COREL-07149; No of Pages 6 Journal of Controlled Release xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel
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Davide Brambilla, Paola Luciani, Jean-Christophe Leroux ⁎
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Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland
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Article history: Received 8 February 2014 Accepted 21 March 2014 Available online xxxx
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What if we could open the 2044 special issue of the Journal of Controlled Release? Which drug delivery technologies will have led the field? Which ones will have successfully reached the marketplace? In attempting to answer these questions, we selected a few recent technologies and concepts that could, in our opinion, play a crucial role in coming years. In each case, emblematic papers are cited to introduce and discuss the selected topic. © 2014 Published by Elsevier B.V.
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1. Introduction
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In this special anniversary issue, the Journal of Controlled Release takes readers on a spatio-temporal journey through the world of controlled release, directly escorted by main actors in the field. The objective of this manuscript is to provide a personal viewpoint on drug delivery topics that could play an important role in the near future. We are aware that this is a delicate and subjective exercise, but are confident that some of the presented technologies and concepts in their current or modified form will still be present 30 years from now. An analysis of the literature published in the last 5 years might shed light on rising trends in controlled drug release. By entering the words “drug delivery” in Scopus, the top cited original papers in the last 5-year period (2008–2013) deal with functional nanocarriers [1–5]. More generally,
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⁎ Corresponding author. Tel.: +41 446337310. E-mail address: [email protected] (J.-C. Leroux).
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Introduction . . . . . . . . . . . . . . . . . . . EPR enhancement . . . . . . . . . . . . . . . . Beyond EPR: extracorporeally-guided drug delivery . Biotechnological approaches to drug delivery . . . . 4.1. Cell-derived membrane vesicles (CMVs) . . . 4.2. Cells as in vivo drug bioreactors . . . . . . . 4.3. Cells as carriers of oncolytic viruses . . . . . 5. “Computer-assisted” drug delivery . . . . . . . . . 6. Transdermal delivery, the next generation of patches. 7. Conclusions . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .
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Breakthrough discoveries in drug delivery technologies: The next 30 years
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nanoparticle-mediated drug delivery thoroughly dominated the research landscape in recent decades [6–10]. Unfortunately, despite its exciting translational potential, this great scientific effort resulted in a mitigated clinical success. With relatively few products on the market, there is a discrepancy between the amount of research devoted to the topic and its translation to patients, leading some observers to call for trend reversal [11,12]. However, on the timescale of pharmaceutical research, the field of nanotechnology is still young, and it is not surprising that more time is needed to surmount all obstacles to commercialization. Delays in reaching the clinical stage can partly be attributed to the fact that functional nanocarriers are often quite sophisticated in their design and difficult to characterize from a pharmaceutical and toxicological viewpoint. Sensibly, most of the work has been devoted to cancer chemotherapy, and the major achievement of nanocarriers so far has been to reduce systemic drug toxicity (e.g. doxorubicin cardiotoxicity), while their success in improving therapeutic efficacy is more debatable [13]. The tumoral
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Please cite this article as: D. Brambilla, et al., Breakthrough discoveries in drug delivery technologies: The next 30 years, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.03.056
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The limitations of nanoparticle-mediated drug delivery become clear when organs other than the liver, spleen or the vascular system are targeted. Even when the EPR effect occurs, and when active targeting moieties (antibodies, peptides, aptamers) are employed, total amounts of drugs that reach desired tissues remain relatively low [30]. Achieving spatial control of carrier movements in the body could be instrumental in favoring carrier accumulation at sites of interest [31]. Extracorporeal devices to guide nanocarriers in real time – and trigger the release of their cargo in specific locations – are particularly attractive. Magnetic resonance navigation (MRN) has recently been investigated to steer particles for tumor chemo-embolization [32]. Magnetic microparticles loaded with a cytotoxic anticancer agent were steered transversally in the blood flow of rabbits by a modified magnetic resonance imaging system to embolize specific liver sections (Fig. 1). This strategy differs from conventional magnetic targeting [33,34], as it follows and precisely guides magnetically-responsive carriers to deep tissues. MRN is only in the proof-of-concept stage, and will have to be optimized for smaller particles and applications other than embolization. Interestingly, recent reports have described the magnetic steering of intact cells, with different therapeutic functions, to target tissues [35,36]. The combination of cell therapeutics (vide infra) with advanced guidance strategies could represent major advance in drug delivery and tissue engineering.
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4. Biotechnological approaches to drug delivery
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The biotechnology revolution remarkably altered the pharmaceutical landscape in the last 30 years. It stimulated the development of potent and specific drugs, paving the way for personalized medicine. As a result, biopharmaceuticals now represent about 30% of new medicines brought to market [37]. The area of controlled release has certainly benefited from progress in biotechnology, and different bio-derived/inspired targeting systems are being proposed to achieve favorable drug biodistribution. We have selected 3 particularly interesting strategies to exemplify the potential of biotechnology in drug delivery (Fig. 2).
