Muriel Blanzat

Drug Delivery by Soft Matter: Matrix and Vesicular Carriers

The increasing need for drug delivery systems that improve specificity and activity and at the same time reduce toxicity to ensure maximum treatment safety has led to the development of a great variety of drug vectors. Carriers based on soft matter have particularly interesting characteristics. Herein we present the current standing of the research in this area, and focus on two main families, namely matrix systems and vesicles. We outline the structure, properties, and potential applications of these vectors, and discuss their main advantages and drawbacks in their synthesis.

Dendritic Catanionic Assemblies: In vitro Anti‐HIV Activity of Phosphorus‐Containing Dendrimers Bearing Galβ1cer Analogues

Two series of water‐soluble dendritic catanionic assemblies, acting as multisite analogues of galactosylceramide (Galβ1cer), have been prepared with the goal of blocking HIV infection prior to the entry of the virus into human cells. Trifunctional and hexafunctional cinnamic acid‐terminated dendrimers have been synthesized from phosphorus‐containing dendrimers bearing aldehyde end groups. A classical acid–base reaction performed in water between acid‐terminated dendrimers and stoichiometric amounts of N‐hexadecylamino‐1‐deoxylactitol (3) provided the expected catanionic assemblies. Antiviral assays on these supramolecular entities confirmed the crucial roles both of multivalency effects and of lipophilicity on the biological activity of Galβ1cer analogues. Moreover, correlation between in vitro tests and molecular modeling highlights the specific influence of the assembly shape on the anti‐HIV efficiency, with the tri‐ and hexafunctional cored dendrimers, both decorated with 12 sugar moieties, exhibiting IC50 values of 1.1 and 0.12 μM, respectively.

Sugar-Derived Tricatenar Catanionic Surfactant: Synthesis, Self-Assembly Properties, and Hydrophilic Probe Encapsulation by Vesicles

A new sugar-derived tricatenar catanionic surfactant (TriCat) was developed to obtain stable vesicles that could be exploited for drug encapsulation. The presence of the sugar moiety led to the formation of highly hydrophilic stoichiometric catanionic surfactant systems. The three hydrophobic chains permitted vesicles to form spontaneously. The self-assembly properties (morphology, size, and stability) of TriCat were examined in water and in buffer solution. Encapsulation studies of a hydrophilic probe, arbutin, commonly used in cosmetics for its whitening properties, were performed to check the impermeability of the vesicle bilayer. The enhancement of hydrophobic forces by the three chains of TriCat prevented surfactant equilibrium between the bilayer and the solution and enabled the probe to be retained in the aqueous cavity of the vesicles for at least 30 h. Thus, the present study suggests that this tricatenar catanionic surfactant could be a promising delivery system for hydrophilic drugs.

Polyvalent catanionic vesicles: Exploring the drug delivery mechanisms

Among drug delivery systems, catanionic vesicles now appear as powerful candidates for pharmaceutical applications because they are relatively cheap and easy to use, thus well corresponding to industrial requirements. Using labelled vesicles made of a tricatenar catanionic surfactant, the work reported here aims at exploring the mechanisms by which internalisation into a cell occurs. The study was performed on various cell types such as phagocytic as well as non-phagocytic cells using confocal laser scanning microscopy and flow cytometry. Using various inhibitors, endocytosis and also a passive process, as probably fusion, were highlighted as interaction phenomena between catanionic vesicles and cell membranes. Finally, the interaction modelled with giant liposomes as membrane models confirmed the hypothesis of the occurrence of a fusion phenomenon between the nanovectors and cell membranes. This process highlights the potential of catanionic vesicles for a future pharmaceutical application as a universal drug delivery system.

Sugar-derived tricatenar catanionic surfactant: self-assembly and aggregation behavior in the cationic-rich side of the system.

The aggregation behavior of the cationic-rich side of a sugar-based tricatenar catanionic mixture was investigated in water, and it was shown that the excess of cationic sugar-based surfactant enhanced vesicle stability as well as encapsulation properties. Moreover, when the system was diluted, the vesicular solution collapsed into a lamellar phase, whereas, when it was concentrated, no major impact on the shape and stability of the aggregates was observed. We also showed that both an increase in temperature and the addition of salt induced reversible vesicle aggregation, which appeared to be salt-specific, following the direct order of the Hofmeister series. A proper adjustment of these parameters should then enable better control of the shape, stability, and even encapsulation ability of the aggregates formed by these tricatenar cationic/anionic mixtures.

