Synthesis and supramolecular assemblies of bipolar archaeal glycolipid analogues containing a cis-1,3-disubstituted cyclopentane ring

Unsymmetrical archaeal tetraether glycolipid analogues 1-2 incorporating a 1,3-disubstituted cyclopentane ring into the bridging chain have been synthesized. The cyclopentane has been introduced with a totally controlled cis configuration, either into the middle of the aliphatic chain or at three methylene groups from the glycerol unit linked to the bulkier disaccharide residue. Freeze-fracture and cryotransmission electron microscopy experiments clearly demonstrated unprecedented glycolipid supramolecular organizations involving two-by-two monolayer associations coupled with interconnection and fusion phenomena. Furthermore, a significant difference in the hydration properties and in the lyotropic liquid crystalline behavior of bipolar lipids 1-2 was found depending on the position of the cyclopentane residue.     

Scleroglucan: a versatile polysaccharide for modified drug delivery

Scleroglucan is a natural polysaccharide, produced by fungi of the genus Sclerotium, that has been extensively studied for various commercial applications (secondary oil recovery, ceramic glazes, food, paints, etc.) and also shows several interesting pharmacological properties. This review focuses its attention on the use of scleroglucan, and some derivatives, in the field of pharmaceutics and in particular for the formulation of modified-release dosage forms. The reported investigations refer mainly to the following topics: natural scleroglucan suitable for the preparation of sustained release tablets and ocular formulations; oxidized and crosslinked scleroglucan used as a matrix for dosage forms sensitive to environmental conditions; co-crosslinked scleroglucan/gellan whose delivery rate can be affected by calcium ions. Furthermore, a novel hydrogel obtained with this polysaccharide and borate ions is described, and the particular structure of this hydrogel network has been interpreted in terms of conformational analysis and molecular dynamics. Profound attention is devoted to the mechanisms involved in drug release from the tested dosage forms that depend, according to the specific preparation, on swelling and/or diffusion. Experimental data are also discussed on the basis of a mathematical approach that allows a better understanding of the behavior of the tested polymeric materials.     

Principles of electrostatic interactions and self-assembly in lipid/peptide/DNA systems: Applications to gene delivery

Recently, great progress has been achieved in development of a wide variety of formulations for gene delivery in vitro and in vivo, which include lipids, peptides and DNA (LPD). Additionally, application of natural histone–DNA complexes (chromatin) in combination with transfection lipids has been suggested as a potential route for gene delivery (chromofection). However, the thermodynamic mechanisms responsible for formation of the ternary lipid–peptide–DNA supramolecular structures have rarely been analyzed. Using recent experimental studies on LPD complexes (including mixtures of chromatin with cationic lipids) and general polyelectrolyte theory, we review and analyze the major determinants defining the internal structure, particle composition and size, surface charge and ultimately, transfection properties of the LPD formulations.     

Structural properties of solid lipid based colloidal drug delivery systems

For about 20 years nanoparticles based on solid lipids have been under investigation as drug carrier systems. They can be prepared from a broad variety of lipid matrix materials including glycerides, fatty acids and waxes and are stabilized by physiologically compatible surfactants. Although the matrix lipids principally retain their material properties when dispersed into the colloidal state there are various peculiarities that have to be observed when dealing with such systems. In particular, the crystallization behavior and the polymorphic transitions are altered in the nanoparticulate systems. These properties as well as the particle shape and structure may be affected by the type of surfactants used for stabilization. Also incorporated drugs can modify the structural characteristics of the nanoparticles. Interactions between the individual particles may lead to alterations of the macroscopic behavior of the dispersions, especially of their rheological properties. Such structural parameters can influence the drug carrier properties of the dispersions.     

Archaeosomes based on synthetic tetraether-like lipids as novel versatile gene delivery systems

Novel cationic liposomes, termed "archaeosomes", based on mixtures of neutral/cationic bilayer-forming lipids and archaeobacterial synthetic tetraether-type bipolar lipids show efficient in vitro gene transfection properties and represent a new approach for modulating the lipidic membrane fluidity of the complexes they form with DNA.     

Regioselective synthesis of folic acid conjugates from diether-type archaeal lipid analogues

A regioselective access to both α- and γ-folic acid conjugates derived from archaeal lipid analogues is described. The synthetic approach is based on conveniently protected glutamates that led first to α- and γ-glutamate derivatives. The final reconstruction of the folic acid moiety was achieved through the reaction of a protected/activated pteroate followed by a simple deprotection step. These α- and γ-folic acid conjugates would permit to establish the importance of a regiocontrolled introduction of folic acid on the folic acid/folate receptor interaction in the case of a targeted drug/gene delivery.     