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3. Beyond EPR: extracorporeally-guided drug delivery
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The EPR effect, first postulated by Matsumura and Maeda in the 1980s [15], represents the main tumor targeting principle of nanocarriers and macromolecules. It has been well-described in rodent models [16], and is the very basis for the clinical evaluation of most nanosized anticancer drug delivery systems, including those that specifically recognize solid tumor cells with targeting ligands. Recently, the relevance of EPR in a number of human tumors has been questioned partly because of its high clinical failure rate, emphasizing the need for improvement [17,18]. The chaotic organization of excessive and leaky tumor vessels is one of the factors that hinders nanocarrier penetration into tumoral matrices, leading to heterogeneous blood perfusion and elevated interstitial fluid pressure [19]. Indeed, it has been determined that tumor perfusion is important for efficient nanocarrier accumulation [20]. Understanding EPR in humans will allow the implementation of strategies that could enhance this effect via modulation of the tumor environment. Anti-angiogenic therapies, originally conceived to correct excessive neo-angiogenesis signaling and reduce tumor blood supply, have the potential to repair abnormalities in vascular functions, facilitating convective penetration of molecules within the tumor parenchyma [19]. EPR modulation by pharmacological means was first demonstrated with angiotensin-II [21] and then confirmed with vasoactive molecules (e.g. TβR-I inhibitors, nitroglycerin, heme oxigenase-1, telmisartan) [22–25]. In 2013, the group of Jain reported that normalization of the tumor microenvironment by vascular endothelial growth factor (VEGF) receptor inhibition enhanced the efflux of smaller particles (12 nm), whereas no effect was observed with larger particles (up to 250 nm). The authors also conceived a mathematical model to elucidate and predict the effect. These findings were reproduced in mice with the commercial nanomedicines Doxil® (100 nm) and Abraxane® (10 nm). VEGF inhibition enhanced Abraxane's effectiveness but did not impact Doxil's antitumor activity [26]. This work demonstrated the worth of tumor/formulation-specific vascular normalization in cancer targeting.
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Concomitantly with pharmacological approaches, consistent research has lately been devoted to physical methods, such as hyperthermia or ultrasound-induced cavitation, to improve tumor mass penetration by particles, macromolecules and oncolytic viruses [27–29]. Interestingly, these methods might also facilitate the spatio-temporal control of drug release. Overall, such investigation will hopefully provide a crucial boost to nanomedicine's translation to the clinic and foster studies of related strategies that could enhance nanodrug efficacy.
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microenvironment is complex, with strong inter/intra-tumor heterogeneity influencing the effectiveness of anticancer drug delivery systems. Systematic quantitative analyses of extravasation and the intratumoral distribution of differentially-formulated drugs will certainly be performed extensively in the next decade. On the heels of the bioinformatics revolution in cancer typing, a visionary goal would be the implementation of accessible and reliable databases listing the main features (size, shape, surface chemistry, etc.) required for nanocarriers to efficiently reach (and disseminate within) precise tumor classes. Confident that nanoparticles (with their “unlimited” variations and improvements) and other well-established technologies will continue to play a fundamental role in the future and will be comprehensively discussed in this special issue, we decided to focus our attention more on recent trend-setting drug delivery principles than on nanoparticle technologies per se. Enhanced permeation and retention (EPR) remains the governing principle with most nanocarrier systems. However, the EPR effect, which is often inadequately characterized in humans, may be insufficient for high drug deposition at tumoral sites in a number of neoplasias. Therefore, we believe that approaches aimed at better exploiting and increasing this effect are of paramount importance and will therefore be discussed here. We will also present extracorporeal tools to precisely guide drug carriers in the body in real time, introduce biotechnological systems that take advantage of Nature's optimized machinery for targeting purposes, and discuss the possible impact of bioengineering and computer sciences on controlled drug delivery. A final topic that will be addressed is the rapid development of transdermal microneedle patches. Although this simple, ground-breaking technology was reported as early as the 1970s [14], it only recently unveiled its full potential. The approach is expected to gain further popularity, especially when considering the value of worldwide accessibility to vaccination programs.
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Fig. 1. Schematic representation of magnetic-based extracorporeal navigation of drug delivery to the hepatic left lobe. Adapted from [32] with permission.
