A smart pill
The medical field awaits new methods to enable fast and efficient treatment. Professor Gleb Sukhorukov from Queen Mary University of London, UK, highlights the development of a multifunctional pill delivery system.
The emerging interdisciplinary field of bionanotechnology expands over a broad range of research subjects. Developing nanostructured delivery systems is a significant aim, and one of the main challenges is to build multifunctional particles or vesicles as intelligent drug carriers enabling remote interrogation. Once placed, or injected, into the blood stream or tissue, the capsules find their target, deliver active substances locally, repair or kill damaged cells, report as a distributed diagnostic system, and degrade or leave the body without any further damage. As futuristic as it sounds, it is becoming a realistic agenda.
Progress has been achieved in fabricating/ engineering nano- and microcarriers for active components, such as catalysts, drugs, enzymes or DNA. Yet despite a variety of techniques developed to address specific encapsulation and release requirements, many bioactive compounds fail in their practical use, due to an inability to be delivered to the appropriate cells and tissues. This is because of a lack of specificity, metabolic stability or bioavailability.
Approaches are often limited in their applicability, due to the range of materials that can be used in the human body.
Active substances should be placed in confined carriers and are supposed to act either because of release upon certain conditions, or upon an external signal. Magnetic liposomes or magnetic carriers with immobilised receptors are already used, as well as polymers bearing drugs and liposomes that are able to cleave drugs or to open once an area is reached within a certain pH.
On the surface
One approach to engineering nanoscale vesicles is based on layer-by-layer adsorption of oppositely charged species, mainly polyelectrolytes (PE) or macromolecules, on colloidal particles. These multilayers are made out of a variety of constituents, such as synthetic and natural PEs, proteins, nucleic acids, nanoparticles, lipids, and multivalent dyes. The build-up is modular with regards to tailoring the functional constituents into a capsule wall.
The shell thickness is determined by the layer number and is defined in the range of a few nanometres. The particle core can be pre-encapsulated with active substances, or dissolved to create hollow capsules that are re-filled with substances of choice. The latter exploits tuneable permeability properties proved by functionalised multilayers.
The variable capsule size is controlled from 50nm to tens of micrometres, with the defined size providing controlled release in response to pH, temperature, ions and metabolites, such as sugars.
Schematic of multifunctional nanocapsules interrogation while inside cells. Capsules are depicted with incorporated nanoparticles for remote addressing, loaded with sensing reporter molecules and with enzymes delivering function to the cells
The nature of this surface functionalisation process means the last layer can incorporate specific functional groups for intracellular cell delivery (see image above). Capsules made of biodegradable polymers, like polypeptides and polysaccharides, gradually degrade while being delivered to the cells, and release their content over time at a given composition and thickness. Incorporating a set of enzymes makes these capsules a good model for cell organelles, where incoming substrates are converted via sequential enzymatic reaction to a product that can leave the vesicles.
Getting a tattoo
A micrometre-sized bioreactor, based on encapsulated technology, serves as a sensor for different metabolites, when conversion of the metabolite is coupled with a fluorophore sensitive dye. For instance, urea is detected using capsules containing urease and a pH sensitive dye to register the change. Such sensitive capsules, called Smart Tattoo systems, enable simultaneous screening of a number of biochemical compounds. Embedded close underskin, with access to blood circulation substances, these ‘Smart Tattoos’ can report almost non-invasively about biochemical processes via optical readout devices applied back to the skin.
A key advantage over many conventional encapsulation techniques is the ability for remote navigation and activation of the encapsulated materials. Inorganic nanoparticles incorporated in PE shells are susceptible to remote physical influences, such as magnetic field, light, ultrasound and possibly microwave radiation. An entire capsule containing magnetic nanoparticles in its wall is guided by a magnetic field.
Light absorption by the nanoparticles leads to local heat and hence disruption of the PE shells (see image below). The susceptibility of metal or semiconductor nanoparticles to vis/near infrared irradiation can be tuned in at a range of a few nanometres, which makes it possible to activate different capsules (containing particular nanoparticles) and enable the release of various encapsulated materials.
The five micrometre capsules containing silver nanoparticles in the walls are intact before interaction with laser light (arrow shows irradiation spot). Right: They rupture during exposure to the laser beam, forming debris. Image courtesy of A Skirtach, MPI, Potsdam, Germany
Use of ultrasound has been envisaged as another solution as composite organic/inorganic materials undergo significant stress while being exposed to sonication. This is due to the density gradient across the films.
Inorganic particles embedded within a PE multilayer lead to breaking of the entire multilayer capsule wall and release of the materials. Meanwhile, light-induced release of bioactive materials inside biological cells has been shown to interfere with intercellular processes. Use of harmless infrared light to activate the capsules is a potential approach.
The possibility of tailoring different functionalities opens an avenue in versatile biological and medical applications. Bio-friendly capsules have been tested on animals and only a mild inflammatory response has been reported.
Longer circulation time in blood is achieved by pegylation of the capsule surface. Unlike particles used as delivery systems, these capsules can deform and squeeze through narrow vessels. Although not yet proven for clinical study, they represent a good option for intracellular delivery of protein and nucleic acid-based vaccines. Once in the cells, the shell is degraded and release of the vaccine causes an immunological response.
A more realistic view of multilayer capsule technology is that it is rather costly for smart delivery systems. The fabrication of such a complex tool-box will be attractive for in situ sensing and for exploring the biological environment within cells or tissue. This appears to be a more realistic future. Multifunctional cages with designed surfaces for use as carrier systems, in vitro and in vivo, with remote stimulicontrolled activation, will have a strong impact in many areas.
Gleb Sukhorukov, Centre for Materials Research, Queen Mary University of London, Mile End Road, London, E1 4NS, UK. Tel: +44 (0)20 7882 5508. Email: firstname.lastname@example.org