Art and drug delivery system design: dissonance or a harmony?

KEYWORDS:

• Drug delivery
• art
• creativity
• design

As usual, the article might need a brief introduction on the subject it covers; however, in this very special and apparently odd topic, it needs a more detail and broader look as two seemingly different subjects are to be connected. The majority of readers may be to some extent familiar with art while a few actually being artists in specific areas; however, a considerable number of audiences may be confused with the clear definition of art covered in this article, thus an introduction to both subjects are provided in the next paragraphs.

The history of modern-day drug delivery merely exceeds 60 years from the first generation of many oral and transdermal controlled release formulations for clinical applications. While the focus of the first-generation design was physicochemical properties, the fundamental understanding of drug delivery field was indeed based during this first development cycle [1]. The new term ‘sustained release’ was introduced with Dexedrine (dextroamphetamine sulfate) (1952) as the first product using Spansule® technology developed by Smith Kline and French, further frequently referred as exchanged terms of ‘controlled released,’ ‘timed released,’ or ‘extended release’ [2]. The next wave of developments were accompanied with further progresses on pharmacodynamic and cellular biology knowledge, leading to ‘smart delivery systems’ dealing with more challenging formulations such as design of tumor-targeted nanosystems. Without regard to the type of development, the whole concept of drug delivery always was connected with more controlled and specific therapies, tackling the limitations of conventional medicines such as need of the higher doses, side effects, lower patient’s compliance, and intervals of medicine administration [3]. Since 1950s, increasing efforts in the field of drug delivery has leaded to magnificent achievements, especially in pharmacokinetic view, brand-new solutions were proposed for physicochemical improvements of many drugs [4]. However, the growing progress faced a decline in its steep, mainly due to the nature of the newer problems to overcome. The first designs of the drug delivery systems were made to struggle physicochemical hurdles using the then mechanisms, namely, dissolution-controlled and diffusion-controlled systems and to fewer extent osmosis-based formulations. A thorough knowledge of pharmacokinetic and physicochemical properties of a drug was sufficient for developing clinically useful formulations. Nevertheless, as our understanding of cellular biology increased, drug delivery systems attempted to aim targets at cellular levels, assigning a new role for drug delivery techniques [5,6]. Thus, a different and lesser-encountered row of problems arose, hindering the rise of new products. Biological barriers made it difficult to predict the behavior of a drug delivery system within the human body as delivery system interaction with blood negatively charged components as an instance, question the practical use of many delivery systems [7,8]. In cancer therapy, the problem appeared differently. Inadequate understanding of the tumor biology and effect of the delivery system on cellular levels in cancer cells resulted in failure of recent-decades uses of drug delivery for anticancer treatments [9,10]. Conventional strategies no longer met the needs of scientists to overcome the obstacles. There seemed to come a new era where new problems needed new solutions.

The advent of nanotechnology has broadened the available approaches in drug delivery system design. Capacity of nanoparticles to be produced in various size and shapes and the ability to control parameters affecting physicochemical properties, resulted in new promising solutions to the so-called insoluble problems [11]. In vitro studies of nanoparticles demonstrated a drastically increased effect of the drug trapped in or loaded on these systems while off-target effects meaningfully reduced in many cases. However, the promising results observed in small animal models fail to translate to benefits in human [12]. Nanoparticles are not able to show their targeting behavior as if in vitro studies, meaning accumulation at the site of interest does not occur as expected. In anticancer application of nanoparticles, the widely-kwon ‘enhanced permeability and retention effect’, at least in large part, is not capable to quantitatively prove the higher presence of the nanoparticles within the tumor site [13,14]. Many observations made in mice could not be correctly extended to human as proportion of blood volume in these species is by far incommensurate. Even small tumors weighting few grams in weight or centimeters in diameter can form a considerable portion of a mice body. Thus, in vivo data needs to be more cautiously translated into clinical practice. Moreover, application of many nano-based delivery systems is limited due to the toxicity profile of the carrier [15]. Considering polyethylenimine, although the polymer is a gold standard in nonviral gene delivery, its practical application is greatly suffered from the toxicity issues [16]. Undoubtedly, advances in drug delivery field have made considerable contribution to the clinical therapies for a large range of diseases; however, there still are critical gaps between outcomes in small animal models and actual human products.

