Mesoporous carbon nanomaterials in drug delivery and biomedical application

Abstract

Recent development of nano-technology provides highly efficient and versatile treatment methods to achieve better therapeutic efficacy and lower side effects of malignant cancer. The exploration of drug delivery systems (DDSs) based on nano-material shows great promise in translating nano-technology to clinical use to benefit patients. As an emerging inorganic nanomaterial, mesoporous carbon nanomaterials (MCNs) possess both the mesoporous structure and the carbonaceous composition, endowing them with superior nature compared with mesoporous silica nanomaterials and other carbon-based materials, such as carbon nanotube, graphene and fullerene. In this review, we highlighted the cutting-edge progress of carbon nanomaterials as drug delivery systems (DDSs), including immediate/sustained drug delivery systems and controlled/targeted drug delivery systems. In addition, several representative biomedical applications of mesoporous carbon such as (1) photo-chemo synergistic therapy; (2) delivery of therapeutic biomolecule and (3) in vivo bioimaging are discussed and integrated. Finally, potential challenges and outlook for future development of mesoporous carbon in biomedical fields have been discussed in detail.     

Developmental toxicity of low generation PAMAM dendrimers in zebrafish

Biological molecules and intracellular structures operate at the nanoscale; therefore, development of nanomedicines shows great promise for the treatment of disease by using targeted drug delivery and gene therapies. PAMAM dendrimers, which are highly branched polymers with low polydispersity and high functionality, provide an ideal architecture for construction of effective drug carriers, gene transfer devices and imaging of biological systems. For example, dendrimers bioconjugated with selective ligands such as Arg-Gly-Asp (RGD) would theoretically target cells that contain integrin receptors and show potential for use as drug delivery devices. While RGD-conjugated dendrimers are generally considered not to be cytotoxic, there currently exists little information on the risks that such materials pose to human health. In an effort to compliment and extend the knowledge gleaned from cell culture assays, we have used the zebrafish embryo as a rapid, medium throughput, cost-effective whole-animal model to provide a more comprehensive and predictive developmental toxicity screen for nanomaterials such as PAMAM dendrimers. Using the zebrafish embryo, we have assessed the developmental toxicity of low generation (G3.5 and G4) PAMAM dendrimers, as well as RGD-conjugated forms for comparison. Our results demonstrate that G4 dendrimers, which have amino functional groups, are toxic and attenuate growth and development of zebrafish embryos at sublethal concentrations; however, G3.5 dendrimers, with carboxylic acid terminal functional groups, are not toxic to zebrafish embryos. Furthermore, RGD-conjugated G4 dendrimers are less potent in causing embryo toxicity than G4 dendrimers. RGD-conjugated G3.5 dendrimers do not elicit toxicity at the highest concentrations tested and warrant further study for use as a drug delivery device.     

Effect of mesoporous silica nanoparticles on cell viability and markers of oxidative stress

Abstract

In the recent years, the use of mesoporous silica nanoparticles (MSNs) has been extended in biomedical fields such as cancer therapy, drug and gene delivery, biosensors, and enzyme immobilization. Although nanomaterials are currently being widely used in modern technology, there is a lack of information regarding to the health and environmental implications of manufactured nanomaterials. In the present study, the effects of MSNs and surface functionalized MSNs on cell viability, markers of oxidative damages (mainly intracellular reactive oxygen species (ROS) formation), and oxidative DNA damage were investigated in vitro in rat pheochromocytoma PC12 cells. Following exposure of these nanoparticles (1.95–1000?µg/mL) to PC12 cells for 12 and 24?h, no significant reduction of cell viability was observed compared with control. Moreover, ROS formation and oxidative DNA damage were not significantly changed by these nanoparticles even at high concentrations or prolong exposures. In conclusion, the results showed that neither MSNs nor functionalized MSNs exhibited any remarkable in vitro toxic properties in PC12 cells even at high concentration.     

Graphene Quantum Dots for Theranostics and Bioimaging

Since their advent in the early 1990s, nanomaterials hold promise to constitute improved technologies in the biomedical area. In particular, graphene quantum dots (GQDs) were conjectured to produce new or improve current methods used for bioimaging, drug delivery, and biomarker sensors for early detection of diseases. This review article critically compares and discusses current state-of-the-art use of GQDs in biology and health sciences. It shows the ability of GQDs to be easily functionalised for use as a targeted multimodal treatment and imaging platform. The in vitro and in vivo toxicity of GQDs are explored showing low toxicity for many types of GQDs.     

