Nanotechnology and controlled drug delivery
Nanotechnology advances in drug delivery deal with the development of synthetic nanometer sized targeted delivery systems for therapeutic agents of increased complexity, and biologically active drug products. Therapeutic systems in this class are up to a million times larger than classical drugs like aspirin. Being larger there is more scope for diversity and complexity, which makes their protection much more challenging and their delivery more difficult. Their increased complexity however, gives these systems the unique power to tackle more challenging diseases. Targeted delivery systems can have multiple functions, a key one being their ability to recognize specific molecules which can be located either on the membrane of target cells, or in specific compartments within the cell.
Introduction
Nanomedicine is defined as the application of nanotechnology to achieve breakthroughs in healthcare. It exploits the improved properties and often physical, chemical and biological properties of materials at the nanometer scale. At this scale, manmade structures match typical sizes of natural functional units in living organisms thus allowing them to interact with biomolecules. Major goals of nanomedicine in terms of controlled drug delivery, are the maximization of drug availability and efficacy, the control of pharmaco-kinetics, pharmaco-dynamics, non-specific toxicity,immunogenicity and bio-recognition as well as the overcoming of obstacles(e.g., air-blood barrier, blood-brain barrier).
Why it is Important in Clinical Medicine
Nanomedicine has the potential to enable early detection and prevention, and to essentially improve diagnosis, treatment and follow-up of diseases (e.g., combination of diagnostic devices and therapeutics with a real benefit for patients). Nanomedicine is a very special area of nanotechnology, because: (I) it is an extremely large field ranging from in vivo and in vitro diagnostics to therapy including targeted delivery and regenerative medicine, (II) it interfaces nanomaterials with “living” human material and (III) it creates new tools and methods that impact significantly existing conservative practices.
Before and After Nanotechnology Revolution
As shown in Table below, the drug delivery technologies in relation to the current nanotechnology revolution can be classified into three categories: before nanotechnology revolution (past); current transition period (present); and mature nanotechnology (future). The examples of drug delivery systems of the past (prior to the current nanotechnology revolution) are liposomes, polymeric micelles, nanoparticles, dendrimers, and nanocrystals, as mentioned above. The current drug delivery systems include microchips, micro needle-based transdermal therapeutic systems, layer-by-layer assembled systems, and various micro particles produced by ink-jet technology. These efforts are just beginning and many fabrication methods have been developed. The future of drug delivery systems, as far as nanotechnology is concerned, is to develop nano/micro manufacturing processes that can churn out nano/micro drug delivery systems. The current technology of fabrication and manufacturing of engineering materials at the nano/micro scale is advanced enough to develop nano/micro scale processes for producing products other than semiconductors. Imagine that the current soft gelatin capsules, which are in the centimeter scale, are manufactured at the nano/micro scale.
| Period | Before nanotechnology (past) | Transition period (present) | Mature nanotechnology (future) |
| Technology | Emulsion-based preparation of nano/micro particles | Nano/micro fabrication | Nano/micro manufacturing |
| Examples | Liposomes | Microchip systems | Nano/micro machines for scale-up production |
| Polymer micelles | Micro needle transdermal delivery systems | ||
| Dendrimers | Layer-by-layer assembled systems | ||
| Nanoparticles | Micro dispensed particles | ||
| Nanocrystals | |||
| Micro particles |
Development and Delivery
A challenging objective of targeted drug delivery is the development of innovative specialties approaches for the design, synthesis and functionalization of modern nano-carriers for targeted delivery of protein/peptide (P/P) drugs via oral, pulmonary and nasal administration routes as well as the manufacturing of “smart” miniaturized drug delivery devices able to release a variety of drugs on demand.
Another challenge of nanomedicine is the delivery of P/P drugs via alternative noninvasive administration routes (e.g., oral, pulmonary and nasal). Currently, the majority of biopharmaceutics are delivered by injection. However, since some P/P drugs can be rapidly cleared from the body before achieving their therapeutic goal, patients have to undergo more frequent injections, to enhance the therapeutic effectiveness, which is inconvenient and painful. The above goals are expected to be achieved, through the development of targeted drug delivery systems that can be selectively delivered to specific areas in the human body. However, since drug characteristics differ substantially with respect to chemical composition, molecular size, availability, optimum concentration range, etc., the essential characteristics that identify the efficiency of the drug delivery system are highly complex. Thus, their development has to be pursued as a multi-disciplinary effort, firmly built on extensive experience in polymer science, pharmacochemistry, pharmacology, molecular biology and toxicology.
Current State of Development & Applications
The countless benefits promised by nanoscience and nanotechnology in making medicines more efficacious have been endlessly pronounced since the inception of the concept. Nevertheless, the field and its applications in drug delivery are still in a nascent phase and the infinite possibilities it offers remains to be studied. Here are a few highlights:
Nanoparticles: Nanoparticles are currently the most studied branch of nanotechnology. Scientists at Rice University, Texas have developed small, uniform nanospheres of cerium oxide – a highly popular industrial antioxidant – which have the capability of treating cardiac arrest, traumatic brain injuries, and even Alzheimer’s.
At the time of a traumatic injury, for instance, blood contains increased levels of reactive oxygen species (ROS), which deprive cells of their oxygen and result in significant damage to their structures. By removing these free radicals from the bloodstream, cerium oxide nanoparticles can help cells survive, thus preventing further damage.
