Ultrasound‐Triggered Release from Multilayered Capsules

Abstract

The growing need for drug-delivery systems that release their contents in a desired fashion has intensified research for “smart carriers” with intelligent properties. Compared to more established delivery vehicles, such as polymeric micelles, liposomes, and small colloidal particles, polymeric polyelectrolyte multilayered capsules 8] are emerging materials with high potential as macromolecular drug-delivery systems. The major advantages of these microcapsules are their loading capacity and the possibility to precisely tailor their properties by choosing the components of the capsules. Considerable amounts of macromolecular therapeutics can be encapsulated inside these capsules and, depending on the choice of coating material (i.e., synthetic or biological), one can render capsules nondegradable or degradable. Also, their mechanical strength can be tailored by varying the number of coating layers, inclusion of nanoparticles, or by thermal treatment. 17] Once their target site is reached, it is of utmost importance to have a mechanism that causes release of encapsulated species from these capsules. Externally triggered release has recently been shown to be possible by laser-light illumination. The principle of this system is based on heating of metal nanoparticles, which causes changes in permeability of the outer shell and even total disruption of the shell, finally resulting in the release of the encapsulated material. These laser-light-sensitive capsules could, for example, be activated after cellular uptake or be used for transdermal activated-drug release. Herein, we report the use of ultrasound to trigger release from multilayered capsules. Ultrasound has been used widely in biomedical applications for improving drug uptake, anti-inflammatory treatment, or imaging. Upon propagation, an ultrasound wave undergoes both viscous and thermal absorption as well as scattering. At low frequency the temperature difference between the particle and the medium will be in equilibrium, whereas at high frequency only a small portion of the surface will be affected by thermal waves. Similar frequency dependence is applicable to viscous losses, wherein extensive particle motion occurs at low frequency while little movement takes place at high frequencies. Figure 1 shows schematically the fabrication of the capsules and the effect of ultrasound on their integrity. When the capsules are subjected to ultrasound, a morphological change of the capsule wall occurs due to the creation of shear forces between the successive fluid layers, which results in the disruption of the capsule membrane and release of encapsulated species. Multilayered capsules were fabricated using the LbL technique by successive coating of CaCO3 microparticles with different layers of polyelectrolytes and gold nanoparticles. This process is shown schematically in Figure 1. During fabrication, the CaCO3 microparticles were filled with 2000-kDa fluorescein isothiocyanate (FITC)-labeled dextran by co-precipitation. This is an elegant method, which allows a high degree of loading and avoids a post-filling step of the capsules. Co-encapsulation in CaCO3 microparticles is typically performed in the case of macromolecules, and leads to a large quantity of encapsulated macromolecules without loss of biological activity. This approach is less suited to the encapsulation of low-molecular-weight drugs, as such molecules would tend to diffuse outwards during LbL coating of the CaCO3 microparticles, or they would diffuse outwards through the LbL membrane upon dissolution of the CaCO3. Two different types of capsules were fabricated: Type 1 consisted solely of polyelectrolytes, while type 2 were hybrid capsules consisting of polyelectrolytes and gold nanoparticles (AuNPs). Sodium poly(styrene sulfonate) (PSS) was used as polyanion while poly(allylamine hydrochloride) (PAH) was used as polycation. AuNPs were fabricated according to the method reported by Kimura et al. , which resulted in AuNPs with a diameter ranging from 1 to 5 nm (as verified by transmission electron microscopy; data not shown) and a negative surface charge (as verified by measuring the electrophoretic mobility) due to the presence of carboxyl groups on the surface of the AuNPs. Multilayer buildup between the PSS/PAH (in the case of type 1 capACHTUNGTRENNUNGsules) and AuNP/PAH (in the case of type 2 capsules) was driven by the electrostatic interactions between the cationic amino groups of the PAH and the anionic sulfonate of the PSS and carboxyl groups, respectively. For each type of cap[*] Prof. G. B. Sukhorukov Department of Materials Queen Mary University of London London E1 4NS (UK) Fax: (+44)20-8981-9804 E-mail: g.sukhorukov@qmul.ac.uk