Porous, fluorescent zirconia particles of nearly 380 nm diameter were prepared without template molecules or labeling dyes. The porous structure is the result of aggregation-induced particle formation. The inherent fluorescence is assigned to coordinatively unsaturated Zr 4+ ions at the sol-gel derived ZrO 2 surface. After physico-chemical characterization of the native zirconia particles carboxyl and/or amine bearing drug molecules (D,L-a-difluoromethylornithine -DFMO, ursolic acid -UA and doxorubicin -DOX) were adsorbed onto their surface, and the products were analyzed with Fourier-transform infrared spectroscopy (FTIR), thermogravimetry (TG), small-angle X-ray scattering (SAXS), fluorimetry and zeta potential vs. pH measurements. We have found that DOX complexes coordinatively unsaturated Zr 4+ ions without dislocating them, while carboxyl-bearing drugs interact with basic surface Zr-OH sites eliminating some of the carbonate species. The adsorption of UA at the zirconia surface shifts considerably the isoelectric point of the surface and thus provides kinetic stability to the particles at physiological pH. An in vivo biodistribution study in two healthy dogs performed by SPECT/CT detection after 99mTc labeling of the nanocarriers has shown the possibility of drug delivery application.
IntroductionNano-and microparticles of various kinds are currently investigated with the prospect of drug delivery application. The requirements to be fulfilled are numerous: drug carrier particles should encapsulate, transport and release drug molecules in a controlled way in living organism. 1 Multifunctionality is, therefore, inevitable and -when coupled to easy synthesisrepresents a great advantage. Among inorganic particles silica 2,3 is preferred for its controlled synthesis, low toxicity, established conjugation methods and high drug loading capacity (for mesoporous silica).Zirconia, a ceramic material, is used for biomedical applications e.g. in dental and chirurgical implants. [4][5][6] It is known to be biocompatible, and we have shown in our preliminary experiments that zirconia is also biodegradable under certain circumstances. The surface of zirconia is chemically active, having both acidic and basic sites. 7 This explains that zirconia chemisorbs both NH 3 and CO 2 . 8 Under ambient conditions, the zirconia surface is always covered by CO and CO 2 adsorbed from the air. 9,10 Complex formation has also been observed with the carboxyl groups of citric acid and poly-e-caprolactone. 11,12 As was observed by Pokrovski et al. CO 2 adsorption on monoclinic (m-) ZrO 2 is more than an order of magnitude higher than that on tetragonal (t-) ZrO 2 . 13 High-temperature synthesis or annealing of ZrO 2 leads to the transformation of the monoclinic phase into tetragonal. However, the lack of a generally approved synthetic method providing stable m-ZrO 2 colloid hinders its use as a drug carrier. Nanocrystalline powders of t-ZrO 2 are produced by aqueous phase reaction followed by annealing.14-17 These materials sintered by a fi...