Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: physico-chemistry and molecular modeling.

The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino-occlusive disease.

Freeze-drying of composite core-shell nanoparticles.

The effects of four sugars (glucose, saccharose, maltose, trehalose) and one surfactant (Poloxamer 188), on the freeze-drying of poly(isobutylcyanoacrylate) (PIBCA), poly(epsilon-caprolactone)-poly(ethylene glycol) (PCL-PEG), and novel core (mainly PIBCA)-shell (principally PEG) composite nanoparticles (CNP) obtained by co-precipitation were investigated. The efficiency of the additives against the adverse effect of freeze-drying on the redispersibility of the nanoparticles was evaluated, based on the visual appearance of the nanoparticle suspensions (Tyndall effect and aggregation), and on the determination of the mean diameter ratio of the nanoparticles before and after freeze-drying. The results indicated that the addition of both sugars and surfactant was essential for the good redispersion of freeze-dried nanoparticles displaying hydrophobic (PIBCA) or hydrophilic (PCL-PEG and CNP) surfaces.

Structural characterization of ultrasmall superparamagnetic iron oxide (USPIO) particles in aqueous suspension by energy dispersive X-ray diffraction (EDXD).

Ultrasmall superparamagnetic iron oxide (USPIO) particles were structurally characterized in situ in an aqueous dilute suspension by energy dispersive X-ray diffraction (EDXD) and ex situ as powders obtained by lyophilization of the suspension by angular dispersive X-ray diffraction (ADXD) at 20 degrees C. Structural parameters obtained by the Rietveld method on ADXD data were used as starting parameters for modeling the structure of the particles in suspension. Although each particle is a single crystal, as evidenced by conventional X-ray diffraction, our results indicate that the structural order, specific to a crystal, does not extend to the entire volume of the particle.

Protein driven patterning of self-assembled cubosomic nanostructures: long oriented nanoridges.

Self-assembly lipid/protein cubosomic nanostructures are generated at high hydration level (dispersion of 5% lipid only) and examined by freeze-fracture electron microscopy (FF-EM) and synchrotron X-ray diffraction (XRD). The fracture surface of the three-dimensional (3D) soft-matter membranous assembly reveals starlike nanopatterns of oriented 100-nm-long cubosomic nanoridges with lateral periodicity defined by their 21-nm diameters. The average water channel radius in these liquid crystalline cubosomic nanoarchitectures, determined by high-resolution FF-EM and XRD, is 18.

Nanotechnology: intelligent design to treat complex disease.

The purpose of this expert review is to discuss the impact of nanotechnology in the treatment of the major health threats including cancer, infections, metabolic diseases, autoimmune diseases, and inflammations. Indeed, during the past 30 years, the explosive growth of nanotechnology has burst into challenging innovations in pharmacology, the main input being the ability to perform temporal and spatial site-specific delivery. This has led to some marketed compounds through the last decade.

Antisense oligonucleotide nanocapsules efficiently inhibit EWS-Fli1 expression in a Ewing's sarcoma model.

The cytogenetic abnormality of Ewing's sarcoma is related to the presence of a balanced t(11;22) translocation expressing the EWS-Fli1 chimeric fusion protein. Oligonucleotides (ODNs) are specific compounds that inhibit gene expression at the transcriptional level. They possess a poor bioavailability and are degraded by nucleases very rapidly.

Efficacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma.

The EWS-Fli1 fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS-Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target.

Detailed structure of diamond-type lipid cubic nanoparticles.

Supramolecular three-dimensional self-assembly of nonlamellar lipids with fragments of the protein immunoglobulin results in a bicontinuous cubic phase fragmented into nanoparticles with open water channels (cubosomes). The structure of the diamond-type cubic nanoparticles is characterized experimentally by freeze-fracture electron microscopy, and it is mathematically modeled with nodal surfaces emphasizing the fluid-like undulations of the cubosomic interfaces. Based on scaling-up and scaling-down approaches, we present stable and intermediate-kind nanoparticles resulting from the cubosomic growth.

New self-assembled nanogels based on host-guest interactions: characterization and drug loading.

We show here, for the first time, that two neutral polymers may completely associate together in water to spontaneously form supramolecular nanoassemblies (nanogels) of spherical shape. The cohesion of these stable structures of about 200 nm is based upon a "lock and key" mechanism: inclusion complexes are formed between the hydrophobic alkyl chains grafted on a polysaccharide (dextran) and the molecular cavities contained in a poly-cyclodextrin polymer. Production yields reached 95%.

Novel composite core-shell nanoparticles as busulfan carriers.

This study presents a method for the design of novel composite core-shell nanoparticles able to encapsulate busulfan, a crystalline drug. They were obtained by co-precipitation of mixtures of poly(isobutylcyanoacrylate) (PIBCA) and of a diblock copolymer, poly(epsilon-caprolactone)-poly(ethylene glycol) (PCL-PEG), in different mass ratios. The nanoparticle size, morphology and surface charge were assessed.

In vivo potentialities of EWS-Fli-1 targeted antisense oligonucleotides-nanospheres complexes.

The EWS/FLI-1 fusion gene, resulting from a t(11;22) translocation, plays a key role in the pathogenesis of Ewing sarcoma. Previously, we have shown that antisense oligonucleotides designed against EWS-Fli-1 inhibited tumor growth in nude mice provided they were delivered intratumorally by nanocapsules or by CTAB-coated nanospheres. In this study, we have used two types of nanospheres (designated as type 1 and type 2 nanospheres) stabilized with chitosan for both intratumoral and systemic administration of oligonucleotides.

Sustained delivery of growth factors from methylidene malonate 2.1.2-based polymers.