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4.3. Cells as carriers of oncolytic viruses
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Oncolytic viruses preferentially infect and kill tumor cells without harming normal tissues. This specificity could be a natural feature of viruses or a result of genetic engineering [49]. However, the administration of free oncolytic viruses has two main limitations: (i) immune responses to the virus capsid, and (ii) poor preferential migration to tumors. Generally, it is believed that around 0.001% of injected viruses reach target tissues, a proportion that can be improved several folds by deploying specific cells as carriers [50]. By mimicking the natural ability of certain viruses to exploit circulating cells to migrate and invade target cell populations, it is possible to enhance the targeting efficiency of oncolytic viruses via their incorporation into cell carriers. Qiao et al. [51] investigated autologous T cells that naturally reside in lymph nodes and lymphoid organs, to carry therapeutic oncolytic viruses and purge metastatic cells from tissues. They demonstrated that adoptive transfer of T cells loaded with vesicular stomatitis virus reduced/ eradicated lymph node-resistant metastatic cells from draining lymph nodes and spleen in mice. Importantly, similar results were obtained in virus-immune animals, although the viral load had to be carefully selected. Such an approach could be applicable to various cancers in which malignant metastases spread to distal areas via lymphoid organs. The technology has been adopted in other studies to target different tissues, and readers are referred to a recent review by Roy and Bell [52] for more information on this fascinating topic. Among the challenges associated with such therapies are the selection of the best virus/cell combination and its clinical translation. In this regard, a study describing the use of human adipose tissue cells from patients to derive tumor-homing MSCs targeting ovarian cancer was published in 2013. The authors proposed a protocol to obtain, expand, and load clinically-relevant amounts of cells with the measles virus within 14 days and showed their capacity to migrate to ovarian cancer cells in mice [53].
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5. “Computer-assisted” drug delivery
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Combination of bioengineering, informatics and material sciences recently helped shape new, promising drug delivery concepts. Indeed, aside from data storage and management, computer science and bioelectronics are expected to drastically influence diagnostic and therapeutic protocols. Large investments have lately been made to develop miniaturized diagnostic biosensors for real time disease tracking and prediction [54]. Implantable microdevices for controlled drug release are emblematic examples of the effort devoted to implement bioelectronics in drug delivery [55,56]. These “clever” devices can enable the control of dose amount, time, location, and drug-release rate. A recent paper by Langer's group and microCHIPS, Inc. described the first human test of a breakthrough technology initially conceived about a decade ago (Fig. 3) [57]. In this work, teriparatide, a drug usually administered daily via subcutaneous injection to treat osteoporosis, was delivered in 8 post-menopausal women by implanted microchip consisting of 20 individually-sealed reservoirs. To control drug release, the reservoirs were capped with a thin metal layer which melted when a small electrical current was applied. Importantly, the device was equipped with a miniaturized, wireless controller, allowing bidirectional communication with a computer to schedule drug liberation.
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conditions could represent safe rescue approaches. In this regard, Altaner and coworkers [47,48] proposed an interesting variant of this approach, known as “prodrug enzyme gene therapy”. MSCs derived from human adipose tissue were engineered to express cytosine deaminase–uracil phosphotransferase, which converts the inactive prodrug 5-fluorocytosine to highly-cytotoxic 5-fluorouracil. At tumor sites, the enzyme locally produced 5-fluorouracil from the prodrug, resulting in complete tumor regression in up to 50% of treated animals. This approach was tested successfully on different tumor models.
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Cells represent potentially powerful drug transporters in view of their multiple functions and ability to respond to the environment and exogenous triggers. Three main classes of cells (transformed, immune and progenitor) have been proposed so far for the transport of various drug classes. Particular attention has been paid to mesenchymal stem cells (MSCs) in the treatment of cancer. These cells exhibit pathotropic (tumor microenvironment, metastasis and ischemia) properties, although the mechanisms of migration are not fully understood [43,44]. MSCs have also been engineered to operate as in vivo bioreactors for the sustained production and release of therapeutic molecules at action sites. This concept has been applied to produce different kinds of anticancer biological drugs: interleukins, pro-apoptotic proteins, growth factor antagonists, etc. [45,46]. However, engineering of cell vectors to construct bioactive compounds could be hazardous to hosts if they remain active after cancer eradication. The integration of human-inducible suicide genes or regulatable promoters to activate gene production only under desired
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CMVs are important tools for cell-to-cell material/information transfer, making them very attractive drug carriers. Different CMV subsets exist, and are usually categorized according to their intracellular origin. Exosomes, which derive from multivesicular bodies, are certainly the most investigated CMVs for drug delivery purposes [38]. One of the main advantages of autologous carriers is the expected absence of immunogenicity. In a breakthrough work, Alvarez-Erviti et al. [39] demonstrated that exosomes could overcome the blood–brain-barrier. Mouse-harvested immature dendritic cells served as sources of “selfexosomes” for autologous administration. The targeting ligand was obtained by fusing a brain-specific peptide coding sequence (encoding a peptide able to bind acetylcholine receptors) to the gene encoding an abundant protein in exosome membranes. Exosomes were loaded with glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-specific small interfering RNA (siRNA). These siRNA-loaded exosomes significantly/specifically reduced mRNA and GAPDH expression within the brain after systemic injection. Although peptide targeting was shown to be necessary to generate RNAi responses within the brain, the blood–brain-barrier crossing mechanism remains unknown at the moment. Other papers have reported the relevance of CMVs in drug delivery, and databases on lipids, proteins and nucleic acids composing the CMVs (Exocarta, Vesiclepedia) epitomize the rising attention being paid to endogenous vesicles [40–42].
