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The aim of this work was to study the potential of pegylated poly(anhydride) nanoparticles as carriers for the oral delivery of paclitaxel (PTX). Paclitaxel is an anticancer drug, ascribed to the class IV of the Biopharmaceutical Classification system, characterised for its low aqueous solubility and to act as a substrate of the P-glycoprotein and cytochrome P450. For the pegylation of nanoparticles, three different poly(ethylene glycol) (PEG) were used: PEG 2000 (PTX-NP2), PEG 6000 (PTX-NP6) and PEG 10000 (PTX-NP10). The transport and permeability of paclitaxel through the jejunum mucosa of rats was determined in Ussing chambers whereas its oral bioavailability was studied in rats. The loading of PTX in pegylated nanoparticles increased between 3 and 7-times the intestinal permeability of paclitaxel through the jejunum compared with the commercial formulation Taxol®. Interestingly, the permeability of PTX was significantly higher for PTX-NP2 and PTX-NP6 than for PTX-NP10. In the in vivo studies similar results were obtained. When PTX-NP2 and PTX-NP6 were administered to rats by the oral route, sustained and therapeutic plasma levels of paclitaxel for at least 48-h were observed. The relative oral bioavailability of paclitaxel delivered in nanoparticles was calculated to be 70% for PTX-NP2, 40% for PTX-NP6 and 16% in case of PTX-NP10. All of these observations would be related with both the bioadhesive properties of these carriers and the inhibitory effect of PEG on the activity of both P-gp and P450 cytochrome.

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Drug delivery systems containing gentamicin were studied as a treatment against experimental brucellosis in mice. Micro-and nanoparticles prepared by using poly(D,L-lactide-coglycolide) (PLGA) 502H and microparticles made of PLGA 75:25H were successfully delivered to the liver and the spleen, the target organs for Brucella melitensis. Both polymers have the same molecular weight but have different lactic acid/glycolic acid ratios. Microparticles of PLGA 502H and 75:25H released their contents in a sustained manner, in contrast to PLGA 502H nanoparticles, which were degraded almost completely during the first week postadministration. The values of the pharmacokinetic parameters after administration of a single intravenous dose of 1.5 mg/kg of body weight of loaded gentamicin revealed higher areas under the curve (AUCs) for the liver and the spleen and increased mean retention times (MRTs) compared to those for the free drug, indicating the successful uptake by phagocytic cells in both organs and the controlled release of the antibiotic. Both gentamicin-loaded PLGA 502H and 75:25H microparticles presented similar pharmacokinetic parameter values for the liver, but those made of PLGA 75:25 H were more effective in targeting the antibiotic to the spleen (higher AUCs and MRTs). The administration of three doses of 1.5 mg/kg significantly reduced the load associated with the splenic B. melitensis infection. Thus, the formulation made with the 75:25H polymer was more effective than that made with 502H microspheres (1.45-log and 0.45-log reductions, respectively, at 3 weeks posttreatment). Therefore, both, pharmacokinetic and pharmacodynamic parameters showed the suitability of 75:25H microspheres to reduce the infection of experimentally infected mice with B. melitensis.Brucellosis remains a major zoonosis worldwide (17), and it is among the microorganisms most likely to be used as biological weapons (24). Specific therapy reduces morbidity, shortens the duration of illness, and decreases the incidence of complications (31); however, relapse currently presents a significant problem (27). Long-lasting combined drug treatments are difficult to achieve (27); and also the intracellular location of the pathogen in phagocytic cells, mainly in the liver and the spleen, are involved in therapeutic failure (22). Drug delivery systems containing gentamicin (GEN) have been developed as potential alternatives to classical therapy, and the usefulness of these vectors has been shown (5, 7, 10, 23, 30). Although GEN is effective against the pathogen in vitro (11, 18, 25), it shows a low level of intracellular penetration due to its polar nature; hence, its entrapment in particulate carriers might facilitate the entrance of the drug into the cells. Moreover, sustained drug delivery could avoid long-term treatment, eliminating the toxic systemic levels achieved during classical antibiotic therapy with the free drug. Despite the promising results obtained with GEN-containing liposomes (7,10,30), important drawbacks are attributed to the...