Pierre Thouvenot

Lymphatic targeting of polymeric nanoparticles after intraperitoneal administration in rats.

Following intraperitoneal administration, the lymphatic targeting of polyacrylic nanoparticles has been evaluated in thoracic duct cannulated rats. The dosage forms administered consisted of carbon-14 polyhexylcyanoacrylate nanoparticles (PHCA) and polymethylmethacrylate (PMMA) nanoparticles. The carbon-14 concentrations were much higher in the excreted thoracic lymph than in the blood for both types of particles. The most dramatic results were found in the mediastinal nodes since the carbon-14 concentrations of rats receiving PHCA and PMMA nanoparticles by the ip route were 70-to more than 2000-fold higher than in the corresponding nodes of animals treated by the intravenous route. This potential lymphatic targeting could prove valuable in cancerology to treat tumors that metastasize in the peritoneal cavity or via lymphatic pathways such as colon carcinomas.

Hydrocortisone delivery to healthy and inflamed eyes using a micellar polysorbate 80 solution or albumin nanoparticles

Abstract Hydrocortisone was loaded onto albumin nanoparticles by sorption. Two systems were tested, one comprised of a 0.03% saturated drug solution, the other of a 0.2% micellised drug solution. In both cases 45–70% of the originally available drug was bound to the carrier surface. The systems were further tested by measuring the in vitro transport of radiolabelled hydrocortisone through porcine cornea. Nanoparticles led to sustained drug transport through the cornea. The distribution of both 0.2% hydrocortisone preparations (nanoparticles and solution) was then evaluated under in vivo conditions in healthy and inflamed eyes of rabbits. In all tissues the level of drug was higher in the inflamed than in the healthy eye due to increased cell permeability as a result of inflammatory processes. The application of nanoparticles led to lower hydrocortisone tissue concentrations than the reference solution due to the strong binding of hydrocortisone onto the particle system and the resulting slow release. An exception occurred with the reference solution in the conjunctiva, as less drug was found in the inflamed than in the normal tissue, since enhanced lacrimation led to increased drug drainage. In contrast, the corresponding nanoparticle preparation was more efficiently retained at the inflamed than at the normal conjunctiva. Consequently, in the inflamed eye, hydrocortisone-loaded nanoparticles enabled targeting to the precorneal area away from the inner segments of the eye.

Natural polyphenols-iron interaction: its biological importance.

The iron-binding capacity of different fractions of natural polyphenols extracts was determined by chromatographic and electrophoretic methods. Their effects on iron-induced calcium homeostasis changes in liver tissue suspension showed that mate tea and green tea extracts provoke a very significant inhibition of the iron effects, whereas it is much less significant with red wine extract. The biological importance of this phenomenon is discussed.

ATP in Cellular Calcium-Overload by Trivalent Metal Ions

Extracellular Ca2+-influx induced by trivalent metal ions (Fe3+, Al3+, Cr3+, In3+, Ga3+, and La3+) in Ehrlich carcinoma cells is enhanced by ATP. This action seems to be related to the high coordination capacity of the ATP ligand that inhibits the polymerization of the solvated cations taking place at physiological pH, and consequently permits their biological activity. A general relationship between induced lipid peroxidation and increased calcium uptake was not found. These results emphasize the ATP role in the toxicity of trivalent metals, and its possible involvement, via cellular calcium overload, in a neurodegenerative process, such as Alzheimers and Parkinsons diseases, in whose etiology the implication of aluminum and iron has been suggested.

The role of ATP as a mediator in the action of iron complexes on cellular calcium homeostasis

The effects of the interaction between low molecular weight iron complexes (citrate, lactate, and ATP complexes) with ATP and proteins, on the modification of Ehrlich carcinoma cell calcium homeostasis have been studied. In that modification the ferric-ATP complex shows much higher activity than the others. Sodium ATP, by iron translocation from citrate and lactate, increases their activity. This phenomenon implicates ATP as a mediator on the cellular activity of the complexes. Proteins, particularly ferritin, appear to moderately reduce their activity, whereas glutathione and ascorbic acid, acting as lipid peroxidation-inhibitors, show only a slight reduction of the iron complex’s effects on cellular calcium uptake.

Molecular exchange of metal ions and tissular calcium overload

In vitro and in vivo, mouse tissues assayed for 45Ca2+ uptake have shown that ATP increases the Ca2+ take-up in the presence of lactates of iron and aluminum, but this effect is absent with the citrates. The in vitro metal ion exchange with ATP has been demonstrated by electrophoresis and by chromatography. It is considered the cause of the increased capacity of ATP to modify the cellular effects of lactates. The in vitro modifications of Ca2+ uptake by lactates when in the presence of ATP are much more important than those of citrate. In general, aluminum compounds show a higher Ca2+ uptake and, coincidentally, they have shown a higher carcinogenic capacity than iron ATP.

Role of lipid peroxidation in iron-induced cellular calcium overload

Calcium overload is the common pathway leading to cell injury. The role of iron-induced lipid peroxidation in the modification of Ehrlich carcinoma cells calcium homeostasis has been studied. There is a lack of correlation between that modification and the value of lipid peroxidation. The stability characteristics of low-mol-weight iron complexes affect lipid peroxidation and, to a lesser extent, cellular calcium uptake. Lipid peroxidation appears not as a triggering factor of cellular calcium homeostasis modification, but as a concomitant phenomenon.

Effects of Low-Molecular-Weight Aluminum Complexes on Brain Tissue Calcium Homeostasis

The in vitro effects of low-molecular-weight aluminum complexes (citrate, lactate, and ATP complex) on the Ca2+ uptake and aluminum-induced lipid peroxidation of brain tissue show that the modification of the calcium homeostasis is determined by the nature of the ligand and that there is no correlation between the aluminum-induced lipid peroxidation and the Ca2+ uptake. The same characteristics have been shown by a similar study performed with Ehrlich carcinoma cells. The electrophoretic analyses of the aluminum lactate-albumin and aluminum lactate-ATP interactions indicate an aluminum transfer from the lactate to the albumin and ATP ligands. The increased Ca2+ uptake when ATP is present in the incubation medium with aluminum citrate and aluminum lactate corroborates the suggested mediator role of ATP in cellular calcium homeostasis modification induced by iron.

Role of iron-ATP complex in lymphocyte proliferation and infiltration.

The roles of sodium-ATP (NaATP) and ferric-ATP complex (FeATP) on the proliferation and infiltration of lymphocytes have been studied by evaluation of the hypertrophy and histopathologic examination of spleen and liver, as well of the modifications in the elemental balance of iron, calcium, magnesium, and phosphorus. The results showed that in the implicated biochemical processes, calcium and magnesium have a principal role. An in vitro study on a cell model has permited one to evaluate the effects of deferoxamine, a known iron chelator and inhibitor of human lymphocyte proliferation, on FeATP-modified cellular calcium fluxes. These findings showing a reduced 45Ca2+ uptake in the presence of deferoxamine appear to indicate that in vivo the chelation of blood-borne iron by ATP might play a key role in proliferation and infiltration of lymphocytes, leading to lymphoma development.