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Fig. 2. Schematic representation of the 3 cell-based biotechnological approaches to drug delivery. A) Cells as in vivo drug bioreactor; B) Cells as carriers of oncolytic viruses; C) Cell-derived membrane vesicles.
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Inadequate vaccine coverage across developing countries is responsible every year for millions of casualties caused mainly by the relatively high costs of vaccination programs (healthcare personnel, vaccine stability, etc.) [61,62]. The quest for an inexpensive way to reach more patients worldwide has in recent years boosted the field of non-invasive transdermal delivery. The presence of dendritic cells in the dermis triggers strong immune responses, making transdermal administration an appealing route for vaccination [63]. A significant step forward lies in the optimization of transdermal microneedle patches [64]. Microneedles as safe and pain-free alternatives to conventional injection modes were introduced decades ago [65], but the most recent examples are perhaps the most relevant. In the milestone paper published by Prausnitz and coworkers [66], a new concept was proposed for the transdermal delivery of influenza virus vaccine. The system, which consisted of poly(N-vinylpyrrolidone) microneedles, dissolved within minutes under the skin after administration, eliminating the production of biohazardous waste while retaining the delivery properties of vaccines in lyophilized form. Humoral and cellular responses equaling or even outperforming those obtained by intramuscular injection were achieved in mice. Such a result, together with the practical advantage of not needing vaccine reconstitution prior to administration, makes this contribution highly promising. Interesting developments arose from this original concept. Microneedles were equipped with a poly(vinyl alcohol)-based detachable arrowhead that allowed the metallic section to be discarded a few seconds after application to the skin [67]. Detachable chitosan matrices embedded with a model antigen, ovalbumin, were designed recently and tested in vivo in rats as warheadlike parts of a microneedle platform for deposit under the skin via poly(N-vinylpyrrolidone)-coated, poly(lactic acid)-supporting arrays [68]. Poly(lactic acid) microneedles coated with adenoviral vectors dispersed in a sucrose–sugar-glass matrix showed translational potential in recent successful trials in non-human primates [69]. Transdermal delivery via microneedle patches is not limited to vaccines, and holds much hope for the administration of potent drugs with low bioavailability and biomacromolecules that are poorly permeable through the skin.
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This review reflects our opinion on plausible, leading directions in drug delivery in the future. Of course, many other emerging concepts
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The results demonstrated a pharmacokinetic profile comparable to subcutaneous injection and greater control over amounts released. Generally, the implant was as well tolerated as already-used electronic implants (e.g. pacemakers) [58]. Further improvement of this technology would be the design of closed-loop, implantable systems able to autonomously “detect” a pathological state and accordingly release appropriate drug doses [59,60]. We refer to Santini et al. in this issue for more details on this subject.
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Fig. 3. Schematic representation of computer assisted micro-implants drug delivery.
(e.g. controlled release systems based on 3D-printing technologies, advanced gene delivery systems) have not been discussed here and are also rapidly evolving [70,71]. In cancer chemotherapy, it is clear that better understanding of tumor physiopathology will be instrumental in the optimal use of nanoparticles and theranostic agents. Moreover, the continuing commitment to increasingly personalized medicine is giving birth to a great diversity of experimental cell-based therapeutics. These biotechnologies will foster versatile and multifunctional nonimmunogenic human cells as well as cell derivatives with targeting and controlled drug-producing properties [38,50]. Bacteria will also be harnessed to deliver in body areas like the gastrointestinal tract a wide range of therapeutic compounds such as anti-inflammatory interleukins, toxin-neutralizing antibodies, antigens and allergens (to induce tolerogenic responses) [72]. Similarly to conventional drug carriers, thorough characterization of these novel systems will be required to avoid unforeseen side-effects. However, the use of “living” materials heavily complicates the quality control process due to their intrinsic complexity, potential out-ofhand evolution and batch-to-batch variability. Concomitant with scientific challenges, the evolution of these new-generation medicines will require the design of adapted drug approval protocols. Fundamental support will also derive from informatics and bioelectronics in general. Multitasking biosensors able to constantly monitor body parameters and accordingly trigger the release of precise amounts of medicine will profoundly change the daily life of chronic patients. Generally, fundamental research using breakthrough technologies such as the optogenetics (to regulate the activity of individual neurons in vivo) and CLARITY (for the three dimensional staining of intact organs) will notably improve our understanding of human physiology and diseases. Major fundamental discoveries will in the future be probably accompanied by innovative delivery concepts that are today difficult to predict with the current knowledge [73,74]. For instance, the recent finding that sleep induces a striking increase in convective exchange of cerebrospinal–interstitial fluids within the brain opens new interesting avenue for brain drug delivery [75]. The launch of ambitious super-computational biology projects (Human Brain Project, BRAIN Initiative) might lay the foundations to body-in-a-box machines allowing disease and drug (delivery) simulations, drastically accelerating the characterization of new delivery systems while decreasing their development costs. In conclusion, the controlled release field is entering a fascinating era, and we hope that the Journal of Controlled Release will continue to be a mainstream venue for diffusing innovative data at the forefront of drug delivery research.
