Investigating oxidation state-induced toxicity of PEGylated graphene oxide in ocular tissue using gene expression profiles

Abstract

Graphene and its derivatives are widely used for a variety of industrial, biomedical, and environmental applications. However, the potential harm caused by exposure of the eyes to graphene-based nanomaterials is scarce. Given the potential for these materials to be used in multiple applications, there is a pressing need to evaluate their ocular toxicity, and understand the relationships between their physico-chemical properties and the resulting toxicity. In this study, the toxicity of PEGylated graphene oxide (PEG-GO) with differing oxidation levels and/or surface charges (positive, negative and neutral charge) was evaluated using two in-vitro models of the eye: primary human corneal epithelial cells and human retinal capillary endothelial cells. The results showed that oxidation level, but not surface charge, had a pivotal effect on the toxicity of graphene-based nanomaterials. Typically, PEG-GO sample with a higher oxidation level caused more serious cytotoxicity than those with a lower oxidation level. Furthermore, by analysis of global gene expression profiles, we found that the foremost cellular response to PEG-GO sample with a high oxidation level was the oxidative stress response. Next, via exploring the underlying molecular mechanism of oxidative stress-induced cytotoxicity, we showed that PEG-GO sample with a high degree of oxidation induced reactive oxygen species (ROS) via NDUFB9-mediated biological pathway. This work has significant implications for design of safe graphene-based nanomaterials for biomedical applications.     

The application of graphene oxide in drug delivery

Introduction: As a shining star in material science, graphene oxide (GO) and its derivatives possess potential applications in a variety of areas. Among them, the application of GO to drug delivery has attracted ever-increasing interest in the past few years.

Areas covered: In this article, the authors summarize the latest progress of utilizing GO in the field of drug delivery. In particular, the functionalization of GO, cytotoxicity of GO and its derivatives, in vitro and in vivo drug delivery and the comparison with carbon nanotube-based delivery systems are discussed. Future perspectives and possible challenges in this emerging field are briefly described.

Expert opinion: GO and its derivatives are highly attractive for the application to drug delivery due to their exceptional physiochemical properties and unique planar structure in spite of some existing challenges, such as the reproducibly smart functionalization of GO and the investigation of its long-term toxicology.     

Recent advances in the role of supramolecular hydrogels in drug delivery

Introduction: Supramolecular hydrogels, formed by noncovalent crosslinking of polymeric chains in water, constitute an interesting class of materials that can be developed specifically for drug delivery and biomedical applications. The biocompatibility, stimuli responsiveness to various external factors, and powerful functionalization capacity of these polymeric networks make them attractive candidates for novel advanced dosage form design.

Areas covered: This review summarizes the significance of supramolecular hydrogels in various biomedical and drug delivery applications. The recent advancement of these hydrogels as potential advanced drug delivery systems (for gene, protein, anticancer and other drugs) is discussed. The importance of these hydrogels in biomedical applications, particularly in tissue engineering, biosensing, cell-culture research and wound treatment is briefly described.

Expert opinion: The use of supramolecular hydrogels in drug delivery is still in very early stages. However, the potential of such a system is undeniably important and very promising. A number of recent studies have been conducted, which mainly focus on the use of cyclodextrin-based host–guest complex as well as other supramolecular motifs to form supramolecular hydrogels for delivery of various classes of drugs, therapeutic agents, proteins and genes. However, there are still plenty of opportunities for further development in this area for drug delivery and other biomedical applications.     

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.     

Phosphorus-containing nanoparticles: biomedical patents review

Introduction: The beginning of the nano-era started with the appearance of artificial nanosized supramolecular systems called nanomaterials and nanoparticles (NPs).

Areas covered: In the present review, we have analyzed the patents on phosphorus-based nanomaterials (fullerenes, quantum dots [QDs], graphene, liposomes, dendrimers, gold and silver NPs) in biology and medicine. Their impact in treatment of cancer, viral infections and cardiovascular diseases is discussed.

