessitates repeated drug administration. To address this, injectable IbS loaded PEGylated gelatin nanoparticles (PIG NPs) of size ~ 200 nm and entrapment efficiency ~ 70%, providing sustained release in vitro were prepared by a modified two-step desolvation process. The developed nanomedicine, containing a range of IbS concentrations up to 1 mg/mL proved to be non-toxic, hemocompatible and non-immunogenic, when tested through various in vitro assays and was reaffirmed by in vivo cytokine analysis. HPLC analysis of intravenously administered PIG NPs showed a sustained release of IbS for ~ 4 days with improved bioavailability and pharmacokinetics when compared to bare IbS and IbS-loaded non-PEGylated GNPs. Histological analysis of liver and kidney revealed tissue integrity as in the control, indicating biocompatibility of PIG NPs. The results demonstrate improved plasma half-life of IbS when encapsulated within nanogelatin, thereby aiding reduction in its frequency of administration.From the Clinical EditorIn this preclinical study, improved plasma half-life of ibuprofen sodium was demonstrated when encapsulated within PEGylated gelatin nanoparticles of ~200 nm size, expected to lead to reduced frequency of administration in future clinical applications.     

Cellular uptake and nanoscale localization of gold nanoparticles in cancer using label-free confocal Raman microscopy

This work demonstrates the use of confocal Raman microscopy (CRM) to measure the dynamics of cellular uptake and localization of gold nanoparticles (GNP) with nanoscale resolution. This is important as nanoparticle cellular interactions are increasingly under investigation to support applications as diverse as drug delivery, gene transfection and a variety of heat and radiation based therapeutics. At the heart of these applications is a need to know the dynamics of nanoparticle cellular uptake and localization (i.e., cell membrane, cytoplasm or nucleus). This process can change dramatically based on size, charge, shape and ligand attached to the nanoparticle. While electron microscopy, atomic emission spectroscopy and histology can be used to assess cellular uptake, they are labor intensive and post-mortem and can miss critical dynamics of the process. For this reason investigators are increasingly turning to optically active nanoparticles that allow direct microscopic interrogation of uptake. Here we show that CRM adds to this evolving armamentarium as a fast, noninvasive, and label-free technique to dynamically study cellular uptake of GNPs with subcellular detail in cancer. Raman laser interaction with GNPs inside cells shows unique spectroscopic features corresponding to the intracellular localization of GNPs over 2 to 24 h at the membrane, cytoplasm or nucleus that are separately verified by histology (silver staining) and electron microscopy. These results show that CRM has the potential to facilitate high-throughput study of the dynamics and localization of a variety of GNPs in multiple cell types.