Materials for Drug Delivery: Innovative Solutions to Address Complex Biological Hurdles

The field of drug delivery focuses on the development of technologies to deliver biomolecules to the site of the disease so as to maximize therapeutic benefits, minimize side effects and enhance patient compliance. The key hurdle in this journey is the complexity of the path through which the drug has to navigate before arriving at the target site. Another hurdle is the limited availability of tools to control this navigation. Free drugs, when administered into bloodstream, are subjected to various metabolic processes, primarily renal clearance and distribution in non-target tissues. These processes not only reduce the drug concentration at the active target site but also increase the likelihood of unwanted side effects. The best examples of drugs suffering from these limitations are chemotherapeutic agents. While many chemotherapeutics are highly effective in a petri dish in vitro, clinical utility of these agents is often limited by severe restrictions on doses that are posed by their toxic side effects. These limitations can be potentially overcome by designing carriers that perform multiple tasks including encapsulation and controlled release, minimization of immune-clearance, penetration of biological barriers and targeting the disease site.1-3 This issue of Advanced Materials is dedicated to an overview of these challenges and innovative materials that are being developed to address them. The central premise of encapsulation of drugs in carriers is to alter their biodistribution or deliver combinations of drugs through single administration. Carriers can protect drugs from the physiological clearance mechanisms and thus enhance stability, while allowing for defined release profiles to be governed by designed chemistries, rather than biological mechanisms. Carrier systems have been designed to exhibit extended release of therapeutic drug doses at the target site, while decreasing overall systemic drug dose to levels below the toxicity threshold. Benefits of this strategy include higher therapeutic efficacy, fewer side effects, and reduced number of administrations. The performance of drug carriers is strongly related to a number of key design parameters including the choice of material, carrier architecture and their surface modification. Polymers are one of the most commonly used materials for designing drug delivery carriers.4 The carrier material needs to be compatible with the drug to ensure stability during synthesis, storage, and administration. A number of different strategies have been employed to control the release profiles of polymeric delivery systems: In this configuration, drugs are loaded into an inert polymeric matrix and the drug release profile is governed by the diffusion of the drug through the matrix structure. This principle has been successfully employed in drug-eluting stents,5 and is also pursued in a number of particle-based delivery systems.6 Small molecule drugs and macromolecular drugs alike have been entrapped in water-swellable polymers, such as hydrogels.6 Upon exposure to a physiological environment, the hydrogel hydrates, expands, and releases the incorporated payload. If the drug carrier is made of a material that is hydrolytically labile, the exposure to a physiological environment can trigger degradation of the polymer matrix. As the polymer degrades, previously incorporated payloads are released exhibiting profiles that can be engineered through modulation of the hydrolytic stability of the carrier polymers.7 Recent research has increasingly focused on the development of stimulus-responsive release systems. Specifically, biologically responsive nanoparticles have been at the forefront of research (see review by Grinstaff in this issue). The drug is encapsulated within a carrier particle that continues to shield the drug from the human body, even after administration. It is only after exposure to a specific stimulus, that the particles undergo a phase transition or chemical reaction that leads to the local release of the payload at a target site. Stimuli-responsive systems can respond to internal or external stimuli. Internal stimuli include changes in the pH value, temperature, or the presence of specific enzymes. External stimuli include exposure to light, electromagnetic waves, magnetic fields, or ultrasound.7 An elegant example is provided in the form of plasmonic nanobubbles for delivery of chemotherapeutics (see paper by Lapatko and co-workers in this issue). While diffusion-based and solvent-activated delivery systems often use isotropic-monolithic delivery architectures, particle engineers have increasingly sought after strategies that take advantage of finer control of the carrier architectures.8 For instance, in case of polymer micelles, the drug-containing core is encapsulated by a polymer shell that ensures particle stability, provides opportunities for surface modification, and controls the release profile of the drug.9 Thus, the circulation times and release profiles obtainable with polymer-based micelles can substantially diverge from conventional micelles. The exploration of increasingly complex carrier architectures becomes even more important since multifunctional particles are