Increased cytotoxicity of nanoparticle-carried Adriamycin in vitro and potentiation by verapamil and amiodarone

The cytotoxicities of free cyanoacrylic nanoparticles, free Adriamycin, Adriamycin-loaded nanoparticles and a mixture of Adriamycin and nanoparticles are compared in cancer cell cultures. Increased cytotoxicity was observed in the sensitive (DC3F) subline when Adriamycin was in particulate form rather than free. In the derived pleiotropic resistant subline (DC3F AD/AZA), sensitivity to Adriamycin was completely restored with the conjugate. Addition of verapamil or amiodarone allowed an enhancement of efficiency of tenfold for free Adriamycin and between two- and fourfold for its conjugate form. Vectorization by nanoparticles and pharmacological modulation of cell membrane can act in synergy in synergy to overcome the resistance to Adriamycin in vitro.     

Multiple emulsion technology for the design of microspheres containing peptides and oligopeptides

This paper reviews the preparation and characterization of small poly(lactic-co-glycolic acid) microspheres (mean size lower than 10 μm) containing small peptides and prepared by a water-in-oil-in-water emulsion solvent evaporation technique. These microspheres were shown to encapsulate very efficiently a 33 amino acid peptide (V3 BRU) and in vitro release kinetics studies showed that such microspheres could be employed for both oral vaccination and controlled release. The encapsulation of a seven amino acid peptide (pBC 264) led on the contrary to a very low encapsulation efficiency. In order to increase the encapsulation of pBC 264, two strategies were adopted: (i) taking into account the solubility of pBC 264 at different pH, the inner aqueous phase was maintained at a basic pH where the peptide was soluble, while the external aqueous phase was acidic; (ii) ovalbumin was added to stabilize the inner emulsion. These two strategies allowed us to increase significantly the encapsulation rate of pBC 264. Nevertheless, the in vitro release kinetics of the peptide were strongly influenced by the presence of ovalbumin which seems to form pores in the microsphere structure. By contrast, when ovalbumin was replaced by Pluronic(R) F68, microspheres did not have pores, thus the release profile and the extent of the burst were much smaller. When microspheres were stereotactically implanted in the rat brain, in vivo release profiles were in good agreement with the release observed in vitro. In conclusion, these microspheres are well suited for the slow delivery of neuropeptides in the brain, a feature expected to facilitate the study of long term effects of these compounds.     

Pharmacokinetics and Biodistribution of Oligonucleotide Adsorbed onto Poly(isobutylcyanoacrylate) Nanoparticles After Intravenous Administration in Mice

Purpose. The goal of this study was to evaluate the ability of nanoparticles to be used as a targeted delivery system for oligonucleotides. Methods. Pharmacokinetic and tissue distribution were carried out in mice by measuring the radioactivity associated to the model oligothymidylate ³³P-pdT₁₆ loaded to poly(isobutylcyanoacryrate) (PIBCA) nanoparticles. In addition, we have used a TLC linear analyzer to measure quantitatively on a polyacrylamide gel electrophoresis, the amount of non degraded pdT₁₆ Results. Organ distribution study has shown that nanoparticles deliver ³³P-pdT₁₆ specifically to the liver reducing its distribution in the kidney and in the bone marrow. Nanoparticles could partially protect pdT₁₆ against degradation in the plasma and in the liver 5 min after administration, whereas free oligonucleotide was totally degraded at the same time. Conclusions. Nanoparticles protect oligonucleotides in vivo against degradation and deliver them to the liver.     

Liposomes and Nanoparticles in the Treatment of Intracellular Bacterial Infections

The treatment of infections caused by obligate or facultative intracellular microorganisms is difficult because most of the available antibiotics have either poor intracellular diffusion and retention or reduced activity at the acidic pH of the lysosomes. The need for antibiotics with greater intracellular efficacy led to the development of endocytosable drug carriers, such as liposomes and nanoparticles, which mimic the entry path of the bacteria by penetrating the cells into phagosomes or lysosomes. This Review assesses the potential of liposomes and nanoparticles in the targeted antibiotic therapy of intracellular bacterial infections and diseases and the pharmaceutical advantages and limitations of these submicron delivery systems.     