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Davide Brambilla, Paola Luciani, Jean-Christophe Leroux ⁎
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Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland
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Article history: Received 8 February 2014 Accepted 21 March 2014 Available online xxxx
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What if we could open the 2044 special issue of the Journal of Controlled Release? Which drug delivery technologies will have led the field? Which ones will have successfully reached the marketplace? In attempting to answer these questions, we selected a few recent technologies and concepts that could, in our opinion, play a crucial role in coming years. In each case, emblematic papers are cited to introduce and discuss the selected topic. © 2014 Published by Elsevier B.V.
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In this special anniversary issue, the Journal of Controlled Release takes readers on a spatio-temporal journey through the world of controlled release, directly escorted by main actors in the field. The objective of this manuscript is to provide a personal viewpoint on drug delivery topics that could play an important role in the near future. We are aware that this is a delicate and subjective exercise, but are confident that some of the presented technologies and concepts in their current or modified form will still be present 30 years from now. An analysis of the literature published in the last 5 years might shed light on rising trends in controlled drug release. By entering the words “drug delivery” in Scopus, the top cited original papers in the last 5-year period (2008–2013) deal with functional nanocarriers [1–5]. More generally,
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⁎ Corresponding author. Tel.: +41 446337310. E-mail address: [email protected] (J.-C. Leroux).
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Introduction . . . . . . . . . . . . . . . . . . . EPR enhancement . . . . . . . . . . . . . . . . Beyond EPR: extracorporeally-guided drug delivery . Biotechnological approaches to drug delivery . . . . 4.1. Cell-derived membrane vesicles (CMVs) . . . 4.2. Cells as in vivo drug bioreactors . . . . . . . 4.3. Cells as carriers of oncolytic viruses . . . . . 5. “Computer-assisted” drug delivery . . . . . . . . . 6. Transdermal delivery, the next generation of patches. 7. Conclusions . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .
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Breakthrough discoveries in drug delivery technologies: The next 30 years
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nanoparticle-mediated drug delivery thoroughly dominated the research landscape in recent decades [6–10]. Unfortunately, despite its exciting translational potential, this great scientific effort resulted in a mitigated clinical success. With relatively few products on the market, there is a discrepancy between the amount of research devoted to the topic and its translation to patients, leading some observers to call for trend reversal [11,12]. However, on the timescale of pharmaceutical research, the field of nanotechnology is still young, and it is not surprising that more time is needed to surmount all obstacles to commercialization. Delays in reaching the clinical stage can partly be attributed to the fact that functional nanocarriers are often quite sophisticated in their design and difficult to characterize from a pharmaceutical and toxicological viewpoint. Sensibly, most of the work has been devoted to cancer chemotherapy, and the major achievement of nanocarriers so far has been to reduce systemic drug toxicity (e.g. doxorubicin cardiotoxicity), while their success in improving therapeutic efficacy is more debatable [13]. The tumoral
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Please cite this article as: D. Brambilla, et al., Breakthrough discoveries in drug delivery technologies: The next 30 years, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.03.056
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The limitations of nanoparticle-mediated drug delivery become clear when organs other than the liver, spleen or the vascular system are targeted. Even when the EPR effect occurs, and when active targeting moieties (antibodies, peptides, aptamers) are employed, total amounts of drugs that reach desired tissues remain relatively low [30]. Achieving spatial control of carrier movements in the body could be instrumental in favoring carrier accumulation at sites of interest [31]. Extracorporeal devices to guide nanocarriers in real time – and trigger the release of their cargo in specific locations – are particularly attractive. Magnetic resonance navigation (MRN) has recently been investigated to steer particles for tumor chemo-embolization [32]. Magnetic microparticles loaded with a cytotoxic anticancer agent were steered transversally in the blood flow of rabbits by a modified magnetic resonance imaging system to embolize specific liver sections (Fig. 1). This strategy differs from conventional magnetic targeting [33,34], as it follows and precisely guides magnetically-responsive carriers to deep tissues. MRN is only in the proof-of-concept stage, and will have to be optimized for smaller particles and applications other than embolization. Interestingly, recent reports have described the magnetic steering of intact cells, with different therapeutic functions, to target tissues [35,36]. The combination of cell therapeutics (vide infra) with advanced guidance strategies could represent major advance in drug delivery and tissue engineering.
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The biotechnology revolution remarkably altered the pharmaceutical landscape in the last 30 years. It stimulated the development of potent and specific drugs, paving the way for personalized medicine. As a result, biopharmaceuticals now represent about 30% of new medicines brought to market [37]. The area of controlled release has certainly benefited from progress in biotechnology, and different bio-derived/inspired targeting systems are being proposed to achieve favorable drug biodistribution. We have selected 3 particularly interesting strategies to exemplify the potential of biotechnology in drug delivery (Fig. 2).
