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.     

Drug targeting to infectious diseases by nanoparticles surface functionalized with special biomolecules

The potential to deliver nanoparticles directly into the targeted cells is important in the therapeutic applications for infectious diseases. The possibility of therapeutic agent being attached to the nanoparticles by chemical modification has provided a novel drug delivery option. Interestingly, the discovery of carbon nanotubes and graphene has given an excellent imaging and therapeutic agent for the biomedical applications. In spite of continuous advancement in pharmaceutical drug delivery viz. micelles, vesicles, liquid crystals, etc., during the past decades, their prohibitive production has limited their use. Nanomaterials with their properties of biodegradation, equal biodistribution, mass production, and long time storage make them attractive alternatives for future biomedical applications. Nanoparticles surface functionalized with specific biomolecules based drug delivery has driven new direction for modulating the pharmacokinetics, pharmacodynamics, biorecognition, and increasing the efficacy of targeted drugs. These new strategies are likely to minimize drug degradation and loss, increase drug availability, and opens up new vistas for drug delivery.     

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.     

Polymeric nanohybrids and functionalized carbon nanotubes as drug delivery carriers for cancer therapy

The scope of nanotechnology to develop target specific carriers to achieve higher therapeutic efficacy is gaining importance in the pharmaceutical and other industries. Specifically, the emergence of nanohybrid materials is posed to edge over chemotherapy and radiation therapy as cancer therapeutics. This is primarily because nanohybrid materials engage controlled production parameters in the making of engineered particles with specific size, shape, and other essential properties. It is widely expressed that these materials will significantly contribute to the next generation of medical care technology and pharmaceuticals in areas of disease diagnosis, disease prevention and many other treatment procedures. This review focuses on the currently used nanohybrid materials, polymeric nanoparticles and nanotubes, which show great potential as effective drug delivery systems for cancer therapy, as they can be grafted with cell-specific receptors and intracellular targeting molecules for the targeted delivery of therapeutics. Specifically, this article focuses on the current status, recent advancements, potentials and limitations of polymeric nanohybrids and functionalized carbon nanotubes as drug delivery carriers.     

Advances in use of functionalized carbon nanotubes for drug design and discovery

Introduction: As a part of increasing interest in nanobiotechnology, nanoparticle-based drug discovery as well as development and drug delivery constitute an important area in nanomedicine, and it is also driven by search for new drugs by the pharmaceutical industry. Nanomaterials for pharmaceutical application include carbon nanotubes (CNTs).

Areas covered: This article describes the properties of CNTs, both single-walled CNTs (SWCNTs) and multiwalled CNTs (MWCNTs) with relevance to drug discovery and development. Pharmacokinetics of CNTs as well as CNT-based drug delivery is discussed. The article also looks at how the scope for pharmaceutical applications of CNTs is broadened by conjugation with other molecules and presents the potential therapeutic applications. Finally, the toxicology of CNTs is considered with measures under investigation for reducing it. Literature on CNTs, from the past 5 years, was reviewed and selected publications relevant to drug discovery, development, and delivery were included in the bibliography.

Expert opinion: Carbon nanotubes combine more properties relevant to drug development and delivery than any other nanomaterial. Although a tremendous amount of basic research has been done on CNTs during the past decade, little of this is nearing translation into human applications. No CNT-based medicine has reached clinical trials. Nevertheless, CNT conjugation with other molecules has extended the horizons for their potential therapeutic applications. The most promising of these is PEGylation, which extends the survival of CNTs in circulation. Potential future applications of CNTs include combination of diagnostics and therapeutic drug delivery as well as a component of multimodal therapies for tissue regeneration.     

Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.     

Analyzing Nanotheraputics-Based Approaches for the Management of Psychotic Disorders

Psychoses are brain disorders clinically manifested by cognitive conditions such as hallucinations, delirium, dementia, schizophrenia, and delusions. Antipsychotic drugs are associated with significant side effects such as dystonia, tardive dyskinesia, involuntary muscle movement, and metabolic disorders. Moreover, those antipsychotics currently available have poor bioavailability, drug-related adverse effects, poor therapeutic efficacy, and poor brain delivery resulting from the blood-brain barrier. Conventional dosage forms, which release the drugs into the general circulation, fail to deliver the drugs directly to the brain efficiently. Thus, a rational approach based on nanotherapeutics may overcome these limitations; such approaches can be used for the delivery of drug molecules to their targeted site. Nanotherapeutics are colloidal systems comprising nanosize-range particles and unique physicochemical properties; these properties include plasticity, biodegradability, bioacceptability, versatile surface modification properties, and protection of drug molecules from degradation. The present review describes various nanoformulations for delivery of antipsychotic drugs to the brain; these include nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsion, nanosuspensions, and carbon nanotubes. The review also considers the ability of these formulations to improve drug bioavailability and targeting affinity, as well as their ability to circumvent the first-pass metabolism.     