To fill these gaps, numerous trials and errors are gone through in designing nanosystems possessing favorable features to be candidate for clinical studies and product promotion. Over the half-century experience of the drug delivery field, few breakthrough discoveries in drug delivery technologies significantly changed scientific view and promote scientific progress. Many of which were not results or inventions of brand-new and unknown technologies or mass information of long-term studies, but mostly outcomes of a new way of thinking, a novel use of the then available options. It was more like that the needs for better solutions were already existed, yet a brilliant mind was needed to exploit them. Cell-based anticancer solutions were among these innovative solutions. Cell-derived membrane vesicles attracted much attention due to their ability for cell-to-cell material or information transfer, making them as promising drug carriers [17,18]. Their ability to cross blood-brain barrier was observed in a well-known study conducted by Alvarez-Erviti et al., paved the way in brain-targeted delivery systems [19]. Mesenchymal stem cells can act as bioreactors for the production and sustained release of the anticancer agents in the tumor site [20]. Oncolytic viruses can be loaded in cells to mimic their anticancer intrinsic properties to preferentially invade cancer cells [21]. Another attractive strategy in cancer treatment, mostly employed in recent decade, is hybrid nanocarriers. Polymer-lipid, polymer-virus materials, protein-polymer systems and organic-inorganic nanostructures are all examples of the hybrid delivery system category [22–24]. Nanobots, another attractive strategy in targeted drug delivery, are widely believed by a considerable number of researchers, as the next generation of drug delivery systems [25]. These nanoelectromechanical systems are designed to function at nanoscale dimensions. Hypothetically, they are able to reach any site of interest within the human body, capturing images, performing surgeries, delivering drugs and manipulating genes of cells [26].

The concept behind these innovative strategies was creative use of preexisting materials rather than discovering or inventing a completely new and unknown system. ‘Thinking beyond the box’ as the metaphor goes and becoming more receptive to ‘beyond-the-box thinking’, might be the philosophy in demand to address our problems.

There is no one universal definition of art and the term has actually been debated for centuries among philosophers and artists; however, there is a widespread consensus that art is the creation of beautiful or meaningful existences. Nevertheless, there is not such difference in definition of what art does and how it functions and for this matter we are agreed with Linda Naiman picture of art’s obligation as: ‘Art provides an opportunity for kaleidoscopic thinking. Each time we shift the lens of our perceptions, we gain new perspectives – and new opportunities for innovation.’ Scientific evidences are also in agreement with this picture of art. Indeed, from scientific view, a number of studies in the literature demonstrate the impact of art education on academic achievement, social and emotional development and creativity and the evidence is steadily growing [27–30]. It is evident that art could develop neural systems providing a range of advantages such as improved motor skills, creativity and fine emotional balance [31,32]; all are thought to be the driving forces behind all other learning. In a famous study done by Burton et al., art was found to be directly connected with superior ability of creative thinking, problem-solving, and cooperation [33]. Interestingly, the benefits are not limited to a specific type of art. The diversity of supporting material regarding all types of art from visual to musical and kinesthetic art is convincing enough to extent the conclusion to these areas [34–36]. Thus, art can be a tool to improve problem-solving skills as well as increasing creativity which in turn adds on to the mentioned skills since evidences link creativity with the ability to find innovative solutions to problems [37].

This role of art as a driving force of problem solving or a resource of creativity has been employed in design of many technologies. In fact, it is not an unfamiliar use of art in the subject as the idea of contribution of art to scientific discoveries dated back to centuries ago from the well-honed skills of Leonardo Da Vinci to Samuel Morse, Santiago R. y Cajal, John J. Audubon, Maria S. Merian, Anna Atkins, and Alfred L. Copley [38–43]. It is evident that understanding of art, as a big part of art therapy, drastically encourage spontaneous, relational, and creative engagement, all are functions that are proven to be associated with the right hemisphere of the brain [44]. Insight, as defined as ‘the sudden recognition of the alternative approach that leads to the solution of a problem that previously seemed insoluble,’ is to a big part connected with function of right hemisphere [45]. This finding is also supported by observations from other studies. Therefore, art can serve as a creativity-maker machine allowing scientists to face the challenges from a new perspective. From historical view, Da Vinci’s approach to develop ideas for both his paintings and inventions was way ahead of his time. He did not see science and art as two competing or separate entities, but as a unity that inspires each other. From his perspective, the entire world was a masterpiece work of art that needs to be studied through the inquisitive eyes of a researcher. His mindset as one of the leading figures of the Renaissance, can be clearly seen in both his scientific and artistic works. L’uomo vitruviano (the Vitruvian Man) is a typical example of intersection of art and science. Anatomically accurate measurements of a male represented in his work demonstrate his deep understanding of proportion [46]. His curiosity over fluid dynamic behavior of water was not only reflected in ‘Landscape drawing for Santa Maria della Neve,’ but thoroughly discussed in ‘The Codex Leicester’ with over 700 conclusions about water [47]. Flying machine ideas as well as his design of Ornithopter, first raw design of machine gun, armored tank and the first robot were other exceptional works of Da Vinci originated from science and art. Although Leonardo Da Vinci was not the only man who employed art for the benefit of science and science for the benefit of art, he was certainly one of the founding ones. His works remained as perfect examples of complementary role of art and science and his mindset deserves to be utilized today in a boarder way.