Gold nanostars-diagnosis,bioimaging and biomedical applications

Abstract

Gold Nanostars (GNS) have attracted tremendous attention toward themselves owing to their multi-branched structure and unique properties. These state of the art metallic nanoparticles possess intrinsic features like remarkable optical properties and exceptional physiochemical activities. These star-shaped gold nanoparticles can predominantly be utilized in biosensing, photothermal therapy, imaging, surface-enhanced Raman spectroscopy and target drug delivery applications due to their low toxicity and extraordinary optical features. In the current review, recent approaches in the matter of GNS in case of diagnosis, bioimaging and biomedical applications were summarized and reported. In this regard, first an overview about the structure and general properties of GNS were reported and thence detailed information regarding the diagnostic, bioimaging, photothermal therapy, and drug delivery applications of such novel nanomaterials were presented in detail. Summarized information clearly highlighting the superior capability of GNS as potential multi-functional materials for 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.     

Better safe than sorry: Understanding the toxicological properties of inorganic nanoparticles manufactured for biomedical applications

The development of nanoparticles for biomedical applications including medical imaging and drug delivery is currently undergoing a dramatic expansion. However, as the range of nanoparticle types and applications increases, it is also clear that the potential toxicities of these novel materials and the properties driving such toxic responses must also be understood. Indeed, a detailed assessment of the factors that influence the biocompatibility and/or toxicity of nanoparticles is crucial for the safe and sustainable development of the emerging nanotechnologies. This review summarizes some of the recent developments in the field of nanomedicine with particular emphasis on inorganic nanoparticles for drug delivery. The synthesis routes, physico-chemical characteristics, and cytotoxic properties of inorganic nanoparticles are thus explored and lessons learned from the toxicological investigation of three common types of engineered nanomaterials of titania, gold, and mesoporous silica are discussed. Emphasis is placed on the recognition versus non-recognition of engineered nanomaterials by the immune system, the primary surveillance system against microorganisms and particles, which, in turn, is intimately linked to the issue of targeted drug delivery using such nanomaterials as carrier systems.     

Biological responses to nanomaterials: understanding nano-bio effects on cell behaviors

Abstract

The unique properties of nanomaterials in drug delivery and tissue engineering have captured a great deal of attention as experimental tools in bioimaging, diagnostic, and therapeutic processes. A plenty of research have provided a strong evidence that nanostructures not only passively interact with cells but also actively engage and mediate cell functions and molecular processes. Undoubtedly, it is crucially important to better understand biological responses to engineered nanomaterials, especially in view of their potential for biomedical applications. In this review, we shall highlight recent advances in exploring nano-bio effects in diverse systems of nanoparticles, nanotopographies, and mixed composite scaffolds. We will also discuss their manipulating functions on cellular behaviors and important biological processes of adhesion, morphology, proliferation, migration, differentiation, and even hidden mechanisms including molecular signaling pathways. At last, the perspectives will be addressed for further directions of nanomaterial designs with the purpose of better drug delivery and cell therapies.     

骨刺片对斑马鱼胚胎发育的急性毒性研究

目的 研究两批骨刺片样品对斑马鱼胚胎发育的急性毒性作用。方法 以斑马鱼胚胎为试验对象,观察骨刺片样品A（0.01、0.05、0.10、0.20、0.30、0.50、1.00 mg/mL）、样品B（0.01、0.05、0.10、0.50、1.00、2.00、10.00 mg/mL）对斑马鱼胚胎发育的影响,包括胚胎致畸、致死检测;同时采用超高效液相色谱法-四极杆飞行时间-质谱（UPLC-QTOF-MS）对两批样品所含化学成分进行定性分析。结果 两批样品对斑马鱼胚胎发育的影响相似,主要表现为高浓度下的致死作用,低浓度下主要以发育滞后表型为主;但二者作用浓度存在一定差异,样品A的半数致畸剂量（TD₅₀）为225.4 mg/mL,半数致死剂量（LD₅₀）为292.0 mg/mL;样品B的TD₅₀为60.3 mg/mL,LD₅₀为1.382 mg/mL。UPLC-QTOF-MS分析结果显示,两批样品所含主要化学成分基本一致,但某些成分含量存在一定差异;初步分析显示既是有效成分又是毒性成分的士的宁含量与斑马鱼胚胎试验结果呈正相关。结论 斑马鱼胚胎模型可用于评价骨刺片样品的急性毒性,两批骨刺片样品对斑马鱼胚胎发育影响均表现为高浓度下的致死作用,低浓度下,特别是样品B表现为轻度非正常表型,且均可逆。     

Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications

Importance of the field: Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise.

Areas covered in this review: This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical and clinical levels. A discussion regarding the advantages, approaches and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells.

What the reader will gain: This review aims to give an overview of ZnO nanomaterials in biomedical applications.

Take home message: Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be improved further to make them attractive new anticancer agents.     

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.     