Expert opinion: Liposomes and dendrimers had the highest number of biomedical patents. The third candidates were QDs and the fourth and fifth were gold and silver NPs. Fullerenes and carbon nanotubes have the fewest applications in biology and medicine. Thus, our first conclusion was about the ‘unifying nanotoxicology paradigm’, that ‘soft’ NPs are significantly more biocompatible than ‘hard’ NPs. There has been a trend of these nanomaterials being applied in medicine drug and gene delivery, visualization of cells and pathologic processes, using them as antivirals and antimicrobials, contrast agents, antioxidants and photosensitizers. It was unexpected that no patents were found in which phosphorus NPs were used in 3D printing of bones and other biological tissues. The conclusion reached is that nanomaterials are promising tools in future medical applications.     

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.     

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.     

Toxicology of chemically modified graphene-based materials for medical application

This review article aims to provide an overview of chemically modified graphene, and graphene oxide (GO), and their impact on toxicology when present in biological systems. Graphene is one of the most promising nanomaterials due to unique physicochemical properties including enhanced optical, thermal, and electrically conductive behavior in addition to mechanical strength and high surface-to-volume ratio. Graphene-based nanomaterials have received much attention over the last 5 years in the biomedical field ranging from their use as polymeric conduits for nerve regeneration, carriers for targeted drug delivery and in the treatment of cancer via photo-thermal therapy. Both in vitro and in vivo biological studies of graphene-based nanomaterials help understand their relative toxicity and biocompatibility when used for biomedical applications. Several studies investigating important material properties such as surface charge, concentration, shape, size, structural defects, and chemical functional groups relate to their safety profile and influence cyto- and geno-toxicology. In this review, we highlight the most recent studies of graphene-based nanomaterials and outline their unique properties, which determine their interactions under a range of environmental conditions. The advent of graphene technology has led to many promising new opportunities for future applications in the field of electronics, biotechnology, and nanomedicine to aid in the diagnosis and treatment of a variety of debilitating diseases.     

Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery

Introduction: Aptamers are short, single-stranded DNA or RNA sequences that can fold into complex secondary and tertiary structures and bind to various target molecules with high affinity and specificity. These properties, as well as rapid tissue penetration and ease of chemical modification, make aptamers ideal recognition elements for in vivo targeted drug delivery and attractive molecules for use in disease diagnosis and therapy.

Areas covered: The general properties of aptamers as well as advantages over their counterpart antibodies are briefly discussed. Next, aptamer selection by cell- systematic evolution of ligands by exponential enrichment is described in detail. Finally, the review summarizes recent progress in the field of targeted drug delivery based on aptamers and their conjugation to liposomes, micelles and other nanomaterials.

Expert opinion: Advances in nanotechnology have led to new and improved nanomaterials for biomedical applications. Conjugation of nanoparticles (NPs) with aptamers exploits both technologies, making aptamer-NP conjugates ideal agents for drug delivery with proven therapeutic effects and the reduction of toxicity to normal tissue. The use of multivalent aptamer-conjugated nanomaterials represents one of the new directions for drug development in the future; as such, continuing studies of these multivalent aptamers and bioconjugates should result in important clinical applications in targeted drug delivery.     

Reproductive toxicity of nanoscale graphene oxide in male mice

Abstract

In the past few years, much work has been performed to explore the biomedical applications and toxicity of nano-graphene and its derivatives. However, the reproductive toxicity of those carbon nanomaterials has been rarely studied. In this study, we report on the male reproductive toxicity of nanoscale graphene oxide (GO) using a mouse model. The results showed that the adult male mice injected with high dosages of GO (25?mg/kg mouse) via the tail vein exhibited normal sex hormone secretion and retained normal reproductive activity. All untreated female mice mated with the GO-treated male mice could produce healthy pups. There were no significant differences in pup numbers, sex ratio, weights, pup survival rates or pup growth over time between the GO-treated and control groups. Furthermore, these GO-treated male mice could produce a second, third, fourth and even fifth litter of healthy offspring when they lived with the untreated female mice. The testicular and epididymal histology as well as the activities of several important epididymal enzymes including α-glucosidase, lactate dehydrogenase, glutathione peroxidase and acid phosphatase were not affected by GO treatment. In addition, no damaging effects were seen at high dose rates of GO (total 300?mg/kg male mouse, 60?mg/kg every 24?h for 5 days) via intra-abdominal injection. Thus, GO showed very low or nearly no toxicity for male reproduction. This work will greatly enable future investigations of GO nanosheets for in vivo biomedical applications.     

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.     

