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.     

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.     

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.     

Delivering bioactive molecules as instructive cues to engineered tissues

Introduction : Growth factors and other bioactive molecules play a crucial role in the creation of functional engineered tissues from dissociated cells.

Areas covered : This review discusses the delivery of bioactive molecules – particularly growth factors – to affect cellular function in the context of tissue engineering. We discuss the primary biological themes that are addressed by delivering bioactives, the types of molecules that are to be delivered, the major materials used in producing scaffolds and/or drug delivery systems, and the principal drug delivery strategies.

Expert opinion : Drug delivery systems have allowed the sustained release of bioactive molecules to engineered tissues, with marked effects on tissue function. Sophisticated drug delivery techniques will allow precise recapitulation of developmental milestones by providing temporally distinct patterns of release of multiple bioactives. High-resolution patterning techniques will allow tissue constructs to be designed with precisely defined areas where bioactives can act. New biological discoveries, just as the development of small molecules with potent effects on cell differentiation, will likely have a marked impact on the field.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Carbon nanotubes part II: a remarkable carrier for drug and gene delivery

Introduction: Carbon nanotubes (CNT) have recently been studied as novel and versatile drug and gene delivery vehicles. When CNT are suitably functionalized, they can interact with various cell types and are taken up by endocytosis.

Areas covered: Anti-cancer drugs cisplatin and doxorubicin have been delivered by CNT, as well as methotrexate, taxol and gemcitabine. The delivery of the antifungal compound amphotericin B and the oral administration of erythropoietin have both been assisted using CNT. Frequently, targeting moieties such as folic acid, epidermal growth factor or various antibodies are attached to the CNT-drug nanovehicle. Different kinds of functionalization (e.g., polycations) have been used to allow CNT to act as gene delivery vectors. Plasmid DNA, small interfering RNA and micro-RNA have all been delivered by CNT vehicles. Significant concerns are raised about the nanotoxicology of the CNT and their potentially damaging effects on the environment.

Expert opinion: CNT-mediated drug delivery has been studied for over a decade, and both in vitro and in vivo studies have been reported. The future success of CNTs as vectors in vivo and in clinical application will depend on achievement of efficacious therapy with minimal adverse effects and avoidance of possible toxic and environmentally damaging effects.     

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.     

New therapeutic options for onychomycosis

Introduction: Onychomycosis is a fungal infection of the nail apparatus that affects 10 – 30% of the global population. Current therapeutic options for onychomycosis have a low to moderate efficacy and result in a 20 – 25% rate of relapse and reinfection. New therapeutic options are needed to broaden the spectrum of treatment options and improve the efficacy of treatment.

Areas covered: This review discusses the emerging pharmacotherapeutics; including topical reformulations of terbinafine, new azole molecules for systemic and topical administration, topical benzoxaboroles and topical polymer barriers. The paper also discusses device-based options, which may be designed to activate a drug or to improve drug delivery, such as photodynamic therapy and iontophoresis; laser device systems have also begun to receive regulatory approval for onychomycosis.

Expert opinion: Device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Systemic azoles are the only class of pharmacotherapy that has shown a comparable efficacy to systemic terbinafine; however terbinafine remains the gold standard. The most notable new topical drugs are tavaborole, efinaconazole and luliconazole, which belong to the benzoxaborole and azole classes of drugs. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of these devices.     

Update on non-viral delivery methods for cancer therapy: possibilities of a drug delivery system with anticancer activities beyond delivery as a new therapeutic tool

Importance of the field: Cancer is the most formidable human disease. Owing to the heterogeneity of cancer, a single-treatment modality is insufficient for the complete elimination of cancer cells. Therapeutic strategies from various aspects are needed for cancer therapy. These therapeutic agents should be carefully selected to enhance multiple therapeutic pathways. Non-viral delivery methods have been utilized to enhance the tumor-selective delivery of therapeutic molecules, including proteins, synthetic oligonucleotides, small compounds and genes.

Areas covered in this review: As non-viral delivery methods, liposomes and polymer-based delivery materials to target tumors mainly by systemic delivery, physical methods including electroporation, sonoporation, and so on, to locally inject therapeutic molecules, and virosomes to use the viral infectious machinery for the delivery of therapeutic molecules are summarized.

