Peroral administration of 14C-poly(D,L-lactic acid) nanoparticles coated with human serum albumin or polyvinyl alcohol to guinea pigs.

Biodegradable 14C-poly(D,L-lactic acid) (PLA50) nanoparticles coated either with a readily digestible protein albumin or with a non-digestible coating agent, polyvinyl alcohol (PVA), were prepared by the solvent evaporation technique. The nanoparticles were administered perorally to guinea pigs to evaluate the gastro-intestinal degradation of their PLA50 matrix. In the case of PLA50 nanoparticles coated with digestible albumin, substantial gastro-intestinal degradation of the PLA50 matrix occurred, leading to the passage of considerable amount (> or =45%) of water-soluble products across the gastrointestinal barrier. When a non-digestible coating agent like PVA was used, the degradation of the PLA50 matrix in the gastro-intestinal tract was at least two times lower (> or =19%). The results show that it is possible to control the in vivo degradation of PLA50 nanoparticles using appropriate coating agents. The present investigations showed a good correlation between previously observed in vitro results and the in vivo findings.

Degradation of poly(D,L-lactic acid) nanoparticles coated with albumin in model digestive fluids (USP XXII).

Entirely biodegradable poly(D, L-lactic acid) (PLA50) nanoparticles coated with albumin were prepared by the solvent evaporation technique. Their degradative properties were investigated in simulated gastric and intestinal fluids (USP XXII). The degradation of the albumin coating was monitored by HPLC, whereas PLA50 degradation was determined by size exclusion chromatography (SEC) as well as by the detection of lactate in bulk solution by enzymatic assay. As expected, the coating effect of albumin, a readily digestible protein, rapidly disappeared in both gastric and intestinal media, thus exposing albumin-free PLA50 cores to hydrolytic processes. In pepsin-rich simulated gastric fluid, no degradation of the PLA50 core was observed over 8 h incubation time. In contrast, in pancreatin-rich simulated intestinal fluid, the PLA50 nanoparticles were rapidly converted into lactate. The results showed that the PLA50 degradation was mainly due to an enzymatic cleavage process. Further experiments showed the involvement of lipases in the degradation of the PLA50 core in simulated intestinal fluid.

Body distribution of fully biodegradable [14C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats.

Fully biodegradable polylactic acid (PLA) nanoparticles (90-250 nm) coated with human serum albumin (HSA) were prepared by high-pressure emulsification and solvent evaporation, using the protein as surfactant. A new analytical tool was developed, based on Mie's law and size exclusion chromatography, to establish that, after evaporation of the solvent, the protein saturates the surface of the nanoparticles, masking the PLA core. According to this technique, no HSA is encapsulated in the polymer matrix. A radiolabelled [14C]-PLA50 was synthesized to follow the fate of this new drug carrier after i.v. administration to rats. The time necessary to clear the albumin-coated nanoparticles from the plasma was significantly longer than for the uncoated ones but not extended enough to target cells other than mononuclear phagocytes. As deduced from whole-body autoradiography and quantitative distribution experiments, the 14C-labelled polymer is rapidly captured by liver, bone marrow, lymph nodes, spleen and peritoneal macrophages. Nanoparticle degradation was addressed following 14C excretion. The elimination of the 14C was quick on the first day (30% of the administered dose) but then slowed down. In fact, if the metabolism of the PLA proceeds to lactic acid which is rapidly converted into CO2 via the Krebs cycle (80% of the total excretion was fulfilled by the lungs), anabolism from the lactic acid may also have taken place leading to long-lasting radioactive remnants, by incorporation of 14C into endogenous compounds.