The art of attraction: applications of multifunctional magnetic nanomaterials for malignant glioma

Introduction: Malignant gliomas remain one of medicine's most daunting unsolved clinical problems. The development of new technologies is urgently needed to improve the poor prognosis of patients suffering from these brain tumors. Magnetic nanomaterials are appealing due to unique properties that allow for noninvasive brain tumor diagnostics and therapeutics in one multifunctional platform.

Areas covered: We report on the recent advances of magnetic nanomaterials for brain tumor imaging and therapy, with an emphasis on novel approaches and clinical progress. We detail their biomedical applications including brain tumor targeting, MRI contrast enhancement, optical imaging, magnetic hyperthermia, magnetomechanical destruction, drug delivery, gene therapy, as well as tracking of cell-based and viral-based therapies. The clinical cases and obstacles encountered in the use of magnetic nanomaterials for malignant glioma are also examined.

Expert opinion: To accelerate the effective translation of these materials to the clinic as theranostics for brain tumors, limitations such as poor intratumoral distribution, targeting efficiency and nonspecific systemic side effects must be addressed. Future innovations should focus on optimizing and combining the unique therapeutic applications of these magnetic nanomaterials as well as improving the selectivity of the system based on the molecular profiling of tumors.     

Recent progress of functionalised graphene oxide in cancer therapy

Abstract

In recent years, graphene oxide (GO) nanomaterials have attracted wide attention due to their large surface area, strong light sensitivity and good biocompatibility in cancer treatment. The rich oxygen-containing functional groups on the surface provide it with the opportunity to be modified by many functional molecules to expand biological applications and reduce toxicity. In this review, the properties of GO and the methods of surface modification are presented, and the toxicity of GO is analysed. In addition, the current applications of GO in cancer diagnoses and treatments including biological imaging, drug and gene delivery, phototherapy and imaging-mediated combination therapy are summarised. Finally, the prospects and challenges of GO in cancer treatment are discussed.     

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.     

Drug delivery/imaging multifunctionality of mesoporous silica-based composite nanostructures

Introduction: Biocompatible mesoporous silica nanoparticles (MSNs) are regarded as one of the most promising inorganic drug delivery systems (DDSs) to concurrently enhance the therapeutic efficiency and mitigate the side effects of anticancer drugs. Elaborately combining multicomponents with MSNs will endow them with specific functionalities for cancer therapy and diagnosis, such as targeted drug delivery, intelligent on-demand drug releasing, synergistic therapy, diagnostic imaging and so on.

Areas covered: This review discusses the state-of-the-art potential obstacles and further perspectives of the chemical design/synthesis, in vitro/in vivo pharmaceutical evaluations and potential clinical translations of multifunctional mesoporous silica-based nanomaterials for biotechnological and biomedical applications, especially against cancer. These topics cover the years from 2001 to 2013.

Expert opinion: Through the comprehensive evaluations of the biosafety and pharmaceutical efficiency, elaborately designed/fabricated mesoporous silica-based composite nanoparticles show great potentials in clinical applications for efficient diagnostic imaging and chemotherapy of cancer.     

Aptamer-dendrimer bioconjugate: a nanotool for therapeutics,diagnosis, and imaging

Introduction: Aptamers hold great promise as molecular tool in biomedical applications due to the therapeutic utility exhibited by their target specificity and sensitivity. Although current development of aptamer is hindered by its probable in vivo degradation, inefficient immobilization on probe surface, and generation of low detection signal, bioconjugation with nanomaterials can feasibly solve these problems. Nanostructures such as dendrimers, with multivalency and nonimmunogenicity, bioconjugated with aptamers have opened newer vistas for better pharmaceutical applications of aptamers.

Areas covered: This review covers brief overview of aptamers and dendrimers, with specific focus on recent progresses of aptamer-dendrimer (Apt-D) bioconjugate in areas of targeted drug delivery, diagnosis, and molecular imaging along with the discussion on the currently available conjugates, using their in vitro and in vivo results.

Expert opinion: The novel Apt-D bioconjugates have led to advances in targeting cancer cell, have amplified biosensing, and offered in vivo cell imaging. Because of the unique properties and applications, Apt-D bioconjugate propose an exciting future. However, further research in synthesis of new target-specific aptamers and their conjugation with dendrimers is required to establish full potential of Apt-D bioconjugate.     