Recent advances in bioactive 1D and 2D carbon nanomaterials for biomedical applications

One-dimensional (1D) carbon nanotubes (CNTs) and the two-dimensional (2D) graphene represent the most widely studied allotropes of carbon. Due to their unique structural, electrical, mechanical and optical properties, 1D and 2D carbon nanostructures are considered to be leading candidates for numerous applications in biomedical fields, including tissue engineering, drug delivery, bioimaging and biosensors. The biocompatibility and toxicity issues associated with these nanostructures have been a critical impediment for their use in biomedical applications. In this review, we present an overview of the various materials types, properties, functionalization strategies and characterization methods of 1D and 2D carbon nanomaterials and their derivatives in terms of their biomedical applications. In addition, we discuss various factors and mechanisms affecting their toxicity and biocompatibility.     

Developmental effects of coumarin and the anticoagulant coumarin derivative warfarin on zebrafish (Danio rerio) embryos

Coumarin and warfarin, two substances which are intensively metabolized in animals and humans, were tested for teratogenicity and embryo lethality in a 3-day in vitro assay using zebrafish embryos. Warfarin is a coumarin derivative, but in contrast to the mother substance warfarin has anticoagulant properties. Both substances produced teratogenic and lethal effects in zebrafish embryos. The LC(50) and EC(50) values for coumarin are 855 μM and 314 μM, respectively; the corresponding values for warfarin are 988 μM and 194 μM. For coumarin, three main or fingerprint endpoints (malformation of head, tail and growth retardation) were identified, whereas malformation of tail was the only fingerprint endpoint of warfarin. The analysis of the ratios between the zebrafish embryo effect concentrations of both substances and human therapeutic plasma concentrations confirmed the teratogenic potential of warfarin, as well as the equivocal status of coumarin.     

Cellulose nanocrystals: a versatile nanoplatform for emerging biomedical applications

ABSTRACT

Introduction: Cellulose nanocrystals (CNCs) are bio-based nanomaterials typically derived from the acid hydrolysis of the most abundant natural polymer, cellulose. These nanomaterials have garnered significant interest due to their unique properties, such as uniform rod-like shape, high surface area, high strength, liquid crystalline behavior, tailored surface chemistry, biocompatibility, biodegradability, sustainability and non-toxic carbohydrate-based nature.

Areas covered: The recent developments in the use of unmodified and modified CNCs as versatile nanoplatforms for emerging biomedical applications such as drug delivery systems, enzyme/protein immobilization scaffolds, bioimaging, biosensing and tissue engineering are highlighted. A brief discussion of the biological and toxicity properties of CNCs is also presented.

Expert opinion: While a number of recent studies have indicated that CNCs are promising nanomaterials for biomedical applications, there is a substantial amount of work that still remains to be done before realizing the full therapeutic potential of CNCs. Major effort should be focused on detailed in vitro and in vivo studies of modified CNCs constructs in order to better understand the integration of CNCs in the biological systems.     

Investigation of the toxic functional group of cephalosporins by zebrafish embryo toxicity test

2‐mercapto‐5‐methyl‐1,3,4‐thiadiazole (MMTD) is the 3'‐side chain of cephalosporin including cefazolin sodium (CFZL) and cefazedone (CFZD). It is not only present in finished products as the residual precursor, but also produced through drug degradation. Performing the zebrafish embryo toxicity test, we evaluated the toxicity effects of cefazolin sodium, cefazedone, their synthetic precursors and intermediates. Our results suggest that the teratogenic effect of cefazedone and cefazolin sodium on zebrafish embryonic development is associated with the structure of MMTD. They mainly interfere with the development of tissues and organs derived from embryonic ectoderm and mesoderm. We further consider the rationality of the quality control limit of MMTD (1.0%) in the specification. As the acceptable daily intakes (ADIs) of cefazolin is 10 µg/kg per day 16 and the minimum teratogenic concentration of MMTD is tenfold lower than that of cefazolin sodium, we recommend that the acceptable daily intakes of MMTD should be 1 µg/(kg day). In general, the therapeutic dose of cefazolin sodium is 2–4 g/day. Based upon the calculation of MMTD quality control limits (1.0%), MMTD intake can be 20–40 mg/day, which will be much more than the acceptable daily intake value of 1 µg/(kg day). Thus, MMTD should be recommended as a specified impurity and qualified as serious again.     

The advancing uses of nano-graphene in drug delivery

Introduction: Graphene has been received with great interest in various fields including biomedical applications. Due to its ultrahigh surface area and easy surface functionalization, single-layered graphene has been intensively explored for drug and gene delivery. Utilizing their intrinsic high near-infrared absorbance, graphene and its derivatives have been found to be excellent candidates for multimodal imaging guided combined cancer photothermal and chemo- and/or photodynamic therapies.