Physicochemical properties of structured phosphatidylcholine in drug carrier lipid emulsions for drug delivery systems

Drug carrier emulsions were prepared with structured phosphatidylcholine (PC-LM) which has both a long hydrocarbon chain and a medium hydrocarbon chain, and the characteristics of PC-LM as an emulsifier were investigated by measuring the creaming ratio, the surface tension of the emulsion system, and the mean particle size and zeta potential of the oil droplets in emulsions. The emulsion prepared with PC-LM as an emulsifier kept the condition and the ratio of separation was lower than those with purified egg yolk lecithin (PEL). The mean particle size of the emulsion prepared with PC-LM was smaller than that with PEL when using only sonication, approximately 250 nm. When using a high-pressure homogenizer after sonication, the mean emulsion size with PC-LM was also smaller than with PEL, approximately 150 nm. The surface tension of the various emulsions and the zeta potential of the emulsion droplets were measured to investigate the stability of the systems. In emulsions with PC-LM or PEL, the surface tension as an index of stability increased as the pressure of the homogenizer increased. Moreover, the zeta potential of the emulsion droplets prepared with PC-LM also increased with an increase in pressure of the homogenizer. As a result, it was found that the drug carrier emulsion prepared with PC-LM had significant advantages in terms of stability and mean diameter. We considered it could be used for the preparations of nanoparticle dispersion systems in drug delivery systems.     

Archaeabacteria bipolar lipid analogues: structure, synthesis and lyotropic properties

Over the past several years, various archaeal symmetrical/unsymmetrical and acyclic/macrocyclic bipolar lipid analogues have been synthesized to study, from well-defined molecules, the membrane organizing and packing properties of this new class of amphiphiles. This review focuses on the structure and the synthesis of selected bolaamphiphiles and describes their supramolecular self-assembling properties in aqueous media.     

Lipid carrier systems for targeted drug and gene delivery

For effective chemotherapy, it is necessary to deliver therapeutic agents selectively to their target sites, since most drugs are associated with both beneficial effects and side effects. The use of lipid dispersion carrier systems, such as lipid emulsions and liposomes, as carriers of lipophilic drugs has attracted particular interest. A drug delivery system can be defined as a methodology for manipulating drug distribution in the body. Since drug distribution depends on the carrier, administration route, particle size of the carrier, lipid composition of the carrier, electric charge of the carrier and ligand density of the targeting carrier, these factors must be optimized. Recently, the lipid carrier system has also been applied to gene delivery systems for gene therapy. However, in both drug and gene medicine cases, a lack of cell-selectivity limits the wide application of this kind of drug and/or gene therapy. Therefore, lipid carrier systems for targeted drug and gene delivery must be developed for the rational therapy. In this review, we shall focus on the progress of research into lipid carrier systems for drug and gene delivery following systemic or local injection.     

Chemical conjugation with cyclodextrins as a versatile tool for drug delivery

A pillar[5]arene-based N-heterocyclic carbene ligand was prepared by reaction of bromoethoxy pillar[5]arene with excess 1-methylimidazole at 130 °C in the absence of solvent and used as a catalyst for the Suzuki coupling reaction. Excellent yields were obtained when the Suzuki reactions were carried out under ambient atmosphere in ethanol, employing 0.2 mol% ligand, 1 mol% PdCl₂(CH₃CN)₂ and 1.5 mmol of K₂CO₃. The novel pillar[5]arene-based imidazolium salt is a promising material for the construction of highly active supramolecular catalytic systems.     

Two sides to supramolecular drug delivery systems

Although still in its infancy, there is a rapidly increasing interest in the development of supramolecular drug delivery systems (SDDSs). As chemists, the most challenging task ahead of us is to narrow the gap between SDDSs development in the lab, and clinical drug carriers. Only then will we achieve our ultimate goal of the successful translation of SDDSs to life saving medicines.     

Synthesis of degradable functional poly(ethylene glycol) analogs as versatile drug delivery carriers

Poly(ethylene glycol) (PEG) is widely used as a water soluble carrier for polymer-drug conjugates. Herein, we report degradable linear PEG analogs (DPEGs) carrying multifunctional groups. The DPEGs were synthesized by a Michael addition based condensation polymerization of dithiols and PEG diacrylates (PEGDA) or dimethacrylates (PEGDMA). They were stable at pH 7.4 but quickly degraded at pH 6.0 and 5.0. Thus, DPEGs could be used as drug carriers without concern for their retention in the body. DPEGs could be made to carry such functional groups as terminal thiol or (meth)acrylate and pendant hydroxyl groups. The functional groups were used for conjugation of drugs and targeting groups. This new type of PEG analog will be useful for drug delivery and the PEGylation of biomolecules and colloidal particles.     

Stereochemical effect revealed in self-assemblies based on archaeal lipid analogues bearing a central five-membered carbocycle: a SAXS study

The relative stereochemistry (cis or trans) of a 1,3-disubstituted cyclopentane unit in the middle of tetraether archaeal bipolar lipid analogues was found to have a dramatic influence on their supramolecular self-assembly properties. SAXS studies of two synthetic diastereomeric archaeal lipids bearing two lactosyl polar head groups at opposite ends revealed different lyotropic behaviors. The cis isomer led to L(c)-L(α)-Q(II) transitions whereas the trans isomer retained an L(α) phase from 20 to 100 °C. These main differences originate from the conformational equilibrium (pseudorotation) of 1,3-disubstituted cyclopentanes. Indeed, this pseudorotation exhibits quite similar orientations of the two substituents in a trans isomer whereas several orientations of the two alkyl chains are expected in a cis-1,3-dialkyl cyclopentane, thus authorizing more conformational flexibility in the lipid packing.     

