Microsphere formulation strategies, cell uptake studies, and pharmacokinetics in rats

Methods for targeting drugs to specific sites are being studied extensively because the use of such delivery systems frequently results in increased treatment efficacy and reduced adverse drug reactions. An example for targeted drug delivery extensively evaluated in out laboratory, involves the formulation of microspheres consisting of a drug combined with albumin as a matrix, cross-linked with an agent such as glutaraldehyde to provide stabilization.; An area being studied is the use of targeted drug delivery in the treatment of cancerous tumors. It has been observed that some tumor cell lines such as B16 melanoma cells and RAW 264.7 cells take up microspheres by a phagocytic mechanism, resulting in increased toxicity to these cells with reduced general cell toxicity. Endothelial cells can also take up microspheres so that antibiotic loaded microspheres may be used to kill bacteria, which are taken up into the endothelial cells in septic syndrome.; These studies were designed to evaluate two methods for producing albumin microspheres (nebulization and emulsion) containing the anti-tumor agent doxorubicin and the enzyme horse radish peroxidase (HRP). We also conducted studies to elucidate some of the factors affecting phagocytosis such as size and the effect of lipopolysaccharides (LPS), which showed to increase permeability of endothelial cells at low concentration in vitro as well. We conducted pharmacokinetic and bio-distribution studies of increasing doses of fluorescence labeled microspheres.; These studies demonstrated that the nebulization method was more suitable than the emulsion method for production of the microspheres containing doxorubicin or HRP. In vitro studies demonstrated that cell phagocytosis increased as microsphere size increased from 0.1--1.7 microns and that the addition of LPS resulted in an increase in phagocytosis with a concentration-dependent relationship. In vivo studies demonstrated that the pharmacokinetics of microspheres in rats showed a two-compartment model and organs such as the liver, lungs and spleen demonstrated strong phagocytic uptake suggesting that cell phagocytosis of microspheres may be useful in targeting drugs to specific sites.; In summary, these studies concluded that albumin microspheres were a suitable delivery vehicle for both doxorubicin and antibody linked enzyme. Cell phagocytosis could be used as a drug targeting strategy for microspheres.