In all honesty, ‘nanotechnology’, or even ‘nanobiotechnology’, or any surrogate thereof has been around in pharmaceutical sciences and drug delivery for almost 40 years Citation[1]. The fundament for this technology was probably laid even earlier by Paul Ehrlich and other visionary scientists in the beginning of the 20th Century. In his hypothesis of the infamous ‘Zauberkugel’, or ‘magic bullet’, an idea said to be inspired by Carl Maria von Weber’s opera ‘Der Freischütz’, Ehrlich described a vector system able to specifically deliver its cargo to the tissue afflicted Citation[2]. In his Nobel award speech, he also hypothesized on the interaction of ligands with receptors of proteinaceous nature present in cell membranes for targeting and enhanced intracellular uptake Citation[3].
Today, nanotechnology, probably best described as the directed manipulation of all things small (<1 µm), has experienced a renaissance, or better yet, discovery by a range of scientific and medical disciplines, regulatory authorities and funding bodies. The former, of course, have had the greatest input in this development, and set in motion the latter two. The reason for this is the astounding increase in knowledge of the world at this level. Microscopy, not least atomic force microscopy, has given us the opportunity to examine and manipulate systems at the nanoscale. On the biological side, and through the development of genomics, proteomics, and molecular and systems biology to name a few, we can now begin to understand the mechanisms involved in processes at the cellular, cellular compartmental and molecular level in healthy and diseased states. Moreover, by combining nanotechnological and biological knowledge and analysis methods, we can attempt to modify drug delivery systems to show an improved pharmacokinetic profile and to better interact with their target tissue Citation[4]. Today, we are experiencing a change of paradigm when it comes to using nanoscale particulate systems for the delivery of therapeutic agents. With the advent of the production of nanoparticles on an industrial scale, and their use not only in pharmaceuticals, but also convenience products, toxicological concerns have come to the forefront Citation[5]. These include the risk of penetration of such small particles through biological barriers, represented by epithelia and endothelia, including the blood–brain barrier. This is in stark contrast to, or maybe just the flipside of, the work carried out in pharmaceutical research in recent decades, where profound effort has been invested to achieve the permeation of biological barriers. In particular, the penetration of the blood–brain barrier has been in the focus of studies aiming to deliver pharmacologically active compounds into the brain.
Another aspect of particulate drug delivery has been the modification of such delivery systems to avoid premature interaction with the immune system, for example the reticuloendothelial system, to provide for an increase in retention time in systemic circulation and an altered tissue distribution. Nanotechnology at this stage is exemplified by alteration of the surface of particulate carriers by coupling polymers (e.g., surfactants and polyethylene glycol) through covalent binding or adsorption. While targeting to specific organs may be achieved by altering physicochemical parameters, such as size and charge of nanoparticles, targeting to specific cells may be provided by functionalization with targeting moieties, such as monoclonal antibodies or antibody fragments, or by selective adsorption of plasma proteins to the particle surface Citation[6].
We are also experiencing a change of paradigm in that studies aimed at targeting specific cells of the immune system are being performed using nanoparticles specifically altered for this purpose. The aim of these studies is the delivery of vaccines and adjuvants to the immune system, resulting in protective immunity or the resolution of an established disease by activating the host’s immune system. Vaccination, from this perspective, is eliciting an artificial infection to raise the awareness of the immune system against potential antigens.
Of course, this is not a new concept. Nature has, over the period of a couple of eons, developed very simple, yet sophisticated and effective ‘delivery systems’ that meet the aforementioned requirements. These systems – viruses – are indeed nature’s best (and worst) delivery systems. Viruses are ultramicroscopic disease-producing entities of no cellular organization, have no metabolic machinery, are unaffected by antibiotics and are able to alter their phenotype by mutation. In order to develop vaccine delivery systems – using nanotechnology – one might venture into exploring the reasons why viruses are indeed immunogenic.
Three distinctive viral properties might be considered to address this issue, and we may have a blueprint for the development of effective artificial vaccine delivery systems in our hands Citation[7]. First, viruses are particles; their recognition and uptake by antigen-presenting cells is triggered by size, shape and other physical properties, which may be mimicked by designing nanoparticulate systems Citation[8]. Second, viruses show highly ordered repetitive surface structures. These structural features are supposed to directly lead to B-cell activation and the development of specific T-cell-independent IgM. Such structural features may also be realized in self-assembling nanoparticulate systems Citation[9], such as in virus-like particles Citation[10].
Third, viruses activate the immune system through pathogenic pattern-recognition receptors, such as the family of Toll-like receptors that are expressed on various cells of the immune system, and epithelial cells Citation[11]. Conserved throughout evolution, these are able to specifically recognize viral surface patterns and activate the immune system, forming a first line of defense against infection, and bridging adaptive and acquired immunity. Attaching Toll-like receptor ligands to the surface of particulate vaccine carrier systems represents an opportunity to render them more virus-like Citation[12].
Building on our knowledge of the intricacies of activation of the immune response and nanotechnological methods, we should be able to copy and include these viral properties into nanoparticulate vaccine delivery systems. The result of this research will not be the magic bullet envisioned by Ehrlich; instead, it will be a versatile and target-adjusted delivery platform for vaccines, adhering to the principle of inclusion of the antigen and its adjuvant in the same particulate carrier system Citation[13].
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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References
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