Read an Excerpt
Nanostructured Biomaterials for Overcoming Biological Barriers
By Maria Jose Alonso, Noemi S. Csaba
The Royal Society of ChemistryCopyright © 2012 The Royal Society of Chemistry
All rights reserved.
Historical View of the Design and Development of Nanocarriers for Overcoming Biological Barriers
MARÍA JOSÉ ALONSO AND PATRICK COUVREUR
Despite the fact that the first nanocarriers described in the literature were discovered by serendipity, the search for ways to overcome biological barriers has been the major driving force for the significant development of nanocarriers over the last decades. The barriers that drugs need to confront have been recognized, for a long time, in a generic form, however, the knowledge about their specific composition and biological behavior has been limited until quite recently. Fortunately, the important advances made in the last decades in the field of cellular and molecular biology have led to relevant information on the nature and mechanistic behavior of these barriers.
Figure 1.1 illustrates the input of knowledge required for the design and development of new nanomedicine products. As indicated, besides the necessity of an extensive knowledge on the biological barriers, important doses of imagination and creativity have been required for the successful design of nanostructures and the adequate selection of biomaterials. In fact, a critical limitation in the overall evolution of nanocarriers has been the identification of materials that can be acceptable for the human body. In the majority of cases, these materials are natural compounds that are well known with regard to their biological behavior. Examples of these materials include proteins, lipids and polysaccharides, which are present in our body. Other materials, in particular polymers, have been taken from previous applications, such as the preparation of prosthesis and other medical devices.
Another basic element for the development of nanocarriers has been the availability of adequate methodologies to produce them with the sufficient yield and efficiency. In this sense it is important to keep in mind, not only the necessity for the technology to be scalable, and as simple and mild as possible, but also the requisite for the nanocarriers to have an appropriate drug loading and delivery rate. An additional hurdle is often related to the difficulties for preserving the stability of the active compounds associated to the nanostructure. A final, and no less complex, issue is the one related to the pharmaceutical presentation of nanocarriers and the stability during long-term storage. In fact, preserving the colloidal stability of nano-matter is a very difficult task due to its natural thermodynamic tendency to aggregate in order to reduce the specific surface area. This situation often leads to the necessity of adding stabilizers and/or converting them into a powder form, either by lyophilization or spray-drying.
As nanocarriers are intended to solve critical problems of drugs, the evolution of the drug discovery field and the specific pharmaceutical profile of the new drugs has a crucial impact on the design of nanocarriers and, thus, in the selection of biomaterials and nanotechnologies. In this sense, the application of biotechnology within the pharmaceutical arena has led to an increasing number of macromolecular drugs and antigens. Some of these drugs, referred to as biopharmaceuticals, are currently being substituted by low molecular weight peptides and RNA fragments, which are obtained by chemical synthesis. Irrespective of their origin, these macromolecules are very vulnerable in the biological environment as they may suffer extensive degradation before reaching their target and have great difficulties in crossing epithelial barriers.
Finally, we should be aware that having acceptable knowledge of the biological barriers applying rational criteria to the design of nanocarriers is not sufficient in itself to reach the clinical development stage. As a matter of fact, besides the necessary proof-of-efficacy, a mandatory requirement from the regulatory point of view, is the assessment of the safety and mechanism of action. This is not a trivial task, as the analysis of the interaction of nanostructured materials with biological structures requires specific methodologies and validation procedures and standards.
Although relevant discoveries in drug delivery happened by chance or as a result of the enthusiasm of visionaries, the significant development of this field, especially over the last three decades, has been a consequence of important multidisciplinary efforts. Only by a multidisciplinary approach (Figure 1.2) involving knowledge from experts in chemistry, physics, engineering, biology, pharmacy and medicine could one understand the recent past and the even more promising future of nanocarriers and drug delivery field. These complementary efforts required for the advancement of nanotechnologies applied to medicine are well illustrated in the place that nanotechnology takes in the map of science.
The intention of the various chapters and sections of this book is to present an overview of the advances in the knowledge of the biological barriers associated to different modalities of administration and the corresponding development of nanoscience and nanotechnology-based alternatives available for confronting such barriers. In this initial chapter, our goal is to briefly summarize the critical information and to present how knowledge has been used throughout history for the specific design of nanocarriers. The chapter will end with the presentation of the current status of the nanocarriers from the pharmaceutical perspective and the prospects of future developments and cases of success. This initial chapter will be followed by a number of chapters (Sections 2 to 9) intended to describe in detail the limitations of specific barriers associated with different modalities of administration and examples of nanotechnology approaches to confront them. These chapters are described in section 1.3 of this chapter. Because of the intended pharmaceutical and practical projection of this book, it was found critical to include a chapter dealing with toxicological issues (Chapter 10) as well as case study of clinical pharmaceutical development (Chapter 11).
