Constantinos M. Paleos

Hydroxyethyl starch (HES) was interacted with succinic anhydride affording a carboxylated derivative which has proved to be a promising polymeric drug delivery system. Specifically, this polymer is conveniently prepared, is biodegradable, non‐immunogenic, and can encapsulate doxorubicin due to the protonation of the primary amino group of doxorubicin by the carboxylic group located on the branched scaffold of the polysaccharide. In addition, due to the polyhydroxylated character of the polysaccharide, the latter can act as a protective coating in an analogous manner to thePEG‐chains ensuring prolonged circulationin vivo.In vitroexperiments showed controlled release of doxorubicin to the nuclei ofDU145 prostate cancer cells when the anticancer drug is incorporated in the carboxylated hydroxyethyl starch.

Researchers have become increasingly interested in the preparation and characterization of artificial cells based on amphiphilic molecules. In particular, artificial cells with multiple compartments are primitive mimics of the structure of eukaryotic cells. Endosymbiotic theory, widely accepted among biologists, states that eukaryotic cells arose from the assembly of prokaryotic cells inside other cells. Therefore, replicating this process in a synthetic system could allow researchers to model molecular and supramolecular processes that occur in living cells, shed light on mass and energy transport through cell membranes, and provide a unique, isolated space for conducting chemical reactions. In addition, such structures can serve as drug delivery systems that encapsulate both bioactive and nonbiocompatible compounds. In this Account, we present various coating, incubation, and electrofusion strategies for forming multicompartment vesicle systems, and we are focusing on strategies that rely on involving molecular recognition of complementary vesicles. All these methods afforded multicompartment systems with similar structures, and these nanoparticles have potential applications as drug delivery systems or nanoreactors for conducting diverse reactions. The complementarity of interacting vesicles allows these artificial cells to form, and the organization and polyvalency of these interacting vesicles further promote their formation. The incorporation of cholesterol in the bilayer membrane and the introduction of PEG chains at the surface of the interacting vesicles also support the structure of these multicompartment systems. PEG chains appear to destabilize the bilayers, which facilitates the fusion and transport of the small vesicles to the larger ones. Potential applications of these well-structured and reproducibly produced multicompartment systems include drug delivery, where researchers could load a cocktail of drugs within the encapsulated vesicles, a process that could enhance the bioavailability of these substances. In addition, the production of artificial cells with multiple compartments provides a platform where researchers could carry out individual reactions in small, isolated spaces. Such a reactive space can avoid problems that occur when the environment can be destructive to reactants or products or when a diverse set of compounds difficult to obtain in a conventional reactor space are produced. Our work on these artificial cells with multicompartment structures also led us to formulate a hypothesis on the processes that possibly generated eukaryotic cells. We hope both that our research efforts will excite interest in these nanoparticles and that this research could lead to systems designed for specific scientific and technological applications and further insights into the evolution of eukaryotic cells.

Various strategies for constructing artificial multicompartment vesicular systems, which primitively mimic the structure of eukaryotic cells, are presented. These model systems are appropriate for addressing several issues such as the understanding of cell processes, the development of nanoreactors and novel multicompartment delivery systems for specific drug applications, the transport through bilayer membranes, and also hypothesizing on the evolution of eukaryotic cells as originating from the symbiotic association of prokaryotes.

In this review, interactions of selected vesicles, induced either by molecular recognition or by electrostatic interactions, for the simulation of cell–cell and cell–drug interaction processes are discussed. In order of increasing complexity, examples of vesicles adhesion are presented at first, followed by recognition experiments in which fusion takes place. This differentiation in behavior was primarily attributed to the structural features of interacting vesicular pairs primarily affected by concentration and lateral phase separation of the anchored recognizable groups. In certain cases, fusion is accompanied by multicompartmentalization of the obtained aggregates. In connection with the formation of these multicompartment systems, it was proposed that an analogous mechanism could be operating in the evolution of eukaryotes during the symbiosis of prokaryotes.

Importance of the field: The review presents the design strategy and synthesis of multifunctional dendrimers and hyperbranched polymers with the objective to develop effective drug delivery systems. Areas covered in this review: Well-characterized, commercially available dendritic polymers were subjected to functionalization for preparing drug delivery systems of low toxicity, high loading capacity, ability to target specific cells and transport through their membranes. This has been achieved by surface targeting ligands, which render the carriers specific to certain cells and polyethylene glycol groups, securing water solubility, stability and prolonged circulation. Moreover, transport agents facilitate transport through cell membranes while fluorescent probes detect their intracellular localization. A common feature of surface groups is multivalency, which considerably enhances their binding strength with complementary cell receptors. To these properties, one should also add the property of attaining hi...

The structural features of complementary liposomes and factors favoring formation of multicompartment systems are investigated. Specifically, liposomal formulations consisting of PEGylated unilamellar liposomes with guanidinium moieties located at the distal end of polyethylene glycol (PEG) chains interact with complementary multilamellar liposomes bearing phosphate moieties. Furthermore, the number of PEG chains attached to the unilamellar interface of the liposomes is enhanced by incorporating PEGylated cholesterol in their bilayer. While molecular recognition of the liposomes is the driving force for initiating multicompartmentalization, it is the enhanced PEGylation at the liposomal interface that synergistically promotes fusion resulting in large and well-formed multicompartment systems. A mechanism is proposed according to which initial adhesion of the liposomes, followed by reorganization of their membrane lipids, leads to giant bilayer aggregates incorporating large liposomes.