Low-toxicity metallosomes for biomedical applications by self-assembly of organometallic metallosurfactants and phospholipids

Abstract

A new and convenient strategy for the preparation of metallosomes has been developed by mixing organometallic metallosurfactants and phospholipids. These aggregates show the characteristic properties of liposomes (stability upon dilution and low toxicity) and the toxicity is at least ten-fold lower than that of the metallosurfactant aggregates without phospholipids.The preparation and study of nanomaterials by self-assembly in aqueous medium is an increasingly relevant topic. Supramolecular structures for a wide range of applications can be obtained from simple molecules, which can be easily modified to modulate the properties of the aggregates in order to yield new materials with designed properties. Surfactants that contain a metal atom in the molecular structure are named metallosurfactants (MTSs) and they are attractive molecules due to the fact that they can lead to characteristic supramolecular aggregates (micelles, vesicles, etc.), and simultaneously they contain metallic atoms. The presence of the metal makes it possible to use these aggregates in a broad range of applications such as catalysis, optoelectronics, and biomedicine.1 Although in most of the reported MTS the metallic atom is located in the polar group of the molecule, we have recently reported organometallic MTSs wherein the metallic fragment is embedded in the hydrophobic part of the molecule. 2These MTSs render mostly unilamellar vesicles in water if the MTS concentration is higher than the critical value. However, dilution of these suspensions leads to disaggregation of the vesicles, which is a drawback of using them in in vivo applications. To circumvent this disadvantage we considered the possibility of obtaining mixed systems with phospholipids. In particular, we used soybean phosphatidylcholine (SPC), a natural non-toxic phospholipid that is known to form the so-called liposomes, that is, dilution-stable closed vesicles with entrapped water (Scheme 1), and which are used for several medical applications. 3 Our hypothesis is that mixed systems of MTS and phospholipids (Scheme 1) could lead to new supramolecular aggregates with a higher biocompatibility and with useful properties for biomedical applications. Since these new systems contain metallic atoms in the liposome membrane, they can be classified as a new kind of metallosome. 4 In this article, we report the study of the viability of the preparation of metallosomes by mixing SPC with two organometallic MTSs, the molybdenum pentacarbonyl Mo(CO) 5 L (PCO) or the molybdenum tetracarbonyl complex Mo(CO) 4 L 2 (TCO) (L = Ph 2 PCH 2 CH 2 SO 3 Na). It is known that the liposome membrane allows the inclusion of a wide variety of lipophilic or amphipathic substances such as, drugs and proteins. Thus, the incorporation of a bilayer-forming metallosurfactant into a phospholipid bilayer was considered to be a rational choice. The simplest procedure to obtain mixed vesicles involves the Scheme 1 Representation of vesicles obtained with a pure phospholipid or with a metallosurfactant, and when...

Metallosomes for biomedical applications by mixing molybdenum carbonyl metallosurfactants and phospholipids

“…It is apparent that despite the difference in the length and shape between both MTS and SPC, hydration of binary films allows the spontaneous formation of mixed aggregates. This fact parallels the behaviour of the mixtures of PCOL2 and TCOL2 with SPC, which also form aggregates, 17 even though the length of their hydrocarbon chains (2 methylene groups) is one-third those of PCOL6 and TCOL6. Thus, the known capacity of phospholipid fatty acid chains for filling (by rotation) the gaps generated inside the bilayers caused by the inclusion of short and bulky molecules should explain the formation of mixed vesicles.…”

“…Previous studies carried out with MTSs with shorter chains (2 carbon atoms, i.e., TCOL2 and PCOL2) demonstrated that they are stable in the dark, and that UVA and visible irradiations trigger CO release as gas. 17 This capability shows that, in fact, these molecules are photoCORMs, and that their different mixed aggregated structures can be used as drug (CO) delivery systems with potential biomedical applications.…”

“…8) that, from a general point of view, the pentacarbonyl complex is more toxic than the tetracarbonyl complex, as was in the case of the complexes of the L2 family. 17 When cell cultures were incubated with pure MTSs, the LC 50 values were 148 ± 44 μM and 53 ± 0.03 μM for TCOL6 and PCOL6, respectively (calculated using the sigmoidal Hill equation). As regards the mixed TCOL6 systems, the most toxic aggregates were the TCOL6/SPC rods, with an LC 50 value of 234 ± 14 μM.…”

“…In order to improve the properties of these supramolecular systems for biomedical applications, we undertook the study of mixed systems of MTSs and phospholipids. In a recent communication 17 we showed that, in contrast to the aggregates formed by pure MTSs, mixed systems of MTSs and phospholipids lead to vesicular aggregates, very similar to liposomes, which are stable under dilution. These new systems can be named metallosomes, because they are vesicles with entrapped water, and their membrane is analogous to the classical lipid bilayer (Scheme 2).…”

Direct Synthesis of Rhenium and Technetium-99m Metallosurfactants by a Transmetallation Reaction of Lipophilic Groups: Potential Applications in the Radiolabeling of Liposomes

“…On the other hand, we have chosen sodium triphenylphosphine trisulfonate (TPPTS) as a polar monodentate ligand. The bonding of both ligands [bidentate palmitoyl derivative (PD) and monodentate TPPTS] to a metal, as shown in Scheme , should lead to an amphiphilic complex (metallosurfactant), − which is a potential candidate to be incorporated into the liposome bilayer. , Part of this work was previously presented as a poster…”