under development for combined imaging and therapeutic applications (e.g., theranostics). In addition, combination therapies may require the release of multiple therapeutics, ideally with decoupled release kinetics. See an article by Goodwill et al. in this issue for use of use of nanoparticles for imaging. While there are a number of different particle types available for drug delivery, micelles are by the far most widely used delivery systems that have been developed in a number of variations. Different micelle types, such as worm-like micelles, or silica-cored micelles can show significant differences with respect to stability, efficacy, and circulation times.10 Among the most widely used synthetic systems are polymer micelles, circulating capsules, and nanocontainers. Complex release kinetics can be achieved with hierarchically structured micelle particles, such as vesosomes.11 In addition, peptide-based micelles have increasingly attracted a broad interest for biomedical applications. In this special issue, Tirrell and co-workers report peptide-based micelles that display a cytotoxic T-cell epitope for promotion of a protective immune response. In polymer-drug conjugates, the drugs are directly bound to a carrier particle, which typically has a size of less than 10 nm. Compared to the free drug, the carrier-bound drugs exhibit altered biodistribution, longer circulation times, and display in some cases a biologically responsive release trigger mechanism.12 Widely used carrier systems include hydrophilic polymers, dendrimers, albumin, and noble metal nanoparticles.13 An example that uses polymer-drug nanoparticles for two-stage release is provided by the so-called nanocells.14 Combination therapy often requires the release of two or more drugs with distinct therapeutic windows. Therefore, it would be beneficial, at least in some cases, to be able to deliver two different drugs with fully decoupled release profiles. At the first glance, the simplest solution would be the delivery of combinations of particles that carry different drugs. However, it cannot be ensured that the fate of two carriers in the body will be the same and that both particles will act upon a target cell at the same point in time. The solution to this fundamental dilemma may come from a slate of new carrier particles, so called multicompartmental particles,15 where a single particle is comprised of different nanocontainers, or compartments, each being made up of distinct drug/polymer combinations.16 In principle, it is even possible to design different release mechanisms into the same particle (see paper by Misra et al., this issue), or incorporate selective trigger mechanisms. This type of multicompartmental particles is also ideally suited for combined imaging and delivery applications (theranostics). A highly sophisticated example of nanoemulsion composite microgels is presented by An et al. in this issue. In addition, there has been an increasing interest in organic/inorganic hybrid particles that feature dual functionality for imaging and therapy. Recent trends in this area have been reviewed in the paper by Harry and Sailor in this issue. Independent of the base polymers and the drug carrier architectures, there is almost always a need for surface modification of the carrier particles. With few exceptions, therapeutic nanoparticles injected in the body are cleared within minutes.17-19 For intravenous injection of particles, the upper size limit for effective drug delivery is determined by the capillary diameter. Micron-sized particles have been shown to have different velocities, diffusion characteristics and adhesion properties depending on the size.20 Particles less than 200 nm show improved circulation half-life compared to larger particles. However, unmodified nanoparticles often accumulate in liver and spleen within minutes to hours after intravenous injection.21 This defeats the purpose of encapsulation, since the drug is now released in these organs. In spite of major efforts during the last decades, clinical progress towards keeping carriers away from the liver and forcing them to accumulate in target tissues has been only moderately successful; certainly not living up to its potential to provide a “silver-bullet” for targeted drug delivery. The main hurdle in overcoming targeting challenge is the multitude of biological clearance mechanisms that exist in the human body including the reticuloendothelial system (RES). From administration to release - typically in the cytosol of a cell - a series of orthogonal clearance mechanisms prevent effective and targeted delivery. A typical target tissue in the body, for example tumor, is much smaller compared to the liver, lungs and spleen. Further, organs such as liver are highly vascularized. Collectively, the contact time of carriers with the RES is much higher than that with the tumor. This, in combination with the fact that RES macrophages are highly effective in capturing particles, far more than tumor cells, leads to much higher accumulation of particles in the liver and spleen compared to the tumor. To address these hurdles, current strategies seek to combine particle targeting via specific recognition of cancer cell biomarkers and decreased clearance due to “stealth” surface chemistries. A