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The EPR effect, first postulated by Matsumura and Maeda in the 1980s [15], represents the main tumor targeting principle of nanocarriers and macromolecules. It has been well-described in rodent models [16], and is the very basis for the clinical evaluation of most nanosized anticancer drug delivery systems, including those that specifically recognize solid tumor cells with targeting ligands. Recently, the relevance of EPR in a number of human tumors has been questioned partly because of its high clinical failure rate, emphasizing the need for improvement [17,18]. The chaotic organization of excessive and leaky tumor vessels is one of the factors that hinders nanocarrier penetration into tumoral matrices, leading to heterogeneous blood perfusion and elevated interstitial fluid pressure [19]. Indeed, it has been determined that tumor perfusion is important for efficient nanocarrier accumulation [20]. Understanding EPR in humans will allow the implementation of strategies that could enhance this effect via modulation of the tumor environment. Anti-angiogenic therapies, originally conceived to correct excessive neo-angiogenesis signaling and reduce tumor blood supply, have the potential to repair abnormalities in vascular functions, facilitating convective penetration of molecules within the tumor parenchyma [19]. EPR modulation by pharmacological means was first demonstrated with angiotensin-II [21] and then confirmed with vasoactive molecules (e.g. TβR-I inhibitors, nitroglycerin, heme oxigenase-1, telmisartan) [22–25]. In 2013, the group of Jain reported that normalization of the tumor microenvironment by vascular endothelial growth factor (VEGF) receptor inhibition enhanced the efflux of smaller particles (12 nm), whereas no effect was observed with larger particles (up to 250 nm). The authors also conceived a mathematical model to elucidate and predict the effect. These findings were reproduced in mice with the commercial nanomedicines Doxil® (100 nm) and Abraxane® (10 nm). VEGF inhibition enhanced Abraxane's effectiveness but did not impact Doxil's antitumor activity [26]. This work demonstrated the worth of tumor/formulation-specific vascular normalization in cancer targeting.
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Concomitantly with pharmacological approaches, consistent research has lately been devoted to physical methods, such as hyperthermia or ultrasound-induced cavitation, to improve tumor mass penetration by particles, macromolecules and oncolytic viruses [27–29]. Interestingly, these methods might also facilitate the spatio-temporal control of drug release. Overall, such investigation will hopefully provide a crucial boost to nanomedicine's translation to the clinic and foster studies of related strategies that could enhance nanodrug efficacy.
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microenvironment is complex, with strong inter/intra-tumor heterogeneity influencing the effectiveness of anticancer drug delivery systems. Systematic quantitative analyses of extravasation and the intratumoral distribution of differentially-formulated drugs will certainly be performed extensively in the next decade. On the heels of the bioinformatics revolution in cancer typing, a visionary goal would be the implementation of accessible and reliable databases listing the main features (size, shape, surface chemistry, etc.) required for nanocarriers to efficiently reach (and disseminate within) precise tumor classes. Confident that nanoparticles (with their “unlimited” variations and improvements) and other well-established technologies will continue to play a fundamental role in the future and will be comprehensively discussed in this special issue, we decided to focus our attention more on recent trend-setting drug delivery principles than on nanoparticle technologies per se. Enhanced permeation and retention (EPR) remains the governing principle with most nanocarrier systems. However, the EPR effect, which is often inadequately characterized in humans, may be insufficient for high drug deposition at tumoral sites in a number of neoplasias. Therefore, we believe that approaches aimed at better exploiting and increasing this effect are of paramount importance and will therefore be discussed here. We will also present extracorporeal tools to precisely guide drug carriers in the body in real time, introduce biotechnological systems that take advantage of Nature's optimized machinery for targeting purposes, and discuss the possible impact of bioengineering and computer sciences on controlled drug delivery. A final topic that will be addressed is the rapid development of transdermal microneedle patches. Although this simple, ground-breaking technology was reported as early as the 1970s [14], it only recently unveiled its full potential. The approach is expected to gain further popularity, especially when considering the value of worldwide accessibility to vaccination programs.
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Fig. 1. Schematic representation of magnetic-based extracorporeal navigation of drug delivery to the hepatic left lobe. Adapted from [32] with permission.
