In vitro and in vivo evaluation of poly(methylidene malonate 2.1.2) microparticles behavior for oral administration.

The goal of this paper was to investigate the fate of novel poly(methylidene malonate 2.1.2) microparticles with different surface properties, i.e. prepared with or without polyvinylalcohol (PVA), after oral administration, using in vitro cell culture and an in vivo mice model. Incubation of particles with Caco-2 cells induced no cytotoxicity except for the microparticles prepared without PVA at high concentrations. At subtoxic concentrations, microparticles were highly associated to cells, independently of particles concentrations, particles surface properties (with or without PVA) or incubation time. Confocal microscopy analysis revealed that adsorption was the main phenomenon leading to the association of particles to cells. However, association was greater at 37 degrees C than at 4 degrees C, suggesting that an active process, such as endocytosis, could also occur. In vivo, radiolabeled particles were mainly found in luminal content and also adsorbed onto the epithelium. After 24 hours, more than 15% of PVA-free microparticles were still present in the gastrointestinal tract, compared to 5% for particles prepared with PVA. However, histological evaluation revealed low uptake of particles by Peyer's patches. As a conclusion, this study provided a good correlation between in vitro and in vivo evaluation. These particles could be useful for oral sustained release and delivery of drugs to intestinal and colon epithelium.

Biodistribution of long-circulating PEG-grafted nanocapsules in mice: effects of PEG chain length and density.

PURPOSE: To study the pharmacokinetics and biodistribution of novel polyethyleneglycol (PEG) surface-modified poly(rac-lactide) (PLA) nanocapsules (NCs) and to investigate the influence of PEG chain length and content. METHODS: The biodistribution and plasma clearance in mice of different NC formulations were studied with [3H]-PLA. PLA-PEG copolymers were used in NC preparations at different chain lengths (5 kDa and 20 kDa) and PEG contents (10% and 30% w/w of total polymer). In vitro and in vivo stability were also checked. RESULTS: Limited [3H]-PLA degradation was observed after incubation in mouse plasma for 1 h, probably because of to the large surface area and thin polymer wall. After injection into mice. NCs prepared with PLA-PEG copolymers showed an altered distribution compared to poloxamer-coated PLA NCs. An increased concentration in plasma was also observed for PLA-PEG NCs. even after 24 h. A dramatic difference in the pharmacokinetic parameters of PLA-PEG 45-20 30% NCs compared to poloxamer-coated NCs indicates that covalent attachment, longer PEG chain lengths, and higher densities are necessary to produce an increased half-life of NCs in vivo. CONCLUSIONS: Covalently attached PEG on the surface of NCs substantially can reduce their clearance from the blood compartment and alter their biodistribution.

Correlation between membrane potential changes and proliferation of murine peritoneal lymphocytes stimulated by Nocardia water soluble mitogen.

A comparative study of Nocardia water soluble mitogen (NWSM) action on membrane potential and proliferation rate of murine peritoneal lymphocytes was performed at various incubation times. The membrane surface charge was evaluated by laser doppler velocimetry (LDV) through the measurement of the cell electrophoretic mobility at different pH values (from pH 5 to 9). We demonstrated that NWSM treatment decreases the lymphocyte membrane potential. This variation reached a maximal level after 24 hrs. at pH 7 and remained unchanged during the 72 hrs. observation. A significant stimulation of lymphocyte proliferation was noted after a 24 hrs. incubation. However, the highest rate of [3H]-thymidine incorporation was observed at 48 hrs. with a subsequent decrease at 72 hrs. On the basis of these data, it is suggested, that membrane potential changes may represent an early important step in the mechanism of lymphocyte activation by NWSM, as it has been shown for some mitogenic compounds.