myriad of strategies have been developed to address these challenges; one at the time. For example, surface modification with polyethylene glycol (PEG) is commonly used to reduce RES clearance22 and tumor-targeting peptides to reduce off-site accumulation and cell-penetrating peptides to enhance cellular internalization (see a review by Ruoslahti in this issue). Incorporation of vastly different features into single particle architecture has been very difficult, if not impossible. In other words, enabling drug carriers to bypass a cascade of clearance mechanisms requires equipping the same particle with mutually exclusive sets of properties. A Multiple-Particles-in-One strategy, in which different parts of the same particle can be used to address the diverse set of functional requirements, can offer a solution to this problem (in analogy to a Swiss army knife). However, technical realization of such multifunctional particles has been an elusive challenge so far. The optimum surface density of binding sites vs. stealth areas will be one of the critical parameters, which will require entire novel particle architectures with defined surface patterns (i.e., activity clusters). To extend the circulation time of drug delivery particles, the surface of the particles is typically covered by a layer of hydrogels. The most prominent examples include hydrophilic polymers, such as PEG, polysaccharides, such as dextran, or proteins, such as albumin, to minimize interactions of the particle with the immune system23 by decreasing particle hydrophobicity and surface charge density using hydrophilic polymers such as PEG24-26 and its variations.27, 28 This has led to the generation of several methodologies to prepare “stealth” nanoparticles. PEG containing block copolymers such as poloxamines, poloxamers, PEG-PLGA have also been extensively studied.29-32 Some of the liposome-PEG based delivery systems have also been shown to circulate for a couple of days.33, 34 Particle size also plays a crucial role in determining the fate of the injected particles.28, 35, 36 Although these strategies have provided marked improvements over unmodified particles, they have several limitations. Nanoparticles are still removed from circulation possibly due to desorption of the surface coatings or activation of the complement.37 Additionally, surface modified particles are rapidly recognized and removed from circulation upon repeated injection.37-39 Further, modification of nanomaterial surface with PEG compromises the ability to include targeting moieties on the particle surface. In the past few years, there has been a paradigm shift in developing ways to fight the immune clearance. The new strategies take an “active” approach towards evading the immune system. Unlike the conventional approach of using hydrophilic polymers to minimize the interactions with the immune system, the new strategies aim at mastering “communication” with the immune system. For example, researchers have begun exploring the use of CD47, a ubiquitous self-marker as a means of disguising exogenous particles.40 Other innovative approaches such as engineering particle shape41, 42 and mechanical properties18, 43 have also been developed. Particles with certain shapes have been shown to exhibit reduced macrophage uptake and enhanced circulation times and higher targeting to the diseased tissue.36 Flexibility of nanoparticles has also been shown to dramatically enhance circulation times and targeted accumulation.18, 43 Nanoparticles have also been shown to hitchhike on red blood cells44 which leads to enhanced circulation. In another approach, nanoparticles have been encapsulated in autologous red blood cells to prolong the circulation.45 Cloaking nanoparticle surface with red blood cell membrane has also been shown to prolong their circulation.46 Additional strategies including glycocalyx-mimicking particles47 and lipoprotein-mimicking mimicking particles48 have also been explored. In yet another approach, researchers have developed strategies to optimize surface concentrations of PEG and targeting ligands to strike a balance between prolonged circulation and effective tissue accumulation.49 In another example, filomicelles, worm-like polymeric micelles, have been shown to circulate in mouse blood for around a week.18 In this issue, Discher et al. report the simulation studies on release of chemotherapeutic drugs from filomicelles. Drug carriers have to penetrate a variety of tissue- and cell-level barriers including skin and intestinal epithelium, mucosal tissues, endothelium, interstitium and cell membranes depending on the port of administration and ultimate target. Diffusion of nanoparticles across these tissues is very slow due to their size, especially across tissues such as skin and mucosa. Penetration of nanoparticles into skin is limited by its topmost, keratinized the Penetration into skin can be enhanced by with agents such as and have the ability of nanoparticles such as micelles and to enhance penetration into Penetration of and across the intestinal has also been extensively This is limited by two The first the mucosal plays an important role of and clearance of interactions with nanoparticles thus to their and clearance. 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