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Oncolytic viruses preferentially infect and kill tumor cells without harming normal tissues. This specificity could be a natural feature of viruses or a result of genetic engineering [49]. However, the administration of free oncolytic viruses has two main limitations: (i) immune responses to the virus capsid, and (ii) poor preferential migration to tumors. Generally, it is believed that around 0.001% of injected viruses reach target tissues, a proportion that can be improved several folds by deploying specific cells as carriers [50]. By mimicking the natural ability of certain viruses to exploit circulating cells to migrate and invade target cell populations, it is possible to enhance the targeting efficiency of oncolytic viruses via their incorporation into cell carriers. Qiao et al. [51] investigated autologous T cells that naturally reside in lymph nodes and lymphoid organs, to carry therapeutic oncolytic viruses and purge metastatic cells from tissues. They demonstrated that adoptive transfer of T cells loaded with vesicular stomatitis virus reduced/ eradicated lymph node-resistant metastatic cells from draining lymph nodes and spleen in mice. Importantly, similar results were obtained in virus-immune animals, although the viral load had to be carefully selected. Such an approach could be applicable to various cancers in which malignant metastases spread to distal areas via lymphoid organs. The technology has been adopted in other studies to target different tissues, and readers are referred to a recent review by Roy and Bell [52] for more information on this fascinating topic. Among the challenges associated with such therapies are the selection of the best virus/cell combination and its clinical translation. In this regard, a study describing the use of human adipose tissue cells from patients to derive tumor-homing MSCs targeting ovarian cancer was published in 2013. The authors proposed a protocol to obtain, expand, and load clinically-relevant amounts of cells with the measles virus within 14 days and showed their capacity to migrate to ovarian cancer cells in mice [53].
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Combination of bioengineering, informatics and material sciences recently helped shape new, promising drug delivery concepts. Indeed, aside from data storage and management, computer science and bioelectronics are expected to drastically influence diagnostic and therapeutic protocols. Large investments have lately been made to develop miniaturized diagnostic biosensors for real time disease tracking and prediction [54]. Implantable microdevices for controlled drug release are emblematic examples of the effort devoted to implement bioelectronics in drug delivery [55,56]. These “clever” devices can enable the control of dose amount, time, location, and drug-release rate. A recent paper by Langer's group and microCHIPS, Inc. described the first human test of a breakthrough technology initially conceived about a decade ago (Fig. 3) [57]. In this work, teriparatide, a drug usually administered daily via subcutaneous injection to treat osteoporosis, was delivered in 8 post-menopausal women by implanted microchip consisting of 20 individually-sealed reservoirs. To control drug release, the reservoirs were capped with a thin metal layer which melted when a small electrical current was applied. Importantly, the device was equipped with a miniaturized, wireless controller, allowing bidirectional communication with a computer to schedule drug liberation.
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conditions could represent safe rescue approaches. In this regard, Altaner and coworkers [47,48] proposed an interesting variant of this approach, known as “prodrug enzyme gene therapy”. MSCs derived from human adipose tissue were engineered to express cytosine deaminase–uracil phosphotransferase, which converts the inactive prodrug 5-fluorocytosine to highly-cytotoxic 5-fluorouracil. At tumor sites, the enzyme locally produced 5-fluorouracil from the prodrug, resulting in complete tumor regression in up to 50% of treated animals. This approach was tested successfully on different tumor models.
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Cells represent potentially powerful drug transporters in view of their multiple functions and ability to respond to the environment and exogenous triggers. Three main classes of cells (transformed, immune and progenitor) have been proposed so far for the transport of various drug classes. Particular attention has been paid to mesenchymal stem cells (MSCs) in the treatment of cancer. These cells exhibit pathotropic (tumor microenvironment, metastasis and ischemia) properties, although the mechanisms of migration are not fully understood [43,44]. MSCs have also been engineered to operate as in vivo bioreactors for the sustained production and release of therapeutic molecules at action sites. This concept has been applied to produce different kinds of anticancer biological drugs: interleukins, pro-apoptotic proteins, growth factor antagonists, etc. [45,46]. However, engineering of cell vectors to construct bioactive compounds could be hazardous to hosts if they remain active after cancer eradication. The integration of human-inducible suicide genes or regulatable promoters to activate gene production only under desired
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CMVs are important tools for cell-to-cell material/information transfer, making them very attractive drug carriers. Different CMV subsets exist, and are usually categorized according to their intracellular origin. Exosomes, which derive from multivesicular bodies, are certainly the most investigated CMVs for drug delivery purposes [38]. One of the main advantages of autologous carriers is the expected absence of immunogenicity. In a breakthrough work, Alvarez-Erviti et al. [39] demonstrated that exosomes could overcome the blood–brain-barrier. Mouse-harvested immature dendritic cells served as sources of “selfexosomes” for autologous administration. The targeting ligand was obtained by fusing a brain-specific peptide coding sequence (encoding a peptide able to bind acetylcholine receptors) to the gene encoding an abundant protein in exosome membranes. Exosomes were loaded with glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-specific small interfering RNA (siRNA). These siRNA-loaded exosomes significantly/specifically reduced mRNA and GAPDH expression within the brain after systemic injection. Although peptide targeting was shown to be necessary to generate RNAi responses within the brain, the blood–brain-barrier crossing mechanism remains unknown at the moment. Other papers have reported the relevance of CMVs in drug delivery, and databases on lipids, proteins and nucleic acids composing the CMVs (Exocarta, Vesiclepedia) epitomize the rising attention being paid to endogenous vesicles [40–42].
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Fig. 2. Schematic representation of the 3 cell-based biotechnological approaches to drug delivery. A) Cells as in vivo drug bioreactor; B) Cells as carriers of oncolytic viruses; C) Cell-derived membrane vesicles.