MR diagnosis of a congenital abnormality of the thoracic aorta with an aneurysm of the right subclavian artery presenting as a Horner's syndrome in an adult

Congenital abnormality of the aortic arch is a diagnosis made most of the time incidentally in childhood, unless dysphagia or respiratory disorders occur before. A case of a complex aortic arch anomaly with an aneurysm of the right subclavian artery presenting as an isolated Horner's syndrome in an adult is reported herein. Magnetic resonance imaging led to this very unusual diagnosis. Received: 17 March 1999; Revised: 15 July 1999; Accepted: 13 August 1999     

Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-β peptide (Aβ) and especially the Aβ peptide 1-42 (Aβ_1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aβ_1-42 in the blood and promote its elimination through the “sink effect” and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aβ_1-42. Treatment of AD-like transgenic mice with anti-Aβ_1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aβ soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aβ levels in plasma. This study represents the first example of Aβ_1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.     

Fetal toxoplasmosis. In utero treatment with pyrimethamine sulfamides

The mothers of 52 cases of toxoplasmic fetopathy diagnosed in utero by fetal blood and/or amniotic fluid sampling were treated with the combination pyrimethamine-sulfadiazine (or sulfisoxazole) and by spiramycine. The infants were compared with 51 other infants with congenital toxoplasmosis whose mothers had received spiramycine alone. Patients of both groups received the same pyrimethamine-sulfadiazine and spiramycine treatment after birth. Parasitologic examination of the placenta was positive in 42 and 76.6% of patients, in group I and group II respectively. The newborns had specific IgM in 17.4 and 69.2% of cases respectively in both groups. These differences were significant. The mean specific IgG titer was significantly reduced at birth and 4 to 6 months of age in the first group. Patients in group I had more often subclinical infection than patients of the comparison group: 57% vs 33.3%. They had less often a high cerebro-spinal protein content during the first week. Prenatal treatment with pyrimethamine-sulfadrugs resulted in a less progressing infection at birth. However in cases with clinically patent toxoplasmosis, the frequency of overt localizations and their sequellae was not significantly altered. This might be related to a relatively late onset of the treatment. The pyrimethamine-sulfadrug combination given to mothers of proved infected fetuses can be rewarding. The indication might be extended to well-documented seroconverted mothers if, in the future, the acquired experience and necessary pharmacological studies bring the proof of its innocuousness.     

Intranasal immunization with protein-linked phosphorylcholine protects mice against a lethal intranasal challenge with streptococcus pneumoniae

Immunization against phosphorylcholine (PC) linked to a protein protects mice against Streptococcus pneumoniae when used parenterally, and against Salmonella typhimurium when used orally after entrapment in D,L-Lactide-co-Glycolide microspheres. Here, we immunized BALB/c mice intranasally with a serotype 3 S. pneumoniae strain. Immunization was followed by a rise in anti-PC IgA and IgG titers in serum and in pulmonary secretions, but not by any rise in anti ds-DNA antibody nor any glomerular Ig deposition. The survival rates were 91 and 76% in the two groups of mice, respectively. These rates were significantly higher than those in control mice immunized intranasally either with Thyr loaded in microspheres (0%), blank microspheres (22%), free Thyr (17%), and saline (18%). This demonstrates that the mucosal route is effective for vaccination against S. pneumoniae pneumonia with PC linked to a protein carrier. It constitutes another important step forward in the development of the concept that PC can be used as a mucosal immunogen for protection against the different diseases caused by PC-bearing bacteria.     

Pulmonary and systemic vascular abnormalities of the right lung in children

Three children presenting with vascular abnormalities of the right lungs are reported. Clinical symptoms were not specific. Total lack of perfusion associated with normal ventilation at pulmonary scintiscanning was highly suggestive. Diagnosis was confirmed by pulmonary catheterism and angiography. The congenital or acquired nature of these abnormalities is not established. Development of pulmonary arterial hypertension during follow-up may need pneumonectomy.     

Liebow's desquamative interstitial pneumonia. Apropos of a case in an infant

Case report of a Liebow's desquamative interstitial pneumonia in a 3 week-old infant. The disease resulted in permanent respiratory failure. Steroid therapy had no durable effect and death occurred at 4 1/2 months of age.