Nanotechnology and biomimetic methods in therapeutics: molecular scale control with some help from nature

Nanoscale science and engineering has provided new avenues for engineering materials with macromolecular and even molecular precision. In particular, researchers are beginning to mimic biological systems, achieving molecular scale control via self-assembly and directed assembly techniques. Fabrication and manipulation with macromolecular and molecular precision have led and will lead to the development of novel materials, and these materials will facilitate the fabrication of micro- and nanoscale devices, such as self-regulated micro- and nanoscale drug delivery devices that combine diagnostic and therapeutic actions for instantaneous administration of therapy. As the field of nanoscale science and engineering matures, technologies that will revolutionize the way health care is administered will continue to be developed.     

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.     

Nanotechnology for nanomedicine and delivery of drugs

Nanotechnology is an emerging technology seeking to exploit distinct technological advances controlling the structure of materials at a reduced dimensional scale approaching individual molecules and their aggregates or supramolecular structures. The manipulation and utilization of materials at nanoscale are expected to be critical drivers of economic growth and development in this century. In recent years, nanoscale sciences and engineering have provided new avenues for engineering materials down to molecular scale precision. The resultant materials have been demonstrated to have enhanced properties and applicability; and these materials are expected to be enabling technologies in the successful development and application of nanomedicine. Nanomedicine is defined as the monitoring, repair, construction, and control of human biological systems at the molecular level using engineered nanodevices and nanostructures. Electrospinning is a simple and cost-effective technique, capable of producing continuous fibers of various materials from polymers to ceramics. The electrospinning technique is used for the preparation of nanofibers and macroporous scaffolds intended for drug delivery and tissue engineering. These have special characteristics in terms of fabrication, porosity, variable diameters, topology and mechanical properties. This review summarizes the recent developments in utilizing nanofibers for drug delivery and tissue engineering applications.     

Micropatterned surfaces: techniques and applications in cell biology

Importance of the field: Engineering of cell culture substrates provides a unique opportunity for precise control of the cellular microenvironment with both spatial as well as temporal resolutions. This greatly enhances studies of cell-cell, cell-matrix and cell-factor interaction studies in vitro. Areas covered in this review: The technologies used for micropatterning in the biological field over the last decade and new applications in the last few years for dynamic control of surfaces, tissue engineering, drug discovery, cell-cell interactions and stem cell studies are presented. What the reader will gain: The reader will gain knowledge on the state of the art in micropatterning and its wide ranging applications in cell patterning, with new pathways to control the cell environment. Take home message: Micropatterning of cells has been studied and developed enough to be widely applied ranging from single cell assays to tissue engineering. Techniques have evolved from many-step processes to direct writing of biologically selective patterns.     

Micro- and nanotechnologies for intelligent and responsive biomaterial-based medical systems

Advances in medical treatments of a wide variety of pathophysiological conditions require the development of better therapeutic agents, as well as a combination of the required therapeutic agents with device-integrated biomaterials that can serve as sensors and carriers. Combination of micro- and nano-fabricated systems with intelligent biomaterials that have the ability to sense and respond is a promising avenue for the development of better diagnostic and therapeutic medical systems. Micro- and nano-electromechanical systems (MEMs and NEMs) are now becoming a family of potentially powerful new technologies for drug delivery, diagnostic tools, and tissue engineering. Improvements in micro- and nano-fabrication technologies have enhanced the ability to create better performing therapeutic systems for numerous pathophysiological applications. More importantly, MEMS- and NEMS-based tissue regeneration scaffolds, biosensors, and drug delivery devices provide new opportunities to mimic the natural intelligence and response of biological systems.     

Differences in physicochemical properties to consider in the design,evaluation and choice between microparticles and nanoparticles for drug delivery

Introduction: The increase in the development of novel nanoparticle drug delivery systems makes the choice between micro- and nanoscale drug delivery systems ubiquitous. Changes in physical and chemical properties between micro- to nanosized particles give them different properties that influence their physiological, anatomical and clinical behavior and therefore potential application.

Areas covered: This review focuses on the effect changes in the surface-to-volume ratio have on the thermal properties, solubility, dissolution and crystallization of micro- versus nanosized drug delivery systems. With these changes in the physicochemical properties in mind, the review covers computational and biophysical approaches to the design and evaluation of micro- and nanodelivery systems. The emphasis of the review is on the effect these properties have on clinical performance in terms of drug release, tissue retention, biodistribution, efficacy, toxicity and therefore choice of delivery system.

