Impact of nanoscience and nanotechnology on controlled drug delivery

Abstract

NanomedicineVol. 3, No. 4 EditorialFree AccessImpact of nanoscience and nanotechnology on controlled drug deliveryBi-Botti Celestin YouanBi-Botti Celestin YouanDivision of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhil Road, Kansas City, MO 64114, USA. Search for more papers by this authorEmail the corresponding author at youanb@umkc.eduPublished Online:11 Aug 2008https://doi.org/10.2217/17435889.3.4.401AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit The impact of nanoscience and nanotechnology on the field of controlled drug delivery (CDD) is a multifactorial and multilevel concern. This includes: the elucidation of the molecular and chronobiological basis of diseases and drug action (e.g., identification of clinically relevant biomarkers and their spatial and temporal expression) that may contribute to the development of more effective and safer methods of real-time diagnosis, monitoring and/or treatment of diseases; the discovery of new raw materials for better use of old and new bioactive agents; the development of more efficient production and characterization methods, such as those based on combinatorial and high-throughput techniques; and the urgent search for solutions to the related pending regulatory and ethical issues. Moreover, for nanomedicines intended to aid CDD in evolving successfully from laboratories to clinics and compete globally and with perhaps an unlimited lifetime, they should also have proven safety, efficacy, acceptability and availability, which indicate that well-planned interdisciplinary approaches will be required.“What has been will be again, what has been done will be done again; there is nothing new under the sun.” (Eccl. 1:9)This old wisdom may also be true for the nanomedicine era as well. Perhaps the first nanotechnology-based pharmaceutical products may be a submicron (∼200 nm) triglyceride emulsion used in parenteral nutrition that has been commercially available since 1966 [1]. The current emerging interest in nanomedicine, especially for CDD, may be related to advances driven primarily by the electronic industry in the field of nanoscience and nanotechnology (‘Nano’). These advances were themselves consecutive to the discovery of novel scientific tools that provide scientists with better atomic manipulation, observation and resolution. For example, microfabrication techniques, such as electron-beam lithography [2], were made available in the 1970s. Furthermore, in the 1980s, the outstanding works of Gerd Binnig and Heinrich Rohrer (both 1986 Nobel Laureate in Physics) led to the discovery of the first scanning-probe microscope, the scanning-tunneling microscope [3]. The history of scanning-tunneling- and atomic-force microscopy development has been recounted elsewhere [4]. These developments on atomistic scale fabrication and analysis had been predicted since 1959 by Richard Feynman’s (1965 Noble Laureate in Physics) memorable talk entitled ‘There is plenty of room at the bottom’[5]. In that historic talk, the ‘Father’ of Nano discussed and forecasted microtechnology as a frontier to be pushed back, like the frontiers of high pressure, low temperature or high vacuum. In recent years, several informative manuscripts focusing on different aspects of pharmaceutical nanotechnology have been published with special emphasis on aspects such as nanomedicine concepts [6], lipid- or polymer-based nanoparticles [7], pluronic block copolymers as biological modifiers [8,9], polymer vesicles [10], early stages of formulation development [11], long circulation and targeting [12], multifunctional nanocarriers [13,14], cell-based therapeutic issues [15], cancer diagnosis and therapy [16–18], complex diseases [19], clinical development [20], theranostics [21], toxicity potential [22], and pending regulatory [23] and ethical [24] issues. Readers are invited to refer to specific articles for further discussion on each aspect. The focus of this editorial is to provide a holistic view on each of the key aspects related to the impact of Nano on CDD, spanning from the elucidation of diseases processes, the raw material synthesis, nanomedicine production and characterization, to the regulatory and ethical aspects.Elucidation of the molecular & chronobiological basis of diseases & drug actionThe impact of Nano on this first aspect of CDD, especially on pharmacology, may be to provide a more rational and fundamental basis for effective and safe nanomedicine development. This enables elucidation of the molecular basis of diseases and drug action, which provides new opportunities. Genomic methods, together with model systems, provide effective means to characterize the biological activity of small molecules and to identify their cellular targets, which can clarify the mode of action of bioactive agents [25]. For example, the overexpression of ATP-binding-cassette (ABC) transporters is a major adaptive advantage used by tumor cells to evade the accumulation of cytotoxic