Synthesis and anti-HIV activity of catanionic analogs of galactosylceramide

Two-chain and gemini catanionic analogs of galactosylceramide were easily prepared in quantitative yields, affording high anti-HIV activities with low cytotoxicities on human cells (e.g. for gemini 4b an EC50 of 0.5 µM with a CC50 of >100 µM were obtained).

Versatile cellular uptake mediated by catanionic vesicles: simultaneous spontaneous membrane fusion and endocytosis.

Lactose-derived catanionic vesicles offer unique opportunities to overcome cellular barriers. These potential nanovectors, very easy to formulate as drug delivery systems, are able to encapsulate drugs of various hydrophilicity. This article highlights versatile interaction mechanisms between these catanionic vesicles, labeled with hydrophilic and amphiphilic fluorescent probes, and a mammalian cell line, Chinese Hamster Ovary. Confocal microscopy and flow cytometry techniques show that these vesicles are internalized by cells through cellular energy dependent processes, as endocytosis, but are simultaneously able to spontaneously fuse with cell plasma membranes and release their hydrophilic content directly inside the cytosol. Such innovative and polyvalent nanovectors, able to deliver their content via different internalization pathways, would positively be a great progress for the coadministration of drugs of complementary efficiency.

New Rebek imide-type receptors for adenine featuring acetylene-linked π-stacking platforms

Rebek imide-type molecular clefts with pi-stacking platforms attached to the imide scaffold by an acetylene linker have been prepared by Sonogashira cross-coupling. In the solid state, a novel dimerisation mode for this class of imide receptors was found by crystal structure analysis, whereas efficient 1 : 1 complexation with 9-ethyladenine was observed in CDCl3 solution.

Gelled oil particles: A new approach to encapsulate a hydrophobic metallophthalocyanine

Chloroaluminum phthalocyanine (ClAlPc) is a promising sensitizer molecule for photodynamic therapy, but its hydrophobicity makes it difficult to formulate. In this study, we have efficiently encapsulated ClAlPc into gelled soybean oil particles dispersed in water. 12-Hydroxystearic acid (HSA) and polyethyleneimine (PEI) were the gelling and stabilizing agents, respectively. The preparation process involved hot emulsification above the gelation temperature (Tgel), followed by cooling to room temperature, which gave a colloidal dispersion of gelled particles of oil in aqueous medium. The gelled particles containing ClAlPc had a medium diameter of 280 nm, homogeneous size distribution (polydispersity index ≈0.3) and large positive zeta potential (about +50 mV) and showed a spherical morphology. The gelled oil particle formulations exhibited good physical stability over a 6-month period. ClAlPc interfered with the HSA self-assembly only slightly, and decreased the gelation temperature to a small extent; however it did not affect gelation process of the oil droplets. The amounts of PEI and HSA employed during the preparation allowed us to control particle size and the dispersion stability, a phenomenon that results from complex electrostatic interactions between the positively charged PEI and the negatively charged HSA fibers present on the gelled particles surface. In summary, by using the right ClAlPc, HSA, and PEI proportions, we prepared very stable dispersions of gelled soybean oil particles with excellent ClAlPc encapsulation efficiency. The obtained colloidal formulation of gelled oil particles loaded with ClAlPc shall be very useful for photodynamic therapy protocols.

Catanionic vesicles charged with chloroaluminium phthalocyanine for topical photodynamic therapy. In vitro phototoxicity towards human carcinoma and melanoma cell lines

The hydrophobic character of chloroaluminium phthalocyanine (ClAlPc) and its tendency to dimerize in aqueous media reduces its topical penetration as well as its photodynamic efficacy. Lactose-derived catanionic vesicles, spontaneously obtained by mixing oppositely charged surfactants, are proposed as an alternative to other drug delivery systems to tackle this difficulty. Spectrofluorimetry studies confirmed the good loading capacity of the catanionic vesicles. Dynamic light scattering experiments, in various physiological media, were carried out to evaluate the stability of the ClAlPc-loaded system. In vitro phototoxicity studies performed on both human carcinoma and melanoma cell lines with increased light doses that are commonly used in clinical trials, look promising for the success of photodynamic therapy using ClAlPc-loaded catanionic vesicles.