A feasible way to use carbon nanotubes to deliver drug molecules: transdermal application

INTRODUCTION: Nanotechnology has gained increasing importance in the pharmaceutical and medical fields, beyond its importance in physics and technology. Targeting of the drug or active molecules can be achieved rather easily with some nanocarriers because of their unique properties; to program or control of delivery can also be possible. One of the smart nanosystems is carbon nanotubes (CNTs) because they are elecroconductive and they have very big surface area to deliver active molecules. There have been many drug delivery systems proposed to the scientific world using CNTs. One administration way which appears to be the most appropriate for drug delivery is transdermal application. AREAS COVERED: Performed experiments and proposed techniques with the use of CNTs are scrutinized and discussed in this review. EXPERT OPINION: In the light of current knowledge, a feasible way to use CNTs to deliver drug molecules is transdermally.     

In vivo biodistribution of platinum-based drugs encapsulated into multi-walled carbon nanotubes

Carbon nanotubes (CNTs) are promising drug delivery systems due to their external functionalizable surface and their hollowed cavity that can encapsulate several bioactive molecules. In this study, the chemotherapeutic drug cisplatin or an inert platinum(IV) complex were entrapped inside functionalized-multi-walled-CNTs and intravenously injected into mice to investigate the influence of CNTs on the biodistribution of Pt-based molecules. The platinum levels in vital organs suggested that functionalized-CNTs did not affect cisplatin distribution, while they significantly enhanced the accumulation of Pt(IV) sample in some tissues (e.g. in the lungs, suggesting their potential application in lung cancer therapy) and reduced both kidney and liver accumulation (thus decreasing eventual nephrotoxicity, a typical side effect of cisplatin). Concurrently, CNTs did not induce any intrinsic abnormal immune response or inflammation, as confirmed by normal cytokine levels and histological evaluations. Therefore, functionalized nanotubes represent an efficient nano-carrier to improve accumulation of Pt species in targeted tissues/organs.From the Clinical EditorIn this preclinical study functionalized carbon nanotubes are reported to be safe and efficient for targeted delivery of platinum-containing compounds in rodents. Approaches like this may improve the treatment of specific cancers, since platinum based chemotherapies are commonly used, yet limited by toxicity and relatively poor target tissue concentration.     

Intra-articular drug delivery systems: overcoming the shortcomings of joint disease therapy

Background: Intra-articular drug delivery is very useful for treating local disease flare-ups, synovitis and pain in joints. However, the effectiveness of drugs following intra-articular administration is limited by drug delivery issues. Aim: This review addresses critical drug delivery parameters that influence the biocompatibility, tolerability and efficacy of intra-articular administrations and offers an opinion on aspects of formulation design. Methods: The relevant literature was reviewed, focusing on factors influencing tissue targeting, safety and effectiveness of particulate formulations. Results/conclusion: Therapeutic applications of novel drug delivery systems for the localized treatment of joints have lagged significantly. Future innovations in the field will require the discovery of new therapeutic agents for regional delivery, combination regimens, novel biomaterials as drug carriers and targeting carriers to specific molecules.     

碳纳米管作为药物载体的研究进展

新型药物载体的开发对药物的研究具有举足轻重的作用。碳纳米管具有独特的中空结构和纳米管径，可用作药物载体。采用肽、蛋白、核酸及药物分子修饰的碳纳米管作为载体，可运载生物活性分子进入细胞且不产生毒性。本文综述了近年来修饰碳纳米管作为药物载体的研究进展，评述了碳纳米管的细胞穿透性能和细胞毒性，概述了碳纳米管功能化修饰的方法。随着碳纳米管在药物载体领域研究日趋深入，碳纳米管修饰方式与其细胞穿透性能的相互关系、尺寸效应将会深入研究。制备溶解性好、低毒性的修饰碳纳米管作为药物载体，将是今后研究的主要方向。     

Therapeutic applications of colloidal drug carriers

Colloidal drug carriers such as liposomes and nanoparticles can be used to improve the therapeutic index of both established and new drugs by modifying their distribution, and thus increasing their efficacy and/or reducing their toxicity. This is because the drug distribution then follows that of the carrier, rather than depending on the physicochemical properties of the drug itself. If these delivery systems are carefully designed with respect to the target and the route of administration, they may provide one solution to some of the delivery problems posed by new classes of active molecules, such as peptides and proteins, genes and oligonucleotides. They may also offer alternative modes for more conventional drugs, such as highly hydrophobic small molecules. This review discusses the use of colloidal, particulate carrier systems (25 nm to 1 μm in diameter) in such applications.     

SiRNA delivery with functionalized carbon nanotubes

Carbon nanotubes (CNTs) have been studied for drug, antigen and nucleic acid delivery both in vitro and in vivo. Due to their nano-needle structure, they are supposed to cross the plasma membrane and enter directly into the cytoplasm likely upon an endocytosis-independent mechanism without inducing cell death. In this study, two cationically functionalized CNTs (CNT-PEI and CNT-pyridinium) were investigated for siRNA delivery. Both functionalized CNTs complexed siRNA and showed 10-30% silencing activity and a cytotoxicity of 10-60%. However, in terms of reduced toxicity or increased silencing activity, CNT-PEI and CNT-pyridinium did not show an added value over PEI and other standard transfection systems. Probably, the type of functionalization of carbon nanotubes might be a key parameter to obtain an efficient and non-cytotoxic CNT-based delivery system. Nevertheless, in view of the present results and importantly also of the non-degradability of CNTs, preference should currently be given to designing biodegradable carriers which mimic the needle structure of CNTs.     