agents. ABCA2, a transporter highly expressed in the cells of the nervous and hematopoetic systems, is associated with lipid transport and drug resistance in cancer cells. These transporters may be used as a therapeutic target in modulating the drug-resistance phenotype [26]. The development of strategies for bypassing and inhibiting the influence of these ABC transporters is becoming a high priority in pharmaceutical research and may contribute to effective CDD.Organ, vascular and cellular targeting are also among clinically relevant topics for CDD. Ideally, nanomedicine for CDD should be selectively concentrated in the targeted cells or organelles of the body before drug release begins, following the local real-time demand for therapy. For example, a pioneering work used phase-display peptide libraries to provide peptides capable of mediating selective localization of phage to brain and kidney blood vessels and showed up to 13-fold selectivity for these organs. These peptide sequences were among the first steps towards identifying selective endothelial markers, which may be useful in targeting cells, drugs and genes to selected tissues [27]. This type of work eventually led to the field of cell-penetrating peptides for selective drug targeting and homing.Similarly, adhesion molecules [28] and stem cells are being explored for improved drug and gene delivery. The regulated movement of stem cells is critical for organogenesis during development and for homeostasis and repair in adulthood. Their in vivo trafficking governs the successful therapeutic application of hematopoietic stem cells for bone-marrow transplant. Further elucidation of their homing and migration pathways in other systems will enable broader application of stem cells for targeted cell therapy and drug delivery [29]. The caveolae have also been proposed for vascular targeting, especially towards the lung epithelium [30]. Overall, the identification of clinically relevant biomarkers is a critical step towards the development of targeted drug delivery. Other important challenges facing targeted therapy today are achieving specificity and therapeutically relevant local drug dose. However, the effectiveness of targeted nanomedicines is hampered mostly by the suboptimal release of bioavailable drug. A relatively recent solution to these challenges has made use of a novel lipase secreted by the tumor-colonizing anaerobic bacterium Clostridium to induce the targeted release of liposomal-drug payloads within tumors [31,32]. In addition, the role of octaarginine was beneficial in developing a new concept of ‘programmed packaging’, by which a multifunctional envelope-type nanodevice as a nonviral gene-delivery system has been created successfully [14].Recent advances in chronobiology and chronogenetics, also provide new insights into the temporal development of disease at the cellular and molecular level. For example, it is now known that the metabolic status varies predictably on a daily and seasonal basis to adapt to the cyclical environment. These metabolic cycles are coordinated robustly by the hypothalamic circadian pacemaker of the suprachiasmatic nuclei. Disturbances of this coordination, which occur in long-term shift work, have a major impact on health [33]. This chronobiological discovery and knowledge may also be intregrated in future nanomedicine design and delivery for better disease management. Previously, we have introduced the concept of chronopharmaceutics at the interface of other emerging disciplines, such as system biology and nanomedicine, to address these emerging concerns efficiently [34].Discovery of new raw materials & bioactive agents based on NanoThe impact of Nano on this second aspect of CDD (using bottom-up, top-down and/or combinatorial strategies) may be to improve the physicochemical (e.g., solubility/permeability, shape/morphology and combination of properties) and biopharmaceutical (e.g., enhanced selectivity, stimuli-sensitivity and multifunctionality) properties of new or existing bioactive agents.To improve the physicochemical properties of drugs, for example, in the past, many drug development efforts were abandoned for new drug candidates that were water insoluble and, therefore, poorly bioavailable. Today, formulating them into crystalline nanosuspensions gives hope for these drug candidates [35]. Moreover, the practical application of ‘bottom-up’ assemblies requires the ability to predict the type of aggregated structure and to synthesize molecules in a highly controlled fashion that interact with biological interfaces at nanometer-length scales. This strategy resulted in a molecular platform that mimics biological systems with the potential for encapsulating and delivering drug molecules [36]. Moreover, maintaining drug-loaded nanocarriers in the bloodstream for a long time remained a challenge for CDD. Recent work has suggested that adopting the filamentous shape of viruses may lead to better nanocarriers [37]. String-like nanoparticles that were similar to viruses circulated in