The alluring potential of functionalized carbon nanotubes in drug discovery

Importance of the field: The possibility of carbon nanotube integration into living systems for therapeutic and diagnostic purposes has opened the way to explore their applications in drug delivery and discovery. A wide variety of chemical approaches has been developed to functionalize carbon nanotubes with therapeutic molecules towards different biomedical uses.

Areas covered in this review: This review covers the recent advances in the development of functionalized carbon nanotubes to offer improvements for different diseases, in particular for cancer therapy.

What the reader will gain: Functionalized carbon nanotubes are able to transport therapeutic agents. Targeted methodologies using carbon nanotube-based conjugates have been investigated to improve the efficacy of some drugs. The capacity of such nanomaterials to seamlessly translocate into cells with alternative various mechanisms and their pharmacokinetic properties is also discussed.

Take home message: Although at its infancy, functionalized carbon nanotubes are very promising as a new nanomedicine platform in the field of drug discovery and delivery. They have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining – and in some cases improving – their therapeutic efficacy.     

Chitosan-based gastroretentive floating drug delivery technology: an updated review

Introduction: Gastroretentive floating drug delivery systems have emerged as efficient approaches for enhancing the bioavailability and controlled delivery of various therapeutic agents. Significant advancements exploiting chitosan have been made worldwide, in order to investigate these systems according to patient requirements, both in terms of therapeutic efficacy as well as patient compliance. Such systems precisely control the release rate of the target drug to a specific site, which facilitates an enormous impact on health care.

Areas covered: Different novel strategies have been undertaken for the development of various gastric floating dosage forms utilizing chitosan as a promising excipient. The present paper is an earnest attempt to provide new insights on various physicochemical and biological characteristics of chitosan, along with its potential applications in a wide array of biomedical approaches. Numerous and significant research findings in the vistas of chitosan-based gastroretentive floating drug delivery technology are also discussed.

Expert opinion: Chitosan has been considered as a unique and efficacious agent possessing a myriad spectrum of desired characteristics. It is emphasized that recent scientific advancements in the use of this excipient as a carrier will yield new generation gastroretentive drug delivery systems, with better pharmacotherapeutic interventions. Further studies are required to unveil the hidden beneficial properties of chitosan and its derivatives, to obtain newer delivery systems which may hold tremendous prospects in the near future.     

Assessment of the toxic potential of graphene family nanomaterials

Graphene, a single-atom-thick carbon nanosheet, has attracted great interest as a promising nanomaterial for a variety of bioapplications because of its extraordinary properties. However, the potential for widespread human exposure raises safety concerns about graphene and its derivatives, referred to as graphene-family nanomaterials. This review summarizes recent findings on the toxicological effects and the potential toxicity mechanisms of graphene-family nanomaterials in bacteria, mammalian cells, and animal models. Graphene, graphene oxide, and reduced graphene oxide elicit toxic effects both in vitro and in vivo, whereas surface modifications can significantly reduce their toxic interactions with living systems. Standardization of terminology and the fabrication methods of graphene-family nanomaterials are warranted for further investigations designed to decrease their adverse effects and explore their biomedical applications.     

Filled carbon nanotubes in biomedical imaging and drug delivery

Introduction: Carbon nanotubes have been advocated as promising candidates in the biomedical field in the areas of diagnosis and therapy. In terms of drug delivery, the use of carbon nanotubes can overcome some limitations of ‘free’ drugs by improving the formulation of poorly water-soluble drugs, allowing targeted delivery and even enabling the co-delivery of two or more drugs for combination therapy. Two different approaches are currently being explored for the delivery of diagnostic and therapeutic agents by carbon nanotubes, namely attachment of the payload to the external sidewalls or encapsulation into the inner cavities. Although less explored, the latter confers additional stability to the chosen diagnostic or therapeutic agents, and leaves the backbone structure of the nanotubes available for its functionalization with dispersing and targeting moieties. Several drug delivery systems and diagnostic agents have been developed in the last years employing the inner tubular cavities of carbon nanotubes.

Areas covered: The research discussed in this review focuses on the use of carbon nanotubes that contain in their interior drug molecules and diagnosis-related compounds. The approaches employed for the development of such nanoscale vehicles along with targeting and releasing strategies are discussed.

Expert opinion: The encapsulation of both biomedical contrast agents and drugs inside carbon nanotubes is further expanding the possibilities to allow an early diagnosis and treatment of diseases.