Areas covered: This review summarizes recent studies on the biomedical applications of various graphene-based nanomaterials. The authors provide a comprehensive summary on using properly functionalized nano-graphene and its derivatives for drug and gene delivery, as well as combination therapy of cancer.

Expert opinion: Regarding biomedical applications, the authors find that proper surface functionalization and controlled sizes of graphene-based nanomaterials are two crucial factors for efficient drug and gene delivery. Although a lot of work has demonstrated the successful delivery of anticancer drugs and genes using graphene-based nanomaterials as carriers, the correlations of their surface functionalization and size distribution and their therapeutic outcomes need more exploration. On the other hand, the long-term toxicological and metabolic behaviors of nano-graphene still merit significantly more effort before clinical use.     

In vitro developmental toxicity test detects inhibition of stem cell differentiation by silica nanoparticles

While research into the potential toxic properties of nanomaterials is now increasing, the area of developmental toxicity has remained relatively uninvestigated. The embryonic stem cell test is an in vitro screening assay used to investigate the embryotoxic potential of chemicals by determining their ability to inhibit differentiation of embryonic stem cells into spontaneously contracting cardiomyocytes.Four well characterized silica nanoparticles of various sizes were used to investigate whether nanomaterials are capable of inhibition of differentiation in the embryonic stem cell test. Nanoparticle size distributions and dispersion characteristics were determined before and during incubation in the stem cell culture medium by means of transmission electron microscopy (TEM) and dynamic light scattering.Mouse embryonic stem cells were exposed to silica nanoparticles at concentrations ranging from 1 to 100 μg/ml. The embryonic stem cell test detected a concentration dependent inhibition of differentiation of stem cells into contracting cardiomyocytes by two silica nanoparticles of primary size 10 (TEM 11) and 30 (TEM 34) nm while two other particles of primary size 80 (TEM 34) and 400 (TEM 248) nm had no effect up to the highest concentration tested.Inhibition of differentiation of stem cells occurred below cytotoxic concentrations, indicating a specific effect of the particles on the differentiation of the embryonic stem cells. The impaired differentiation of stem cells by such widely used particles warrants further investigation into the potential of these nanoparticles to migrate into the uterus, placenta and embryo and their possible effects on embryogenesis.     

Recent development of silica nanoparticles as delivery vectors for cancer imaging and therapy

In spite of significant advances in early detection and combined treatments, a number of cancers are often diagnosed at advanced stages and thereby carry a poor prognosis. Developing novel prognostic biomarkers and targeted therapies may offer alternatives for cancer diagnosis and treatment. Recent rapid development of nanomaterials, such as silica based nanoparticles (SiNPs), can just render such a promise. In this article, we attempt to summarize the recent progress of SiNPs in tumor research as a novel delivery vector. SiNP-assisted imaging techniques are used in cancer diagnosis both in vitro and in vivo. Meanwhile, SiNP-mediated drug delivery can efficiently treat tumor by carrying chemotherapeutic agents, photosensitizers, photothermal agents, siRNA, and gene therapeutic agents. Finally, SiNPs that contain at least two different functional agents may be more powerful for both tumor imaging and therapy.From the Clinical EditorThis paper summarizes recent progress on the field of silica nanoparticles research as novel delivery vectors for cancer-specific imaging as well as drug delivery of chemotherapeutics, photosensitizers, photothermal agents, siRNA, and gene therapy agents.     

Graphene-based nanocomposites: synthesis and their theranostic applications

Graphene, the mother of all carbon materials, has unlocked a new era of biomedical nanomaterials due to its exceptional biocompatibility, physicochemical and mechanical properties. It is a single atom thick, nanosized, two-dimensional structure and provides high surface area with adjustable surface chemistry to form hybrids. The present article provides a comprehensive review of ever-expanding application of graphene nanomaterials with different inorganic and organic materials in drug delivery and theranostics. Methods of preparation of nanomaterials are elaborated and biological and physicochemical characteristics of biomedical relevance are also discussed. Graphene form nanomaterials with metallic nanoparticles offer multiscale application. First, graphene act as a platform to attach nanoparticles and provide excellent mechanical strength. Second, graphene improves efficacy of metallic nanoparticles in diagnostic, biosensing, therapeutic and drug delivery application. Graphene-based polymeric nanocomposites find wider application in drug delivery with flexibility to incorporate hydrophilic, hydrophobic, sensitive and macromolecules. In addition, grapheme quantum dots and graphene hybrids with inorganic nanocrystal and carbon nanotubes hybrids have shown interesting properties for diagnosis and therapy. Finally, we have pointed out research trends that may be more common in future for graphene-based nanomaterials.