the blood for ten-times longer than their spherical counterparts. These findings suggest that not only the nanomedicine surface chemistry but also shape and morphological considerations may be important in designing better nanomedicines for CDD.To enhance the biopharmaceutical properties of nanomedicine, especially for enhanced selectivity of bioactive agents, one traditionally used strategy has been to couple the nanomedicine to antibodies or other ligands that recognize target-associated antigens. Recently, drug-encapsulated polymeric nanoparticle-aptamer bioconjugates have emerged as an alternative technology. Aptamers are short nucleic-acid molecules with binding properties and biochemical characteristics that may make them suitable for use as targeting molecules [38]. Alternatively, new approaches for the design of multifunctional materials for drug delivery have emerged. For example, to overcome the lack of biofunctionality (a major drawback of most polymeric vesicles, which restricts their ability to interact with cells and tissues), vesicles composed of polyarginine and polyleucine segments have been prepared [39]. They are stable in media, entrap water-soluble species and can be processed to different sizes and prepared in large quantities. The remarkable feature of these materials is that the polyarginine segments both direct structure for vesicle formation and provide functionality for efficient intracellular delivery of the vesicles [39].To make nanomedicine synthesis more effective (less labor intensive and time consuming) and to enhance the probability of success for the identification of lead candidates, high throughput and combinatorial techniques have recently been introduced. For example, these techniques enabled the creation of combinatorial libraries of over 2000 structurally unique poly(β-amino esters). These novel biomaterials, formed by the conjugate addition of amines to diacrylates, have been identified as new promising biomaterials for nonviral gene delivery, owing to their ability to condense plasmid DNA into small and stable nanoparticles and their ability to promote cellular uptake and endosomal escape [40].Development of more efficient production & characterization methods for nanomedicinesThe impact of Nano on this third aspect of CDD includes major challenges, such as optimizing drug encapsulation and payload in a cost-effective manner, preservation of bioactivity during preparation process, control over particle size and size distribution, assessing activity, defect and toxicity at nanoscale, quality control and assurance during production to lead to a more robust, effective and safer formulation.To address some of these challenges, a novel method for the fabrication of polymeric particles has recently been developed. It is an imprint lithographic technique called particle replication in nonwetting templates, which takes advantage of the unique properties of elastomeric molds comprised of a low surface-energy perfluoropolyether network. The approach based on a gentle ‘top-down’ method has a number of advantages over the construction of traditional nanoparticles, such as liposomes, dendrimers and colloidal precipitates. It enables the production of monodisperse, shape-specific nanoparticles from an extensive array of organic precursors. With simultaneous and independent control over particle size and shape, composition and surface functionality, the loading of delicate bioactive agents also become possible [41].In terms of quality control and assurance, during and after nanofabrication, traditionally optical methods have been routinely used to characterize nanomedicines. A description of emerging micro- and nano-technology tools, techniques and devices that are being applied to advance the fields of drug discovery and drug delivery has been provided elsewhere [42]. The complexity of nanomedicine intended for CDD warrants the use of novel characterization techniques, such as cryo-electon tomography, high-content screening-based image analysis and high-throughput and combinatorial techniques. For example, because nanostructures are not amenable to study by standard structural techniques, cryo-electon tomography has been actively applied to study these nanoparticles. This technique has the potential to provide high-resolution structural information and enables the visualization and quantitation of variation in a mixed population [43]. The high-content screening provides ample cellular information that is extracted from the high content cellular images and has been used effectively to confirm that human H4 neuroglioma cells had a dose-dependent toxic response to CuO nanoparticles [44]. In addition, to enhance the efficiency of the characterization process, high-throughput techniques had been investigated. For example, the challenges for designing materials that regulate cell function in a desired manner include the vast material property space to be explored, the complexity of cell-surface interactions and the empirical nature of this research. To