An amphiphilic Gd(III) complex has been efficiently loaded in polylactic-co-glycolic acid nanoparticles (PLGA-NPs) to yield a novel, high sensitive magnetic resonance imaging (MRI) contrast agent for imaging guided drug delivery applications. As the Gd(III) complex is soluble in organic solvents, the nanoparticles were prepared as oil/water emulsions. PLGA-NPs were stable, in buffer, for more than 1 week without any release of the incorporated agents. The millimolar relaxivity of the Gd(III) complex incorporated in the particles (140 nm diameter) was of 21.7 mM(-1) s(-1) at 21.5 MHz, a value that is about 5 times higher than that observed with the commercially available contrast agents used in clinic. The relaxometric efficiency of these particles resulted inversely proportional to the particle size measured by dynamic light scattering. The high stability and sensitivity of PLGA-NPs allowed their accumulation in vivo in murine melanoma xenograft as shown in the corresponding MR images. Once loaded with drug and contrast agents, PLGA nanoparticles can be proposed as efficient theranostic MRI agents.

This work investigates the degradation of PLGA implants in an aqueous medium maintained at physiological pH & 7.4. Two limiting systems are also investigated, which involve the degradation of PLGA microspheres in two different media characterized by: (i) a non-regulated pH, for emulating the autocatalyzed degradation in the implant core; and (ii) a regulated physiological pH, for emulating the uncatalyzed degradation at the implant surface. The degradation experiments were carried out along 40-50 days, and samples withdrawn during this period were characterized by gravimetry, electronic microscopy, and size exclusion chromatography. Experimental results suggest that PLGA implants are degraded according to a time-variant spatial pattern, which depends on the pH of the surrounding medium. Initially, the implants suffered a typically bulk erosion process, governed by the acidification of the implant core; and after breakage of the implant wall, the regulated physiological pH induces a surface erosion process. The two auxiliary microsphere-based experiments were useful to elucidate the degradation phenomena occurring in the PLGA implants. The evolution of the mass loss and the weight-average molecular weight along the degradation can be successfully predicted by simple mathematical models based on first-order kinetics.

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Progesterone pharmacokinetics were analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of 2-coupled first-order (bi-exponential equation), hyperbolic (Michaelis-Menten equation), and sigmoidal (Hill equation) kinetic models to describe the experimental progesterone pharmacokinetic profiles was examined on a statistical basis. After nonlinear regression and statistical analysis of the data-fitting capability, a simple one-compartment model based on Hill equation proved to be most adequate. This model indicates an enzyme-catalyzed metabolism of progesterone involving cooperative substrate-binding sites, resulting from allosteric effects that yield a sigmoidal saturation rate curve. Kinetic parameters were estimated for 2 groups of lactating Holstein cows with different daily milk yields. We found, for the first time, a remarkable quantitative agreement of the Hill coefficient value with that reported in pharmacokinetic studies involving cytochrome P450, family 3, subfamily A (CYP3A)-mediated reactions in other mammals, humans included. It seems that positive cooperativity makes enzymes much more sensitive to plasma progesterone concentration, and their activities can undergo significant changes in a narrow range of concentration as characteristic of sigmoidal behavior. Therefore, the values of classical pharmacokinetic parameters, such as the elimination constant, half-life, and clearance rate, were found to be highly dependent on the plasma progesterone concentration.

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