Expert opinion: Ultimately, the choice between micro- and nanometer-sized delivery systems is not straightforward. However, if the fundamental differences in physical and chemical properties are considered, it can be much easier to make a rational choice of the appropriate drug delivery system size.     

Moving smaller in drug discovery and delivery

Advances in new micro- and nanotechnologies are accelerating the identification and evaluation of drug candidates, and the development of new delivery technologies that are required to transform biological potential into medical reality. This article will highlight the emerging micro- and nanotechnology tools, techniques and devices that are being applied to advance the fields of drug discovery and drug delivery. Many of the promising applications of micro- and nanotechnology are likely to occur at the interfaces between microtechnology, nanotechnology and biochemistry.     

NMR-based approaches for lead discovery

NMR methods have long been used for studying molecular interactions. In the last few years, various NMR approaches have been developed to aid lead discovery. These involve different NMR screening methods to identify initial compounds, which often bind only weakly (in the micro- to millimolar range) to the drug target. Intelligent and focused follow-up strategies enable the development of these compounds into potent, submicromolar drug-like inhibitors for use as leads in drug discovery projects. NMR can be used as both a remarkably reliable screening tool and a structural tool; thus, this technique has unique opportunities for lead discovery.     

Human and mouse artificial chromosome technologies for studies of pharmacokinetics and toxicokinetics

In the earliest stage of drug discovery/development, various cell-based models and animal models were used for the prediction of human pharmacokinetics and toxicokinetics. Unfortunately, drugs under development are often discontinued because their nonclinical results do not extrapolate to human clinical studies in relation to either safety or efficacy. Therefore, it is important to improve the time- and cost-effectiveness of drug development. This might be achieved by developing new technologies including pharmacokinetics and toxicokinetics models that use human and mouse artificial chromosome vectors (HACs/MACs). HACs/MACs are unique vectors with several advantages: 1) independent maintenance, 2) defined copy number and mitotically stable, 3) no silencing of the transgene, and 4) no limitation of DNA insertion size. This review provides information on the advantages and examples of the utility of various models based on the recent advances in HAC/MAC technologies, including multifunctional cell-based models for assaying drug–drug interactions, bidirectional permeability, and cytotoxicity, as well as fully genetically humanized mouse models. We also discuss the future prospects of these technologies to advance drug discovery. In summary, these technologies offer advantages over current conventional models and should improve the success rate of drug development related to efficacy and safety for humans.     

Design,fabrication and characterization of drug delivery systems based on lab-on-a-chip technology

Lab-on-a-chip technology is an emerging field evolving from the recent advances of micro- and nanotechnologies. The technology allows the integration of various components into a single microdevice. Microfluidics, the science and engineering of fluid flow in microscale, is the enabling underlying concept for lab-on-a-chip technology. The present paper reviews the design, fabrication and characterization of drug delivery systems based on this amazing technology. The systems are categorized and discussed according to the scales at which the drug is administered. Starting with the fundamentals on scaling laws of mass transfer and basic fabrication techniques, the paper reviews and discusses drug delivery devices for cellular, tissue and organism levels. At the cellular level, a concentration gradient generator integrated with a cell culture platform is the main drug delivery scheme of interest. At the tissue level, the synthesis of smart particles as drug carriers using lab-on-a-chip technology is the main focus of recent developments. At the organism level, microneedles and implantable devices with fluid-handling components are the main drug delivery systems. For drug delivery to a small organism that can fit into a microchip, devices similar to those of cellular level can be used.     

Microbioreactors for high-throughput cytotoxicity assays

Cell culture plays a fundamental role in the biotechnology and pharmaceutical industries, impacting both drug discovery and manufacturing as well as regenerative medicine. In drug discovery, cell-based assays are increasingly being used for drug target validation and drug ADMET (absorption, distribution, metabolism, elimination and toxicity) studies because cells can provide more representative responses to drugs than simple molecular assays and are easier to use in a high-throughput format than animals. There are, however, intrinsic drawbacks associated with conventional in vitro cellular tests using two-dimensional cultures, in that they lack a three-dimensional (3D) scaffold to support cell growth and proper tissue function, and cannot mimic in vivo cellular conditions. Tailoring scaffold properties for 3D cell cultures is therefore essential in developing a representative in vitro tissue model for cytotoxicity assays. Recently, microfluidic bioreactors with miniaturized culturing vessels and high controllability for operation and on-line monitoring/sensing have gained popularity in bioprocess development and cell-based assays. The advancement in this field has been enabled by the development of novel cell lines and reporter gene techniques, as well as new microfabrication, microfluidics and optical and electrochemical sensor technologies. Non-invasive detection methods using reporter genes and label-free techniques allow for real-time dynamic monitoring of viable cell number and cellular activities. Microbioreactors with continuous perfusion allow for long-term culturing to study chronic toxicity effects. Systemic toxicity and interactions between different cell types can also be studied on a biochip. High-density microfluidic arrays provide a platform for future high-throughput and high-content screening that will contribute to drug discovery and bioprocess development.     

