Sub-micrometer vaterite containers: synthesis, substance loading, and release.

Promising candidates for the development of universal nanoscale delivery systems are porous inorganic nanoparticles. Recently, the applications of porous silicon in a multistage delivery system, in polymer coated nanocarriers, and of porous silica as core material for lipid bilayers have attracted great attention. A system with similarly high potential, but less studied so far, is porous calcium carbonate in the form of polycrystalline vaterite spheres. It has been shown to exhibit various beneficial properties such as biocompatibility, high drug loading capacity, and preservation of the loaded drugs properties. However, all these works on CaCO3 were performed with micrometer-sized particles, since the fabrication of nanocontainers turned out to be a big challenge. The common synthesis method of mixing salt solutions allowed producing container sizes of 3 to 15 mm, while the best reproducibility was reached for sizes of about 4 mm with a porosity of 40%. Yet, the most promising applications demand sub-micrometer size containers, for example, active coating or drug delivery, since smaller sizes favor efficient and homogeneous distribution and give access to micrometer-sized structures such as cells or tissue. Herein we report, for the first time, the fabrication of submicron porous vaterite containers, their loading with a probe payload, and its release. Their synthesis is based on crystal growth of polycrystalline, spherical vaterite particles, precipitated from concentrated solutions of CaCl2 and Na2CO3. [10] The nucleation and growth rate of the vaterite spheres is determined by the supersaturation level of the dissolved amorphous CaCO3. [11] The final size of the vaterite particles depends strongly on the concentration of the reagents, the solubility of the salts, the reaction time, and the rotation during mixing. It was shown that increasing the concentration of the salts up to 1m, the rotation speed up to 1500 rpm, and the reaction time to 2 min allowed reducing the vaterite particle size to 3 mm. A particle size reduction beyond these values has so far not been achieved, since vaterite was found to become unstable in water below this critical size, leading to a rapid recrystallization to the calcite phase. This recrystallization is due to the growing surface-to-volume ratio and enhanced solubility with decreasing particle size. We resolved this problem by adding ethylene glycol (EG) as a solvent, offering an enhanced density and reduced solubility of CaCO3. This diminished the molecular diffusion, reducing the crystal growth rate and the probability of nucleation, which finally stabilized the vaterite crystals. Experimental evidence of these effects is presented in Figure 1, where the average of the vaterite particle size distribution is shown as a function the reaction time for