Magnetic Nanoparticles: Researchers from the University of Maryland (UMD) and Weinberg Medical Physics LLC (WMP) of Bethesda have developed magnetic nanoparticles that can be loaded with drugs or genes and directed towards deep targets in the body by using an external electromagnet.
As drug carriers, magnetic nanoparticles can allow clinicians to target hard-to-reach diseased sites inside our bodies, such as deep-tissue tumors, and avoid the need for systematically administered treatments or complex surgeries. Magnetic nanoparticles can also enable stimulation of stem cells and regeneration of bones.
Self-healing and Injectable Nanomedicines: A team of researchers from the Massachusetts Institute of Technology and Texas A&M University have developed a variety of injectable nanomaterial that could accentuate the process of blood clotting and prevent blood loss in a near-fatal accident. The material is a form of biodegradable gelatin encapsulated by nano-discs that help in coagulation of blood.
Even though the biomaterial is still being tested, the team believes that it could eventually be prefilled into syringes that users can inject on their own, giving them sufficient time to get to a hospital for treatment.
Safety and Ethical Issues
The term ‘‘nanotoxicology’’
first showed up in 2004, which is defined as ‘‘science of engineered
nanodevices and nanostructures that deals with their effects in living
organisms’’. The details about possible risks of the ‘‘ultrafine particle
(UFP)’’ have been described and considered from various angles. Currently, a
major route for nano-sized material to enter into the human body from air
pollution is known to be the respiratory tract. However, the gastrointestinal
tract and skin are now considered to be other major routes. For example, a
recent report showed that even a commercially available nanomaterial, quantum
dot, could be highly permeable to pig skin. Experimentally proven
pathophysiology and toxicity of nanomaterials include reactive oxygen species
(ROS) generation, oxidative stress, mitochondrial perturbation, inflammation,
uptake by reticuloendothelial system (RES), protein denaturation or
degradation, nuclear uptake, and blood clotting. Although many individual
researches have warned that nanomaterials can cause damage to the human body,
the exact mechanisms of toxicity are unknown and conclusive data are yet to be
established. Moreover, reports on nano-toxicity mostly focus on inorganic
nanomaterials consisting of heavy metals. Investigation about the toxic effect
of polymeric nanomaterials on living subjects is also urgently required.
In 2005, the International
Risk Governance Council made a series of surveys about the current situation of
the nanotechnology governance. The report consists of 4 parts, which summarized
representative opinions of governments of 11 countries, 11 industrial organizations,
5 research organizations, and 9 non-government organizations. Most of the
participants in the report recognized the risk of nanotechnology, although the
major focus of governments and industrial organizations was on the research and
development activity as well as potential benefits resulting from
nanotechnology. However, most of the respondents could not identify any
specified national or international regulations for nanotechnology. It is
surprising that, except in USA, there is no government with
nanotechnology-specific legislation or regulation, although the risk of the
environment, health, and safety issue is well accepted. Moreover, it was
reported that governments and industrial organizations did not recognize any
ethical, legal, and social issues of nanotechnology. It is very important to
establish appropriate national regulatory programs and self-regulatory/training
Chapter 19 Nanotechnology in Drug Delivery 589 programs in each organization.
In addition, ethical issues including equality of benefit, individual privacy
and security, environmental protection as well as complication between human
and machine should be considered in detail, if nanotechnology is to be
developed for the welfare of human beings (Jotterand, 2006; Mnyusiwalla, S.,
& Singer, 2003; Sandler, & Kay, 2006).
Nanotechnology for Future Drug Delivery Systems
Predicting the future of nanotechnology in drug delivery systems is not simple because the technology is moving forward fast and dynamically changing, and we are in the middle of such changes. One could, however, find possible clues from the efforts to overcome the problems facing the research community today. One of the first things that can be predicted is the small design of drug delivery systems. Also multifunctional drug delivery systems have been reported, but only few of them were used successfully in small animal models. Recently, the layer-by-layer (LBL) coating technique was introduced to generate multifunctional polymer coating layers, and this LBL technique is expected to find many applications in developing various composites. While nanotechnology is expected to produce new nano/micro devices, it is also expected to revolutionize the way the current drug delivery systems are produced. For example, nano/micro particles are currently made by solvent evaporation/extraction or solvent exchange methods. These approaches have been successfully used in producing a variety of nano/micro particles containing pharmaceutically active ingredients, but the processing methods require significant improvements. Nanotechnology-based approaches, which is often called ‘‘nano/micro fabrication’’ or ‘‘nano/ micro manufacturing,’’ can provide powerful new ways for mass production of nano/micro particles with high drug loading efficiencies. As nanotechnology becomes mature, nano/micro devices are expected to become as practical as macro devices are today. Drug delivery, although it sounds simple, requires complicated adaptation of various fusion technologies to be clinically useful. For example, drug delivery systems with targeting ability require material science for making the right polymers, biology for finding the right ligands able to interact with targets, physics to monitor the location of delivery systems, and chemistry for releasing the active at the right time and place.
References
Article in journal
- Nanotechnology advances in controlled
drug delivery systems; Kiparissides, C.;Physica status solidi. C; 2008; ISSN:1610-1634; Volume: 5; Issue: 12; Page: 3828-3833; DOI: 10.1002/pssc.200780129
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