Computational identification and analysis of G protein‐coupled receptor targets

The completion of the human genome sequence has provided a large pool of potential drug targets for disease therapy. G protein–coupled receptors (GPCRs), which are central to signaling networks that regulate basic cellular processes, represent the most important known class of therapeutic targets for multiple disease states. Bioinformatics approaches can be applied to facilitate the identification of novel GPCRs, understanding their physiological and pathological roles, and screening for drug discovery. The present review summarizes current bioinformatics approaches that can be used to identify and analyze GPCR targets. In addition, the limitations of these technologies with the intention of setting reasonable expectations are also discussed together with some potential avenues for GPCR research. Drug Dev. Res. 67:771–780, 2006. © 2007 Wiley‐Liss, Inc.     

High-throughput screening of cell responses to biomaterials

Biomaterials have emerged as powerful regulators of the cellular microenvironment for drug discovery, tissue engineering research and chemical testing. Although biomaterial-based matrices control the cellular behavior, these matrices are still far from being optimal. In principle, efficacy of biomaterial development for the cell cultures can be improved by using high-throughput techniques that allow screening of a large number of materials and manipulate microenvironments in a controlled manner. Several cell responses such as toxicity, proliferation, and differentiation have been used to evaluate the biomaterials thus providing basis for further selection of the lead biomimetic materials or microenvironments. Although high-throughput techniques provide an initial screening of the desired properties, more detailed follow-up studies of the selected materials are required to understand the true value of a 'positive hit'. High-throughput methods may become important tools in the future development of biomaterials-based cell cultures that will enable more realistic pre-clinical prediction of pharmacokinetics, pharmacodynamics, and toxicity. This is highly important, because predictive pre-clinical methods are needed to improve the high attrition rate of drug candidates during clinical testing.     

The role of electrospinning in the emerging field of nanomedicine

The fact that in vivo the extracellular matrix (ECM) or substratum with which cells interact often includes topography at the nanoscale underscores the importance of investigating cell-substrate interactions and performing cell culture at the submicron scale. An important and exciting direction of research in nanomedicine would be to gain an understanding and exploit the cellular response to nanostructures. Electrospinning is a simple and versatile technique that can produce a macroporous scaffold comprising randomly oriented or aligned nanofibers. It can also accommodate the incorporation of drug delivery function into the fibrous scaffold. Endowed with both topographical and biochemical signals such electrospun nanofibrous scaffolds may provide an optimal microenvironment for the seeded cells. This review covers the analysis and control of the electrospinning process, and describes the types of electrospun fibers fabricated for biomedical applications such as drug delivery and tissue engineering.     

Pluripotent Stem Cell-Derived Human Tissue: Platforms to Evaluate Drug Metabolism and Safety

Despite the improvements in drug screening, high levels of drug attrition persist. Although high-throughput screening platforms permit the testing of compound libraries, poor compound efficacy or unexpected organ toxicity are major causes of attrition. Part of the reason for drug failure resides in the models employed, most of which are not representative of normal organ biology. This same problem affects all the major organs during drug development. Hepatotoxicity and cardiotoxicity are two interesting examples of organ disease and can present in the late stages of drug development, resulting in major cost and increased risk to the patient. Currently, cell-based systems used within industry rely on immortalized or primary cell lines from donated tissue. These models possess significant advantages and disadvantages, but in general display limited relevance to the organ of interest. Recently, stem cell technology has shown promise in drug development and has been proposed as an alternative to current industrial systems. These offerings will provide the field with exciting new models to study human organ biology at scale and in detail. We believe that the recent advances in production of stem cell-derived hepatocytes and cardiomyocytes combined with cutting-edge engineering technologies make them an attractive alternative to current screening models for drug discovery. This will lead to fast failing of poor drugs earlier in the process, delivering safer and more efficacious medicines for the patient.     