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Inadequate vaccine coverage across developing countries is responsible every year for millions of casualties caused mainly by the relatively high costs of vaccination programs (healthcare personnel, vaccine stability, etc.) [61,62]. The quest for an inexpensive way to reach more patients worldwide has in recent years boosted the field of non-invasive transdermal delivery. The presence of dendritic cells in the dermis triggers strong immune responses, making transdermal administration an appealing route for vaccination [63]. A significant step forward lies in the optimization of transdermal microneedle patches [64]. Microneedles as safe and pain-free alternatives to conventional injection modes were introduced decades ago [65], but the most recent examples are perhaps the most relevant. In the milestone paper published by Prausnitz and coworkers [66], a new concept was proposed for the transdermal delivery of influenza virus vaccine. The system, which consisted of poly(N-vinylpyrrolidone) microneedles, dissolved within minutes under the skin after administration, eliminating the production of biohazardous waste while retaining the delivery properties of vaccines in lyophilized form. Humoral and cellular responses equaling or even outperforming those obtained by intramuscular injection were achieved in mice. Such a result, together with the practical advantage of not needing vaccine reconstitution prior to administration, makes this contribution highly promising. Interesting developments arose from this original concept. Microneedles were equipped with a poly(vinyl alcohol)-based detachable arrowhead that allowed the metallic section to be discarded a few seconds after application to the skin [67]. Detachable chitosan matrices embedded with a model antigen, ovalbumin, were designed recently and tested in vivo in rats as warheadlike parts of a microneedle platform for deposit under the skin via poly(N-vinylpyrrolidone)-coated, poly(lactic acid)-supporting arrays [68]. Poly(lactic acid) microneedles coated with adenoviral vectors dispersed in a sucrose–sugar-glass matrix showed translational potential in recent successful trials in non-human primates [69]. Transdermal delivery via microneedle patches is not limited to vaccines, and holds much hope for the administration of potent drugs with low bioavailability and biomacromolecules that are poorly permeable through the skin.
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This review reflects our opinion on plausible, leading directions in drug delivery in the future. Of course, many other emerging concepts
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The results demonstrated a pharmacokinetic profile comparable to subcutaneous injection and greater control over amounts released. Generally, the implant was as well tolerated as already-used electronic implants (e.g. pacemakers) [58]. Further improvement of this technology would be the design of closed-loop, implantable systems able to autonomously “detect” a pathological state and accordingly release appropriate drug doses [59,60]. We refer to Santini et al. in this issue for more details on this subject.
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Fig. 3. Schematic representation of computer assisted micro-implants drug delivery.
(e.g. controlled release systems based on 3D-printing technologies, advanced gene delivery systems) have not been discussed here and are also rapidly evolving [70,71]. In cancer chemotherapy, it is clear that better understanding of tumor physiopathology will be instrumental in the optimal use of nanoparticles and theranostic agents. Moreover, the continuing commitment to increasingly personalized medicine is giving birth to a great diversity of experimental cell-based therapeutics. These biotechnologies will foster versatile and multifunctional nonimmunogenic human cells as well as cell derivatives with targeting and controlled drug-producing properties [38,50]. Bacteria will also be harnessed to deliver in body areas like the gastrointestinal tract a wide range of therapeutic compounds such as anti-inflammatory interleukins, toxin-neutralizing antibodies, antigens and allergens (to induce tolerogenic responses) [72]. Similarly to conventional drug carriers, thorough characterization of these novel systems will be required to avoid unforeseen side-effects. However, the use of “living” materials heavily complicates the quality control process due to their intrinsic complexity, potential out-ofhand evolution and batch-to-batch variability. Concomitant with scientific challenges, the evolution of these new-generation medicines will require the design of adapted drug approval protocols. Fundamental support will also derive from informatics and bioelectronics in general. Multitasking biosensors able to constantly monitor body parameters and accordingly trigger the release of precise amounts of medicine will profoundly change the daily life of chronic patients. Generally, fundamental research using breakthrough technologies such as the optogenetics (to regulate the activity of individual neurons in vivo) and CLARITY (for the three dimensional staining of intact organs) will notably improve our understanding of human physiology and diseases. Major fundamental discoveries will in the future be probably accompanied by innovative delivery concepts that are today difficult to predict with the current knowledge [73,74]. For instance, the recent finding that sleep induces a striking increase in convective exchange of cerebrospinal–interstitial fluids within the brain opens new interesting avenue for brain drug delivery [75]. The launch of ambitious super-computational biology projects (Human Brain Project, BRAIN Initiative) might lay the foundations to body-in-a-box machines allowing disease and drug (delivery) simulations, drastically accelerating the characterization of new delivery systems while decreasing their development costs. In conclusion, the controlled release field is entering a fascinating era, and we hope that the Journal of Controlled Release will continue to be a mainstream venue for diffusing innovative data at the forefront of drug delivery research.
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