Synthesis of PHB-based carrier for drug delivery systems with pH-controlled release

Synthetic route to prepare model PHB-amine conjugate containing hydrolysable imine bond is reported. Short-chain PHB crotonate is converted into PHB glyoxylate via clean and efficient ozonolysis followed by reductive decomposition of peroxidic products with dimethylsulfide. Aldehyde-functionalized PHB is obtained quantitatively without polymer backbone degradation while PHB-amine conjugate is synthesized with very high yield. Release properties of such-prepared conjugate is confirmed in hydrolysis experiment revealing pH-dependent kinetics of amine release. Simplicity of the protocol in conjunction with unique properties of PHB carrier are believed to be powerful tool for development of novel drug conjugates.     

Mini-emulsion solvent evaporation: a simple and versatile way to magnetic nanosensors

Magnetic optical sensor particles were prepared using a mini-emulsion solvent evaporation (MESE) technique. The resulting nanoparticles (NPs) have diameters around 100?nm and relatively narrow size distribution (PDI < 0.2). Incorporation of probes for oxygen or pH resulted in magnetic sensor particles for bioprocess monitoring and imaging applications. The MESE technique yields sensing NPs in higher quantities than obtained by a previously reported nanoprecipitation method, and the size of the NPs is smaller than that of particles made by spray-drying of sensor cocktails. Moreover, the technique is flexible in terms of polymers, solvents and indicators used in that it may be applied??at least in principle??to numerous combinations of two-phase systems.     

A versatile liposome/cyclodextrin supramolecular carrier for drug delivery through the blood-brain barrier

For many commercial drugs, reaching the central nervous system in large amount without damaging the blood-brain-barrier (BBB) remains a challenging task. We present here a supramolecular strategy aiming at using a well-defined cyclodextrin-coated liposomes as drug carrier and adamantoyl saccharides as BBB-interacting ligands. In this study, the liposome is constituted of n-alkyldimethylammoniumcyclodextrins incorporated in the lipid bilayer of a 3/7 cholesterol/dipalmitoylphosphatidylcholine mixture and the ligand is constituted of an adamantoylglucose molecule whose adamantoyl moiety can be included in the CD cavity. The whole supramolecular assembly has been characterized by light-scattering and ³¹P NMR measurements. Toxicity and permeability studies on an in vitro model of the BBB clearly demonstrated a 5-fold improved ability of the modified liposome to enter the BBB-endothelial cells compared to the non-coated liposome. Fluorescence labelling of these liposomes is also displayed with DiI as a fluorescent probe.     

L-cysteine, a versatile source of sulfenic acids. Synthesis of enantiopure alliin analogues

[reaction: see text] l-Cysteine is a stimulating starting product for the generation of transient sulfenic acids, such as 4, 6, 9, and 15, which add to suitable acceptors, allowing formation of sulfoxides showing a biologically active residue. These sulfoxides are easily isolated in enantiomerically pure form. For instance, N-(tert-butoxycarbonyl)-l-cysteine methyl ester (1a) furnished in few steps sulfenic acid 9a, which was readily converted into (R,S(S))-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)ethene (22), the methyl ester of Boc-protected nor-alliin. Moreover, the addition of 9a to 2-methyl-1-buten-3-yne has led to a sulfur epimeric and separable mixture of (R)-2-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)-3-methyl-buta-1,3-dienes 10a and 11a, still possessing a "masked" sulfenic acid function, producible from their cysteine moieties once the dienes have been converted into the desired derivatives.     

The effects of irradiation on controlled drug delivery/controlled drug release systems

The research of radiation effects on drugs over the past 60 years has mainly dealt with radiation sterilization of individual active pharmaceutical ingredients (APIs) in the form of pure substances or injectable solutions. However, the emergence of novel systems for drug administration and targeting via controlled drug delivery (CDD) and/or controlled drug release (CDR) has extended the use of irradiation with respect to pharmaceuticals: the capacity of radiation to act as an initiator of crosslinking has been used in the manufacturing and modification of a number of polymeric carriers with an added advantage of reducing the microbial load of products at the same time. The application of irradiation to these novel systems requires the understanding of radiation action not only on APIs alone but also on drug carriers and on the functioning of the integral CDD/CDR systems. In this paper, the significance of CDD/CDR systems is considered with a special emphasis on the role of irradiation for sterilization and crosslinking in the developments over the past 15 years. Radiation sterilization, crosslinking and degradation of the principal forms of drug carrier systems and the effects of irradiation on the release kinetics of APIs are discussed in light of radiation chemical principles. Regulatory aspects pertaining to radiation sterilization of drugs are also considered. Relevant results are summarized in tabular form.     

Synthesis of neoglycolipids for the development of non-viral gene delivery systems

Synthesis of lipid conjugates with galactose as a targeting ligand intended for the development of non-viral systems for the targeted delivery of nucleic acids into hepatocytes is described. 3,4-Diethoxycyclobut-3-ene-1,2-dione (diethyl squarate) was used to bind the galactose moiety to the lipid component.