Applications of proteomics in oncology

Genomics has expanded the field of molecular oncology, and proteomics is complementing genomics in the fields of elucidation of pathophysiology, gene function, molecular diagnosis and anticancer drug discovery. This trend is reflected in the establishment of the Human Tumour Gene Index by the National Cancer Institute (NCI), which is now followed by the Tissue Proteomics Initiative. Laser capture microdissection (LCM) provides an ideal method for extraction of cells from specimens in which the exact morphologies of both the captured cells and the surrounding tissue are preserved. Proteomic technologies can be applied for the further characterisation and analysis of proteins. LCM can also be combined with the protein chip technology. Proteomic technologies have been used for the study of cancer of various organs including the liver, prostate, breast, bladder and oesophagus. Some of the anticancer strategies are directed against proteases that facilitate several steps in cancer progression. Proteomic mapping of blood vessels in normal and malignant tissues can be used to identify tissue-specific markers on the endothelium that serve as potential targets for in vivo drug delivery. Studies of global protein expression in human tumours have led to the identification of various polypeptide markers, potentially useful as diagnostic tools. Genes that encode proteins that are overexpressed in tumours are being identified. Demonstration of tissue or cell type specific expression of some nuclear matrix proteins has led to the search for tumour specific nuclear matrix proteins. There is considerable activity in the commercial sector to develop diagnostic tests, as well as to facilitate anticancer drug discovery using proteomic technologies. Continued refinement of techniques and methodologies to determine the abundance and status of proteins in vivo holds great promise for future study of normal cells and associated neoplasms.     

Recent advances in inkjet dispensing technologies: applications in drug discovery

Introduction: Inkjet dispensing technology is a promising fabrication methodology widely applied in drug discovery. The automated programmable characteristics and high-throughput efficiency makes this approach potentially very useful in miniaturizing the design patterns for assays and drug screening. Various custom-made inkjet dispensing systems as well as specialized bio-ink and substrates have been developed and applied to fulfill the increasing demands of basic drug discovery studies. The incorporation of other modern technologies has further exploited the potential of inkjet dispensing technology in drug discovery and development. Areas covered: This paper reviews and discusses the recent developments and practical applications of inkjet dispensing technology in several areas of drug discovery and development including fundamental assays of cells and proteins, microarrays, biosensors, tissue engineering, basic biological and pharmaceutical studies. Expert opinion: Progression in a number of areas of research including biomaterials, inkjet mechanical systems and modern analytical techniques as well as the exploration and accumulation of profound biological knowledge has enabled different inkjet dispensing technologies to be developed and adapted for high-throughput pattern fabrication and miniaturization. This in turn presents a great opportunity to propel inkjet dispensing technology into drug discovery.     

How molecular profiling could revolutionize drug discovery

Information from genomic, proteomic and metabolomic measurements has already benefited target discovery and validation, assessment of efficacy and toxicity of compounds, identification of disease subgroups and the prediction of responses of individual patients. Greater benefits can be expected from the application of these technologies on a significantly larger scale; by simultaneously collecting diverse measurements from the same subjects or cell cultures; by exploiting the steadily improving quantitative accuracy of the technologies; and by interpreting the emerging data in the context of underlying biological models of increasing sophistication. The benefits of applying molecular profiling to drug discovery and development will include much lower failure rates at all stages of the drug development pipeline, faster progression from discovery through to clinical trials and more successful therapies for patient subgroups. Upheavals in existing organizational structures in the current 'conveyor belt' models of drug discovery might be required to take full advantage of these methods.     

Repurposing of parenterally administered active substances used to treat pain both systemically and locally

Pain is a constant in our lives. The efficacy of drug therapy administered by the parenteral route is often limited either by the physicochemical characteristics of the drug itself or its adsorption–distribution–metabolism–excretion (ADME) mechanisms. One promising alternative is the design of innovative drug delivery systems that can improve the pharmacokinetics |(PK) and/or reduce the toxicity of traditionally used drugs. In this review, we discuss several products that have been approved by the main regulatory agencies (i.e., nano- and microsystems, implants, and oil-based solutions), highlighting the newest technologies that govern both locally and systemically the delivery of drugs. Finally, we also discuss the risk assessment of the scale-up process required, given the impact that this approach could have on drug manufacturing.Teaser: The management of pain by way of the parenteral route can be improved using complex drug delivery systems (e.g., micro- and nanosystems) which require high-level assessment and shorten the regulatory pathway.     

Multimodal molecular imaging in drug discovery and development

In addition to individual imaging techniques, the combination and integration of several imaging techniques, so-called multimodal imaging, can provide large amounts of anatomical, functional, and molecular information accelerating drug discovery and development processes. Imaging technologies aid in understanding the disease mechanism, finding new pharmacological targets, and assessment of new potential drug candidates and treatment response. Here, we describe how different imaging techniques can be used in different phases of drug discovery and development and highlight their strengths, related innovations, and future potential with a focus on the implementation of artificial intelligence (AI) and radiomics for imaging technologies.