1.2 The Barriers Being Confronted Using Nanocarriers
The most important limitations of current therapies result from their limited success in a significant part of the population. This is largely determined by biological differences among individuals, including distinct disease markers, but also by the low specificity of many drug molecules for their specific targets and the emergence of resistance. The need to target drugs to their site of action was first presented by Paul Ehrlich in the early years of the 20th century. He understood the necessity to devise ways to shuttle drugs in order to have them concentrated in the right place. The work carried-out throughout nearly a century has proven the great challenges involved in making the targeting concept a reality. This could be understood by the fact that humans have not evolved towards making the drug transit through the body easy but, mainly, to prevent the entrance of foreign entities, i.e. drugs, and to destroy them in case they manage to enter the body. The first critical barriers for a drug to reach the internal body compartments are the skin and the mucosal surfaces. Due to the highly restrictive nature of the skin, drug administration through this barrier has been mainly limited to the purpose of local action, although a number of nanotechnology-based approaches have been described in order to disrupt and facilitate the transport of solutes across this barrier (Section 6). In contrast, the intestinal mucosa, highly specialized in the absorption of nutrients, is also permissive to the transport of certain drugs as far as they can diffuse passively or are susceptible of being transported by the biological transporters of the epithelium. Unfortunately, despite this permissive nature, there are increasing numbers of drugs and antigens that are unable to cross this barrier, and many are additionally compromised in their stability in the harsh gastrointestinal environment. This is the case for polar compounds and macromolecules in general, such as peptides, proteins and antigens. As presented in Section 2, there are currently a number of nanocarriers which hold great promise, as they have displayed a capacity to overcome the barriers associated with oral administration. Alternative mucosal modalities of administration have also been explored with some positive results, in particular for the nasal and pulmonary routes. The definition and development of nanocarriers for overcoming these destructive barriers are of key interest for the growing biotech industry. The most relevant efforts towards this goal are described in Sections 3 and 5. There are other hard to access sites on the body, e.g. the eye or the brain, which have attracted the attention of nanotechnologists as well. The effective delivery of drugs either to the surface or to the inner eye or across the blood brain barrier (BBB) has been the goal of a number of nanostructures and large devices with nanostructural patterns (see Sections 4 and 7).
Overall, by reading this book, researchers and students will become aware of the current nanotechnology-based strategies intended to overcome all these external barriers. However, we should keep in mind that reaching the internal body fluids is only the starting point of the hazardous journey that drugs undergo before reaching their target. As shown in Figure 1.3, it is obvious that, given the difficulties and the lack of instructions for these molecules to go to their place of action, many of them will be lost and execute an unsuitable action at the wrong place. Indeed, once drug molecules are in the blood circulation, they will be exposed to the attack of degrading enzymes and/or get sequestered by plasmatic and tissular proteins, the pattern of this binding affinity being a major determinant of the final action (either no effect, the desirable or the unwanted effects).
The use of nanocarriers has been considered a way to protect drugs from degradation for a long time, however, preserving the stability of the nanocarrier itself has always been a concern that has not been sufficiently studied. On the other hand, changing the biodistribution of drugs is not, per se, necessarily good. For example, the nanocarriers developed at first were found to accumulate in the mononuclear phagocytic system (MPS) and related organs, a pattern that was of interest for the treatment of specific diseases, i.e. infectious diseases affecting these organs, but not for others. Fortunately, as described in the following sections, research conducted over the last decades has provided strategies for a greater control of carrier biodistribution. Nevertheless, the current achievements have not yet reached the level of perfect targeting, called by Paul Erlich the "magic bullet". Important advances towards this ambitious goal have been covered in Section 8.
1.3 The Key Milestones in the History of Nanocarriers and Drug Delivery
This section describes the early days when the "nano-drug delivery" field began, the key people who launched this exciting field, and the evolution of the field from its origins in the 1960s to the currently very active era of targeted nano-carriers. This analysis has taken into account a number of historical perspectives reported by key leaders in research. Overall, this half a century period has been characterized by the concurrence of knowledge coming from different areas and a number of extraordinary provident discoveries. These discoveries, coming from the medical and pharmaceutical sectors, occurred as a consequence of the search for medical solutions and the increasing understanding of physio-pathology at both the cell and tissue levels. In the following lines we describe the critical milestones in the development of nanocarriers. These milestones are presented in a flow diagram (Figure 1.4).
1.3.1 Milestone: The Concept of Controlled Drug Delivery
In the 1960s, probably motivated by the progress in biopharmaceutics and pharmacokinetics, the idea of prolonging the residence of drugs in the body by controlling their delivery became a major focus of attention. The pioneer of this concept was Judah Folkman, a surgeon who in the mid-1960s discovered that implanting a Silastic1 (silicone rubber) tubing exposed to anaesthetic gases into rabbits resulted in a prolonged sleep. He proposed that segments of such tubing containing a drug could be implanted in order to achieve a controlled drug delivery. Interestingly, at the same time, Alejandro Zaffaroni, an outstanding biochemist and entrepreneur, had also been thinking about the concept of controlled drug delivery. He heard about Folkman's work and decided to share his vision of founding a company focused on the concept of controlled drug delivery with him. This idea was soon realized and the company Alza started with the help of Folkman and others as the first company specialized in drug delivery.
During the 70s there was a great development of the controlled release idea and a number of devices started entering the market. It was in this active period when Bob Langer developed with Judah Folkman the idea of controlling the release of proteins, using polymer matrices such as polyvyinilacetate. This was the first example of successful delivery of a complex hydrosoluble molecule from a hydrophobic, non-degradable polymer matrix, thus launching the field of controlled delivery of macromolecules. The impact of this discovery has been great, as it stimulated the immense activity and clinical success of micro- and nano-therapeutics to the present day. One of the various targets of application of macromolecular drug delivery promoted by Bob Langer is vaccination. He proposed the single-dose vaccine strategy, consisting of associating an antigen to a polymer device, as a way of improving and simplifying vaccination campaigns. Later on this idea was adopted by the WHO and the "Bill and Melinda Gates Foundation", where it was considered a Grand Challenge in Global Health.
Excerpted from Nanostructured Biomaterials for Overcoming Biological Barriers by Maria Jose Alonso, Noemi S. Csaba. Copyright © 2012 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.