The incorporation of growth factors into new methylidene malonate 2.1.2-based biocompatible polymeric blends of oligomers and polymers to improve their stability and controlled release was investigated.

Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26.

The inhibition of the caspase-3 enzyme is reported to increase neuronal cell survival following cerebral ischemia. The peptide Z-DEVD-FMK is a specific caspase inhibitor, which significantly reduces vulnerability to the neuronal cell death. However, this molecule is unable to cross the blood-brain barrier (BBB) and to diffuse into the brain tissue.

Folate-conjugated iron oxide nanoparticles for solid tumor targeting as potential specific magnetic hyperthermia mediators: synthesis, physicochemical characterization, and in vitro experiments.

New folate-conjugated superparamagnetic maghemite nanoparticles have been synthesized for the intracellular hyperthermia treatment of solid tumors. These ultradispersed nanosystems have been characterized for their physicochemical properties and tumor cell targeting ability, facilitated by surface modification with folic acid. Preliminary experiments of nanoparticles heating under the influence of an alternating magnetic field at 108 kHz have been also performed.

Physico-chemical characterization of polysaccharide-coated nanoparticles.

A series of amphiphilic copolymers (PCL-DEX) made of poly(epsilon-caprolactone) (PCL) side chains grafted onto a dextran (DEX) backbone, was used to modify the surface of PCL nanoparticles. PCL-DEX nanoparticles were prepared by a technique derived from emulsion-solvent evaporation. The purpose of the present study was to investigate the DEX coating (quantification, conformation, mobility) in order to better understand particle surface-protein interactions.

Influence of polysaccharide coating on the interactions of nanoparticles with biological systems.

Since dextran (DEX) grafted with poly(epsilon-caprolacton) (PCL) side chains (PCL-DEX) copolymers could form nanoparticles with a well defined core-shell structure, we investigated the ability of the DEX coating to modify the interactions with the biological media. We first studied the influence of the DEX coating on the phagocytosis of the nanoparticles by human TPH-1 and J774 murine macrophage-like cell lines. Then, the activation of the complement system (CH50 measurement) at the surface of the particles and the adsorption of plasma proteins (2D-PAGE) were investigated, too.

Metallic colloid nanotechnology, applications in diagnosis and therapeutics.

In recent years the fields of medicine and biology assist to an ever-growing innovation related to the development of nanotechnologies. In the pharmaceutical domain, for example, liposomes, polymer based micro and nanoparticles have been subjects of intense research and development during the last three decades. In this scenario metallic particles, which use was already suggested in the first half of the '80, are now experiencing a real renaissance.

Cellular fate of oligonucleotides when delivered by nanocapsules of poly(isobutylcyanoacrylate).

Dual-labeled phosphorothioate oligonucleotides were encapsulated in the internal aqueous core of poly(isobutylcyanoacrylate) nanocapsules with high yields. Intracellular distribution of naked and encapsulated oligomers was assessed on cultured vascular smooth muscle cells using cell fractionation and confocal microscopy methods. The results showed that cell uptake and more interestingly, nuclear accumulation of oligonucleotides were importantly enhanced when the oligonucleotides were associated to the nanocapsules as compared to the naked oligomers.

A methodology to study intracellular distribution of nanoparticles in brain endothelial cells.

Cell internalisation and intracellular distribution of PEG-coated polyhexadecylcyanoacrylate (PEG-PHDCA) nanoparticles in rat brain endothelial cells (RBEC) have been investigated. A cell fractionation method has been developed based on the selective permeabilisation of RBEC plasma membrane by digitonin. By interacting with membrane cholesterol, digitonin creates pores allowing the release of soluble and diffusible species outside the cell.

Phospholipid hydrolysis in a pharmaceutical emulsion assessed by physicochemical parameters and a new analytical method.

The aim of this work was to develop a simple high-performance liquid chromatography (HPLC) technique with evaporative light scattering detection (ELSD) for the separation and quantification of the major phospholipid (PL) and lysophospholipid (LPL) classes contained in a pharmaceutical phospholipid-based emulsion. In the established method, phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyeline (SM), lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) were separated with a PVA-Sil stationary phase and a binary gradient from pure chloroform to methanol:water (94:6 v/v) at 3.4%/min.

A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles.

Poly(MePEG2000cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1.

Nanoencapsulation of a crystalline drug.

The aim of this work was to assess the influence of various formulation parameters on the incorporation of a poorly water-soluble crystalline drug into nanoparticles. For this purpose, the influence of the polymer (polylactic acid, polysebacic acid terminated with lithocholic acid, and polysebacic acid-co-lithocholic acid) as well as the effect of the dispersion medium (aqueous phases at different temperatures, saline medium and ethanol) on the encapsulation was investigated. 3H-labelled drug was used in order to determine the loading efficiency by liquid scintillation counting.

Colloidal carriers and blood-brain barrier (BBB) translocation: a way to deliver drugs to the brain?

The major problem in drug delivery to the brain is the presence of the blood-brain barrier (BBB) which limits drug penetration even if in certain pathological situations the BBB is partly disrupted. Therefore, various strategies have been proposed to improve the delivery of drugs to this tissue. This review presents the status of the BBB in healthy patients and in pathologies like neurodegenerative, cerebrovascular and inflammatory diseases.

Preparation and in vitro evaluation of chitosan nanoparticles containing a caspase inhibitor.

The aim of this work was to develop a formulation for Z-DEVD-FMK, a peptide which is a caspase inhibitor and has been used in experimental animal studies for a decade. Peptide loaded chitosan nanoparticles were obtained by ionotropic gelation process and Z-DEVD-FMK was quantified by an HPLC method. The influence of the initial peptide concentration on the nanoparticle characteristics and release behavior was evaluated.