Pulmonary administration offers excellent advantages over conventional drug delivery routes, including increasing therapeutics bioavailability, and avoiding long-term safety issues. Formulations of nano-in-micro dry powders for lung delivery are engineered using (S)-ibuprofen as a model drug. These biodegradable formulations comprise nanoparticles of drug-loaded POxylated polyurea dendrimers coated with chitosan using supercritical-fluid-assisted spray drying. The formulations are characterized in terms of morphology, particle-size distribution, in vitro aerodynamic particle pulmonary distribution, and glutathione-S-transferase assay. It is demonstrated that ibuprofen-loaded nanoparticles can be successfully incorporated into microspheres with adequate aerodynamic properties, mass median aerodynamic diameter (1.86-3.83 mu m), and fine particle fraction (28%-45%), for deposition into the deep lung. The (S)-ibuprofen dry powder formulations show enhanced solubility, high swelling behavior and a sustained drug release at physiologic pH. Also, POxylated polyureas decrease the (S)-ibuprofen toxic effect on cancer cellular growth. The 3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays show no significant cytotoxicity on the metabolic activity of human lung adenocarcinoma ephithelial (A549) cell line for the lowest concentration (1 x 10(-3) M), even for longer periods of contact with the cells (up to 120 h), and in the normal human dermal fibroblasts cell line the toxic effect is also reduced.