Marie Roland

Pharmacokinetics and Distribution of a Biodegradable Drug-carrier

Abstract This paper describes tissue distribution, blood clearance and excretion of biodegradable cyanoacrylic nanoparticles. After intravenous administration, nanoparticles were rapidly cleared from the blood stream and concentrated mainly in the reticuloendothelial system. When administrated subcutaneously, nanoparticles seemed to avoid the liver and the spleen whereas they concentrated in the gut wall. Whole body autoradiography performed on Lewis Lung carcinoma-bearing mice showed progressive accumulation of the carrier in tumoral tissue. Furthermore a high level of radioactivity was found in the metastatic lungs of cancerous animals, whereas no lung accumulation was observed in healthy mice. Data are given concerning the enzymatic contribution to the degradation of the nanoparticles in vivo.

Degradation of Poly (isobutyl Cyanoacrylate) Nanoparticles

Poly(isobutyl cyanoacrylate) nanoparticles were prepared. They were degraded in two enzyme-free media at pH 7 and 12 in the presence of rat liver microsomes. The conventional formaldehyde-producing degradation route was studied, and showed a very low efficiency. Another pathway, consisting of ester hydrolysis, was identified and studied. In contrast to the formaldehyde pathway, ester hydrolysis was shown to be catalysed by enzymes. Finally, the release rate of adsorbed actinomycin from nanoparticles was proved to correlate exactly with the degradation rate of the polymer.

Nanocapsules: A new type of lysosomotropic carrier

P. COUVREUR +, P. TULKENS ~, M. ROLAND +, A. TROUET ~ and P. SPEISER* +Laboratoire de Pharmacie Gal~nique, Universit~ Catholique de Louvain, B-1200 Brussels, *Laboratoire de Chimie Physiologique, Universit~ Catholique de Louvain, and International Institute of Cellular and Molecular Pathology, B-1200 Brussels, Belgium and *Pharmazeutische Institut, Eidgen6ssische Technische Hochschule, Zfirich, Switzerland

Actinomycin D adsorbed on polymethylcyanoacrylate nanoparticles: Increased efficiency against an experimental tumor

Abstract This paper describes preliminary results of experimental chemotherapy using actinomycin D loaded polymethylcyanoacrylate nanoparticles on the growth of a transplantable soft tissue sarcoma of the rat. These results indicate that the use of polymethylcyanoacrylate nanoparticles as a drug carrier enhances the activity of the drug towards the subcutaneous sarcoma.

Development of a nanoparticle controlled-release formulation for human use

Abstract Prior to the first clinical trials of doxorubicin-loaded nanoparticles, it was necessary to prepare this formulation in such a way as to meet the requirements generally associated with parenteral administration. This paper describes the conditions under which nanoparticles should be prepared and lyophilized in order to be sterile and free of bacterial endotoxins. These nanoparticles were also subjected to a resuspension test and their size and drug adsorption capacity were found practically unchanged. A gel permeation chromatographic method allowed both an estimation of the molecular weight distribution of the cyanoacrylic polymer and the detection of the possible presence of monomeric residues. Additional data have shown that the doxorubicin adsorbed on nanoparticles was released well after intravenous injection in mice. Blood clearance of the drug was observed to be disminished when it was linked to nanoparticles, whereas its cardiac concentration was considerably reduced. Finally, preliminary stability assays, carried out after 6 and 12 months of storage, showed no modification in nanoparticle size, drug content and relative moisture content.

New Magnetic Drug Carrier

We have previously demonstrated the use of polyalkylcyanoacrylate nanoparticles as a drug carrier (Couvreur et al1979a.b). They are able to adsorb a wide variety of drugs and degrade at a rate depending on the length of their alkyl chain (Couvreur et a1 1979~). Their use with adsorbed dactinomycin enhanced its activity against an experimental subcutaneous sarcoma(Brasseur et a1 1980). The possibility of significantly reducing the toxicity of an anticancer drug such as doxorubicin by adsorbing it on polyisobutylcyanoacrylate nanoparticles has been demonstrated (Couvreur et al 1982). Such a carrier could profoundly modify the pattern of tissue distribution of various drugs (Couvreur et al 1980; Kante et al 1980), however, excessive accumulation by the reticuloendothelial system proved difficult to avoid. Therefore biodegradable drug-carriers with magnetic properties have been developed since, magnetic guidance of intravascular particles by an externally placed electromagnet has proved feasible (Widder et a1 1978, 1980). Until now such particles were generally not smaller than 1 pm. We describe preparation of polyalkylcyanoacrylate nanoparticles of about 0.22 pm which respond to a magnetic field. Some toxicological data are also given.