Mediated Matter group projects at MIT is a typical example of creative solutions originated from art for the current problems [48]. Derived from nature, the group’s designs focus on computational design, digital fabrication, materials science, and synthetic biology, followed further by applying that knowledge to design across micro to macro scales. In one of their recent works, chitosan range of angle change was assessed at different pH values. The results reveal a bimodal relationship between bend angle and pH in the range of pH 2–10 [49]. Chitosan is a biocompatible and biodegradable polymer and its use in drug delivery systems as the carrier and coating agent has been extensively explored in a considerable number of studies [50,51]. The findings on chitosan shape change behavior toward various pHs values can be a useful information as tumor microenvironment possesses acidic nature. Surface alteration of objects using 3D-printing technology is another project of this group. With the two-photon polymerization technology, printing on nanoscale can be achievable [52]. As surface plays a crucial role in cell-nanosystem interaction – a key parameter in drug delivery design – this might define a completely new application of the technology in drug delivery field. Stimuli-responsive delivery systems is another state-of-the-art strategy of current research. Redox-responsive, pH-responsive, temperature-responsive, light-responsive, magnetic field-responsive, ultrasound responsive, and multistimuli-responsive delivery systems are among currently available options within this category [53,54]. A recent publication in Nature Communication used an interesting strategy to release drug or gene of interest at the tumor site. Liposomes including gold nanoparticles and photosensitizer verteporfin were prepared to deliver the anticancer agents to the tumor cells. Verteporfin is vulnerable to X-ray radiation and upon exposure, it produces singlet oxygen, which destabilizes the liposomal membrane causing the release of trapped cargo to the tumor microenvironment [55]. Codelivery nanosystems has been attracting much attention recently due to the synergistic or complementary effect of simultaneously release of two or more therapeutic agents. Nanosystems composed of both drug and gene are one of the widely reported examples of codelivery systems. Some codelivery systems targeting tumor cells use a second agent, which lacks an anticancer itself, but possesses a contributory or complementary role to the first main therapeutic compound [56,57]. For example chloroquine, most widely known as an antimalaria drug, can be employed to increase endosomal escape [58] or curcumin – a yellow pigment derived from Curcuma longa- reverses multidrug resistance by inhibiting anticancer drug efflux transporters [59]. Regarding the concept of nanobots, the contributory role of art might be more tangible as the science-fiction movie ‘Fantastic voyage,’ produced in 1966, for instance, pictured an adventure of a submarine crew into a human body for the first time or many other artworks representing the whole idea of a smart micro-scale machine venturing into a human body. ‘Innerspace,’ produced in 1987, depicts a similar microscopic adventure in a living human body. A more interesting look at the concept of nanobots can be found in the novel ‘Prey’ by Michael Crichton. Published in 2002, he introduced a nanosystem which can multiply itself, broadening the scope of a nanomachine function. Additionally, art can also significantly help to visually describe complex ideas of novel drug delivery strategies including nanobots.

1. Expert opinion

History of drug delivery, although is not rich as is the case for conventional medicines, has seen breakthrough time points in which a brilliant idea was proposed that changed the fate of many researches of its time. These ideas often were product of creative mind storming, thinking of the solutions from a brand-new prospective. Art as one of the most conceptual concepts of human is proven to be connected with improvement of creativeness and the ability of problem-solving. This contributory role of art – in its all forms – can be regarded as a tool to facilitate the pathway toward promising drug delivery systems. It is our suggestion that more than any time, the two concepts of art and science be treated not as two different subjects, but a major collaboration between these concepts and their experts are needed. Research groups at universities and laboratories should reconsider art, not a hobby or foreign study field, but as an essential part of their project. As per human historical experience, the available tools might be enough to solve the intractable problems. Art and drug delivery system design are no two separate concepts, but a perfect combination to reach perfect drug delivery systems.

Declaration of interest

The authors have 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

Reviewer disclosures

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Additional information

Funding

This paper was not funded.