What the reader will gain: This article aims to provide an overview of the characteristic properties of each non-viral vector. It will be beneficial to utilize appropriately the vector for cancer treatment.

Take home message: Efficient and minimally invasive vectors are generally considered to be the ideal drug delivery system (DDS). However, against cancer, DDS equipped with antitumor activities may be a therapeutic choice. By combining therapeutic molecules with DDS having antitumor activities, enhancement of the multiple therapeutic pathways may be achieved.     

Ultrasound-mediated drug delivery for cardiovascular disease

Introduction: Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery.

Areas covered: The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies.

Expert opinion: These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments.     

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.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Stents as a platform for drug delivery

Introduction: Drug delivery stents have proved their efficacy at preventing coronary restenosis and their potential in treating the occlusion or stricture of other body passageways, such as peripheral vessels and alimentary canals. The drug delivery systems on such stent platforms contribute to this improved therapeutic efficacy by providing improved drug delivery performance, along with reduced concerns encountered by current stents (e.g., in-stent restenosis, late thrombosis and delayed healing).

Areas covered: A wide variety of drug delivery stents (metallic drug-eluting stents, absorbable drug-eluting stents, and polymer-free drug-eluting stents for coronary and other applications) that are commercially available or under investigation are collected and summarized in this review, with emphasis on their drug delivery aspects. This review also gives insights into the progression of stent-based drug delivery strategies for the prevention of stent-related problems, or the treatment of local diseases. In addition, a critical analysis of the advantages and challenges of such strategies is provided.

Expert opinion: With an in-depth understanding of drug properties, tissue/organ biology and disease conditions, stent drug delivery systems can be improved further, to endow the stents with better efficacy and safety, along with lower toxicity. There is also a great need for stents that can simultaneously deliver multiple drugs, to treat complex diseases from multiple aspects, or to treat several diseases at the same time. Drug release kinetics greatly determines the stent performance, thus effective strategies should also be developed to achieve customized kinetics.     

The development of high-content screening (HCS) technology and its importance to drug discovery

ABSTRACT

Introduction: High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development.

Areas covered: Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology.

Expert opinion: Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.     

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery

Introduction: The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc.

Areas covered: This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered.

Expert opinion: This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.     

Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease

Introduction: Cystic fibrosis (CF) is a multisystem genetic disorder, which usually results in significant respiratory dysfunction. At present there is no cure for CF, but advances in pharmacotherapy have gradually increased the life expectancy of CF patients. As many drugs used in the therapy of CF are delivered by inhalation, the demand for effective and convenient inhalational CF drug formulations will grow as CF patients live longer. Knowledge of the current limitations in inhalational CF drug delivery is critical in identifying new opportunities and designing rational delivery strategies.

Areas covered: This review discusses current and emerging therapeutic agents for CF therapy, selected physiological challenges to effective inhalational medication delivery, and various approaches to overcoming these challenges. The reader will find an integrated view of the known inhalational drug delivery challenges and the rationales for recent investigational inhalational drug formulations.

Expert opinion: An ideal drug/gene delivery system to CF airways should overcome the tenacious sputum, which presents physical, chemical and biological barriers to effective transport of therapeutic agents to the targets and various cellular challenges.     

Drug delivery using multifunctional dendrimers and hyperbranched polymers

Importance of the field: The review presents the design strategy and synthesis of multifunctional dendrimers and hyperbranched polymers with the objective to develop effective drug delivery systems.

Areas covered in this review: Well-characterized, commercially available dendritic polymers were subjected to functionalization for preparing drug delivery systems of low toxicity, high loading capacity, ability to target specific cells and transport through their membranes. This has been achieved by surface targeting ligands, which render the carriers specific to certain cells and polyethylene glycol groups, securing water solubility, stability and prolonged circulation. Moreover, transport agents facilitate transport through cell membranes while fluorescent probes detect their intracellular localization. A common feature of surface groups is multivalency, which considerably enhances their binding strength with complementary cell receptors. To these properties, one should also add the property of attaining high loading of active ingredients coupled with controlled and/or triggered release.

What the reader will gain: Readers will be exposed to the strategy of synthesizing multifunctional polymers, aimed at the development of effective drug delivery systems.

Take home message: Multifunctional systems upgrade the therapeutic potential of drugs and, in certain cases, may even lead to the application of new bioactive compounds that would otherwise not be feasible.