`Nano-dumpling' with drug delivery potential

Abstract

Biomimicry has been used to create spherical nanometer-sized particles that show distinct similarities in function to globular proteins. A team of chemists at Washington University (St Louis, MO, USA) has developed a novel class of synthetic polymer particles too small to be seen by a standard microscope. Karen Wooley and colleagues turned to atomic force microscopy (AFM) in order to visualize the size and shape of the tiny spheres that range in diameter from 10 to 100 nanometres. Tomasz Kowalewski, a Polish AFM expert, produced the first images. Wooley recalls that Kowalewski recognized them immediately, `Tomasz said, “Oh, they look like knedels. You must call them that,” and that's why the new particles are named shell-crosslinked knedels (SCKs)—after a traditional Polish dumpling.'SCKs are spheres in which a hydrophobic core is surrounded and solubilized by a hydrophilic shell (Fig. 1Fig. 1); this gives a core–shell morphology that resembles the structure of lipoproteins. Synthesis of these tiny particles is based upon self assembly. First, given the right conditions, amphiphilic block copolymers (polymer chains composed of one segment that is water soluble and another segment that is water insoluble) nucleate to form a polymer micelle with anywhere between ten and several hundred individual polymer chains. The polymer micelles organize themselves into a glassy core that is shielded from the outer environment by the solubilized outer shell.Fig. 1Schematic diagram of (a) shell-crosslinked knedel-like nanospheres and (b) their appearance by atomic force microscopy. Kindly provided by Dr Karen Wooley, Washington University, St Louis, MO, USA.View Large Image | Download PowerPoint SlideOnce formed, knedels can be extensively manipulated. The overall size of the particles and the relative size and chemical composition of the shell and core can each be controlled. The unique stability of SCKs is imparted through chemical reactions within the shell that bind the chains together and give the stabilized cross-linked structure. However, although the polymer micelles are very stable, they are still dynamic structures and can be destroyed by dilution or when subjected to shear forces.The crosslinked shell acts as a physical barrier or `membrane' to gate the diffusion of small molecules into and out of the particles. SCKs are good scavengers of hydrophobic species, which suggests usefulness as controlled release devices. Since 1996, when the first knedels were synthesized, Wooley's group have changed the composition of the knedel core from a glassy to a rubbery substance similar to the interior of a golf ball. This change was made to improve the uptake of hydrophobic small molecules and also to study the micromechanical properties of these nano-particulate models of macroscale objects. SCK cores could eventually be filled with drugs, enzymes or DNA, creating a versatile carrier system with potential for use in drug delivery systems and in gene therapy.`Degradability is an issue if these particles are to find real biomedical applications, so we are currently developing entirely degradable systems,' says Wooley. `Two graduate students in the group have developed a new family of degradable polymers, based on silyl ester linkages, that can fall apart in water anywhere from a few minutes to a few months. In the near future, we intend to use these substances in SCKs to see if we can make timed-release particles.'Because the shell is the part of the structure immediately in contact with the surrounding environment, its composition and properties are extremely important. The shell has already been extensively manipulated. Placing positively charged, neutral or negatively charged functional groups into the shell layer creates SCKs with widely differing behaviours. SCKs bearing positively charged surface groups bind negatively charged substances such as DNA on their surface, forming small aggregates that protect the attached material from enzyme digestion. Again, this suggests an application in gene therapy, but it might also be of interest to immunologists because antigens too small to provoke an immune response could be attached to the surface of SCKs to make them immunogenic.The surface charge affects the way that SCKs distribute themselves following adsorption onto a surface. Strong SCK–surface interactions give isolated particles, whereas poor SCK–surface interactions tend to produce SCK self-aggregates. Wooley expects that she will be able to manipulate the SCK's shell properties to either encourage or inhibit biomolecule binding.' This allows us, for example, to exclude protein binding and improve biocompatibility. Initial efforts along this line have produced SCKs with a thick, hydrogel-like, mobile shell.'Further studies of the physical and chemical properties of these second-generation SCKs will be required before their full potential in medicine can be realized. The `nano-dumplings' could also have a range of other applications, from removing hydrophobic contaminants from aqueous solutions to being used as recording materials.