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. A challenging objective of targeted drug delivery is the development of innovative multidisciplinary approaches for the design, synthesis and functionalization of novel nano-carriers for targeted delivery of protein/peptide (P/P) drugs via oral, pulmonary and nasal administration routes as well as the fabrication of “smart” miniaturized drug delivery devices able to release a variety of drugs on demand.

Introduction

Nanomedicine is defined as the application of nanotechnology to achieve breakthroughs in healthcare. It exploits the improved and often novel 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. 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 (theranostics) 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 medi-cine, (II) it interfaces nanomaterials with “living” human material and (III) it creates new tools and methods that impact significantly existing conservative practices.Major goals of nanomedicine in terms of controlled drug delivery, are the maximization of drug bioavailability and efficacy, the control of pharmacokinetics, pharmaco-dynamics, non-specific toxicity, immunogenicity and bio-recognition as well as the overcoming of obstacles arising from low drug solubility, degradation, fast clearance rates, relatively short-lasting biological activity and inability to cross biological barriers (e.g., air-blood barrier, blood-brain barrier).

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 (DDS) 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, hydrophilicity, bioavailability, optimum concentration range (above or below which the drug can be toxic or produce no therapeutic benefit at all), etc., the essential characteristics that identify the efficiency of the DDS 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, bio-conjugate chemistry and toxicology.

Before and after nanotechnology revolution

As shown in Table 1, 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.

Safety and Ethical Issues

The term ‘‘nanotoxicology’’ first showed up in 2004 (Service, 2004), which is defined as ‘‘science of engineered nanodevices and nanostructures that deals with their effects in living organisms’’ (Oberdorster, Oberdorster, & Oberdorster, 2005). 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 (Ryman-Rasmussen, Riviere, & Monteiro-Riviere, 2006). 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 (Nel, Xia, Madler, & Li, 2006). 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 nanotoxicity 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 (IRGC) made a series of surveys about the current situation of the nanotechnology governance (I.R.G.C., 2006). 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 (NGOs). 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 (R&D) 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 (21st Century Nanotechnology Research and Development Act, Public Law 108–153, 2003), there is no government with nanotechnology-specific legislation or regulation, although the risk of the environment, health, and safety issue (EHS) is well accepted. Moreover, it was reported that governments and industrial organizations did not recognize any ethical, legal, and social issues (ELSI) 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 minimalistic design of drug delivery systems. Multifunctional drug delivery systems have been reported, but only few of them were used successfully in small animal models (Lanza, Yu, Winter, Abendschein, Karukstis, Scott, Chinen, Fuhrhop, Scherrer, & Wickline, 2002; Reddy, Bhojani, McConville, Moody, Moffat, Hall, Kim, Koo, Woolliscroft, Sugai, Johnson, Philbert, Kopelman, Rehemtulla, & Ross, 2006). As our understanding on nano drug delivery vehicles improves, the system will become simpler and simpler, as that is probably the only way to bring the nanovehicles into clinical applications. Nano/micro- or organic/inorganic composites also have great potential. Combination of different properties using different materials has been successfully used, and this effort will only be expanded in the future. For a representative example, metallic stents have poor biocompatibility resulting in multiple hazardous symptoms after implantation, such as inflammation and restenosis. Coating the stents with biocompatible polymers with loaded drugs improved the biocompatibility significantly (Acharya, & Park, 2006; Levin, Jonas, Hwang, & Edelman, 2005). Recently, the layerby-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 (De Geest, Dejugnat, Verhoeven, Sukhorukov, Jonas, Plain, Demeester, & De Smedt, 2006; Huang, & Yang, 2006; Thierry, Winnik, Merhi, Silver, & Tabrizian, 2003; Ye, Wang, Liu, & Tong, 2005). In developing BioNEMS or BioMEMS, a combination with smart polymers can also result in interesting properties, such as microvalves actuated by environment-sensitive hydrogels (Baldi et al., 2003). 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 (Freitas, Merkle, & Gander, 2005) or solvent exchange (Yeo, & Park, 2004) 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. Current methods based on double emulsion and ultrasonic atomization need significant improvement in the loading efficiency and production scale-up. 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. We can be very optimistic to expect that the current macro devices will be shrunk into the nano/micro scale to manufacture nanovehicles reliably for mass production in the very near future. The future of nanotechnology is expected to bring multitude of fusion technologies. As illustrated in Figure 19.3, different research fields and/or technologies are intimately connected to each other. Different technologies can be fused together to develop better, more useful technologies, and nanotechnology will play a central role in all fusion technologies. 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. Utilization of fusion technologies and sequence of development of drug delivery systems are described in Figure 19.4, which is modified from a FDA report (FDA, Mar 2005). The critical path consists of basic research, material development, prototype design and discovery, pre-clinical development, clinical development, and final launching. Producing clinically useful nanomedicine requires consideration of the three factors of assessing safety, demonstrating medical utility, and industrialization for mass production. During development, efforts to improve the existing drug delivery systems, feedback control between each step, ethical/environmental regulation and standardization in protocol will have to be considered in parallel. The future of nanotechnology in drug delivery is very bright, as combined efforts of scientists in different disciplines are bound to make nanotechnology practical.