address these challenges, combinatorial methods have been developed using gradient libraries of the biodegradable polymers poly(ε-caprolactone) and poly(D,L-lactide) and monitoring qualitatively the alkaline phosphatase activity of osteoblasts. The approach was expanded to measure early events in the osteoblast life cycle quantitatively [45].Overall, the nanomedicine quality-control and assurance issues are still in their infancy. Novel algorithms and decision trees are urgently needed for streamlined and rational production and characterization and as guidance for academia, industry and government. Perhaps, the quality by design concept and the US Food and Drug Administration critical path initiatives [46] may contribute to solving these challenges.Potential solutions for the pending regulatory & ethical issues related to nanomedicinesThe impact of Nano on this fourth aspect of CDD may be to address the pending serious regulatory and ethical issues that should not be overlooked or overshadowed by the hype and hope of nanomedicine. These are also critical and urgent matters because it is now known that materials in the nanosize range approach the length scale at which some specific physical or chemical interactions with their environment can occur. Therefore, their properties differ substantially from those bulk materials of the same composition, enabling them to have exceptional properties, such as conductivity, reactivity and optical sensitivity. These new material properties may lead to harmful interactions with biological systems and the environment, with the potential to generate toxicity. There is an urgent and critical need to establish principles and test procedures to ensure safe manufacture and use of nanomaterials in workplaces, marketplaces and clinics [22]. Nanotoxicological information (currently insufficient) will be critical for academia, industry and regulatory agencies to balance its risk and benefit, thus maximizing the utility of nanomedicines without compromising public health and environmental integrity [23].At this point in time, the evolution of ethical issues related to nanomedicines is completely unpredictable but will probably have a major role in the development and use of nanomedicines for CDD. The complexity of these ethical issues may increase when at the intercept of nanomedicine with another field of health-related research, such as genomics, personalized medicine or bioinformatics. The ethical questions regarding social justice, privacy, confidentiality, long-term risks and benefits, and human enhancement remain to be addressed for each future system. Healthcare providers must be educated to answer these questions for themselves and for their patients [24].Conclusion & future perspectivesKnowing that there is really nothing new under the sun, the future impact and success of Nano on the field of CDD must learn from past nature and life lessons that may be summarized as: ‘simpler is better and always start with the end in mind’. Ironically, the ethical and regulatory constraints warrant the respect of that nature (human or environment) so that the success of nanomedicine is sustained (a win–win situation). Thus, there is still plenty of room at the bottom. Future development in such nanomedicines may make use of the current concept of the molecular ‘machine’ [47–49], perhaps with atomic precision and ultrafast biointeractions (e.g., femtosecond magnitude). Perhaps the most relevant applications of molecular-level machines in future CDD may be related to the mechanical aspect, which can be exploited, for example, for the purpose of molecular-level drug transport, the logical design and the logical operation, which can be further exploited for spatial and temporal drug delivery information loading and processing as molecular computers for drug delivery in vivo. Moreover, for nanomedicines intended for such applications to evolve successfully from laboratory to clinics and compete globally and with perhaps an unlimited lifetime, they should also have proven safety, efficacy, acceptability and availability, suggesting the requirement of well-planned interdisciplinary approaches in this field. If developed successfully, such nanomedicines for CDD may contribute to the current debate of the new use of old drugs that would perhaps decrease drug discovery, development time and costs. I challenge the biomedical research community to create a comprehensive clinical drug library based on drugs already available and to screen every neglected and/or global health-related disease. Safer and clinically cost-effective nanomedicines are needed to justify their benefit/risk ratio and existence.Financial & competing interests disclosureThe 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.Bibliography1 Hallberg D, Schuberth O, Wretlind A: Experimental and clinical studies with fat emulsion for intravenous nutrition. Nutr. Dieta. Eur. Rev. Nutr. 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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.PDF download