Therapeutic delivery opportunities, obstacles and applications for cell-penetrating peptides

Advancements in the development of large bioactive molecules as therapeutic agents have made drug delivery an active and important field of research. Cell-penetrating peptides (CPPs) have the ability to deliver an array of molecules and even nano-size particles into cells in an efficient and non-toxic manner, both in vitro and in vivo. This review aims to give a perspective on the obstacles that CPP-mediated drug delivery is currently facing as well as the great opportunities for improvements that lie ahead. Strategies for delivery of novel gene-modulating agents and enhancing efficacy of classical drugs will be discussed, as well as methods for increasing bioavailability and tissue specificity of CPPs. The usefulness and potential of CPPs as therapeutic drug-delivery vectors will be exemplified by their use in the treatment of cancer, viral infection and muscular dystrophy.     

Microfabrication technologies for oral drug delivery

Micro-/nanoscale technologies such as lithographic techniques and microfluidics offer promising avenues to revolutionalize the fields of tissue engineering, drug discovery, diagnostics and personalized medicine. Microfabrication techniques are being explored for drug delivery applications due to their ability to combine several features such as precise shape and size into a single drug delivery vehicle. They also offer to create unique asymmetrical features incorporated into single or multiple reservoir systems maximizing contact area with the intestinal lining. Combined with intelligent materials, such microfabricated platforms can be designed to be bioadhesive and stimuli-responsive. Apart from drug delivery devices, microfabrication technologies offer exciting opportunities to create biomimetic gastrointestinal tract models incorporating physiological cell types, flow patterns and brush-border like structures. Here we review the recent developments in this field with a focus on the applications of microfabrication in the development of oral drug delivery devices and biomimetic gastrointestinal tract models that can be used to evaluate the drug delivery efficacy.     

Carbon nanotubes in drug delivery: focus on infectious diseases

Carbon nanotubes have the potential to address the challenges of combating infectious agents by both minimizing toxicity by dose reduction of standard therapeutics and allowing a multiple payload capacity to achieve both targeted activity and combating infectious strains, resistant strains in particular. One of their unique characteristics is the network of carbon atoms in the nanometer scale, allowing the creation of nano-channels via cellular membranes. This review focuses on the characterization, development, integration and application of carbon nanotubes as nanocarrier-based delivery systems and their appropriate design for achieving the desired drug delivery results in the different areas of infectious diseases. While a more extensive toxicological and pharmacological profile must be obtained, this review will focus on existing research and pre-clinical data concerning the potential use of carbon nanotubes.     

Influence of protein transduction domains on intracellular delivery of macromolecules

As the plasma membrane and blood-brain barrier selectively restrict the entry of most compounds into cells to < 500 Da, delivering macromolecules into cells was, until recently, little more than a goal. However, with significant effort to capitalise on therapeutic targets available in the post-genomic era, novel approaches for delivering therapeutic macromolecules are being rapidly developed. The discovery of small cationic peptides, termed peptide/protein transduction domains or cell-penetrating peptides, which cross biological membranes, has emerged as a venerable Trojan horse to transport large, biologically active molecules, such as peptides, proteins and oligonucleotides, into mammalian cells in vitro, as well as in preclinical models and clinical trials in vivo. This review discusses the implications of peptide/protein transduction domain-mediated delivery of macromolecules and their possible uses as important primary drug delivery agents.     

Carbon nanotubes for the delivery of therapeutic molecules

Functionalised carbon nanotubes (f-CNTs) are emerging as new tools in the field of nanobiotechnology and nanomedicine. This is because they can be easily manipulated and modified by encapsulation with biopolymers or by covalent linking of solubilising groups to the external walls and tips. The possibility of incorporating f-CNTs into biological systems has opened the way to the exploration of their potential applications in biology and medicinal chemistry. Within the different fields of applications (i.e., biosensors, composite materials, molecular electronics), one use of CNTs is as new carrier systems for the delivery of therapeutic molecules. Research discussed in this review is focused on recent advances in the development of CNT technology for the delivery of drugs, antigens and genes.     

Delivery of proteins and nucleic acids using a non-covalent peptide-based strategy

The recent discovery of new potent therapeutic molecules which do not reach the clinic due to poor delivery and low bioavailability have made of delivery a key stone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetrating peptides (CPPs), which have been successfully applied for in vivo delivery of biomolecules and constitute very promising tools. Distinct families of CPPs have been described; some require chemical linkage between the drug and the carrier for cellular drug internalization while others like Pep-and MPG-families, form stable complexes with drugs depending on their chemical nature. Pep and MPG are short amphipathic peptides, which form stable nanoparticles with proteins and nucleic acids respectively. MPG and Pep based nanoparticles enter cells independently of the endosomal pathway and efficiently deliver cargoes in a fully biologically active form into a large variety of cell lines as well as in animal models. This review will focus on the mechanisms of non-covalent MPG and Pep-1 strategies and their applications in cultured cells and animal models.