Tissue Distribution of [actinomycin-h-3 D Adsorbed On Polybutylcyanoacrylate Nanoparticles

Abstract Suspensions of polybutylcyanoacrylate nanoparticles have been characterized morphologically. The influence of the adsorption of [ 3 H]actinomycin D on these particles upon the tissue distribution of the drug has been studied in rats. It has been demonstrated that 24 h after injection, adsorbed [ 3 H]actinomycin D is 5.6-, 44- and 64-fold more concentrated than the free drug in muscle, spleen and liver respectively. Furthermore, the urinary excretion of [ 3 H]actinomycin D is diminished when the drug is bound to polybutylcyanoacrylate nanoparticles.

Nanoparticles of polyisohexylcyanoaerylate (PIHCA) as carriers of primaquine: formulation, physico-chemical characterization and acute toxicity

Nanoparticles of polyisohexylcyanoacrylate with bound primaquine were prepared by an emulsion polymerization method and an i.v. formulation was obtained after freeze-drying. Such formulation is intended for drug targeting in visceral leishmaniasis. Drug binding seemed largely dependent on pH and formulation conditions were optimized to obtain a polymeric colloidal suspension containing particles in the 200-250 nm size range and 80-90% drug binding (final content of 10 mg of drug per vial). Aspects such as polymer-drug interaction, in vitro drug release and physicochemical stability were studied. A significant reduction in acute toxicity was demonstrated by using the targeted formulation in NMRI mice.

Development of dehydroemetine nanoparticles for the treatment of visceral leishmaniasis

The preparation and physico-chemical characterization of lyophilized polyisohexylcyanoacrylate nanoparticles loaded with dehydroemetine (DHE) for the treatment of visceral leishmaniasis disease is described. The resulting formulation was found to efficiently absorb DHE and gave very reproducible preparations with regard to the size and drug adsorption rate. Stability has been confirmed for at least 24 months. The acute toxicity of DHE was reduced in intravenous administration by its association with nanoparticles. Data concerning tissue distribution in mice showed that DHE nanoparticles were rapidly cleared from the blood stream and that they mainly concentrated in the reticuloendothelial system. Furthermore, DHE linkage to the carrier reduced the cardiac concentrations of the drug.

Comparison of nephrotoxicities of different polyoxyethyleneglycol formulations of amphotericin B in rats.

The aim of the present study was to assess whether amphotericin B (AmB)-Myrj 59, AmB-polyoxyethyleneglycol 24 cholesterol (PC), and AmB-Synperonic A50 (SA50) were less nephrotoxic than AmB-deoxycholate (DC). Rats were treated with the different AmB formulations (10 mg/kg of body weight) intraperitoneally or with the surfactants alone. A group of control rats receiving the vehicle was also examined. After 6 days of daily intraperitoneal injections of AmB-DC, decreased body weight and glomerular filtration rate as well as increased degree of diuresis, uremia, microalbuminuria, and N-acetyl-beta-D-glucosaminidase excretion in urine were noted. Urinary excretion of potassium and sodium was also decreased in AmB-DC-treated rats. Most of these effects were more pronounced with AmB-PC and AmB-SA50. In contrast, AmB-Myrj 59 was less nephrotoxic than AmB-DC. Indeed, after 6 days of treatment with AmB-Myrj 59, the natriuria, kaliuria, albuminuria, and glomerular filtration rates were unchanged compared with those of controls. Moreover, the body weight loss and uremia increase of the rats treated by AmB-Myrj 59 were less than those of the rats treated with the commercial preparation. Among the surfactants, only PC was toxic for the rats. The intrinsic toxicity of PC and the higher systemic exposure to AmB could contribute to increased toxicities of AmB-PC and AmB-SA50, respectively. AmB-Myrj 59 was less nephrotoxic than AmB-DC at equivalent areas under the plasma concentration-time curves. These preliminary results suggest that this formulation could be a good alternative to the commercial product.