In Memoriam: A Tribute to Dr. Constantinos M. Paleos
We are deeply saddened to announce the passing of Dr. Constantinos M. Paleos, former head of the Laboratory of Organized Systems of Supramolecular Structures, Director of the Institute of Physical Chemistry and Vice-President of NCSR "Demokritos". Dr. Paleos passed away on October 1st, 2023 with his family on his side.
His hard work, his broad scientific interests and his overall passion and dedication to research as well as his constant efforts to help, encourage and teach young researchers, inspired us not only in our research efforts but also in our personal lives.
Dr. Paleos was born in the island of Chios, located in the Eastern Agean Sea, where he completed his basic education. He obtained a Diploma in Chemistry from the University of Athens and his PhD from Drexel University in Philadelphia at 1970. After three years with Amoco Chemicals (Naperville, Illinois) and Motor Oil (Athens, Greece), he joined in 1973 the Institute of Physical Chemistry of NCSR “Demokritos”, where he later established the “Laboratory of Supramolecular Organized Structures”. In 1991-1992 he was elected visiting Professor at the University of Strasbourg (then University of Louis Pasteur). He was elected Director of this Institute for two periods (1994-1999 and 2001-2007) until his retirement. During this period,he restructured the Institute, by changing its priorities and establishing new areas of research. Specifically, he established the Programsof “Environmental Science and Technology”, “Chemical Biology” and “Molecular and Supramolecular Nanomaterials”.
After his retirement he remained active as a consultant of the laboratory of Functional Nanomaterials of Organized Structure at the Institute of Nanoscience and Nanotechnologyof NCSR “Demokritos”.
His main research activities and interests were in the area of “Nanomaterials of Supramolecular Organized Structure” including the formation and characterization of novel liquid crystals, molecular recognition of liposomal aggregates, development of materials through non-covalent interactions of complementary molecules. The excellence and diversification of his research activity is reflected in a great number of publications and patents. He has authored together with his co-workers 181 publications which were cited more than 6800 times (Google Scholar, October 2023).
Selected highlights of his work on functional molecular and supramolecular systems are critically described below in chronological order.
Polymerization of Organized Molecular and Supramolecular Systems
Following undergraduate studies in Athens University, Dr. Paleos was for the first time exposed to chemical research and specifically to synthetic organic chemistry during the period of his military service, working as a research assistant in the laboratory of Prof. L. Zervas at the Organic Synthesis Lab of the University of Athens. Zervaswas a pioneer in the field of Peptide Synthesis and specifically on the design and synthesis of protective groups. He had an exceptional ability, or specifically a “feeling”, on designing and preparing organic compounds. The lesson Dr. Paleos had learned during his short staying at his lab was to make him proceed to synthetic experiments, after considering basic steps.
During the period of April to August 1966, he worked at the Biology Department of “Demokritos”, as a research assistant in the laboratory of Dr. A. Bakirtzi-Lemonias, on co-enzyme Q10 characterization. During his staying at this laboratory, he had the opportunity of being exposed in basic biochemical techniques.
The work towards his PhD degree started in 1967, at Drexel University in Philadelphia, USA and he was supervised by Prof. M. M. Labes who is a pioneer in the field of liquid crystals and from whom he was taught to seek innovation and try finding innovative solutions to various problems. Dr. Paleos was introduced to the exciting field of liquid crystals and investigated the role of organization on chemical reactivity and properties of the materials obtained.
An appropriate system for conducting these investigations is to perform polymerization reactions in organized Thermotropic Liquid Crystalline Phases formed by rigid-rod molecules . The emphasis was placed on polymerizations in liquid crystalline media and the effects of organization on reactivity and polymer morphology. The publications of this novel, at that time, work were among the first to appear in the chemical literature.
In those early years and while he was still working on the topic of his PhD thesis, 1967-1970, he started investigating, in parallel, chemical reactions of Nitroxide Stable Free Radicals. These compounds due to their stability are being used in spin-labelling technique. The outcome of this independent work was published in prestigious journals but most importantly, these first publications [2,3] in the field of Nitroxide Free Radicals, convinced him, at this early period, about his ability to conduct independent research.
Liquid Crystals Originating from Amphiphilic Molecules
In the early seventies, upon his return in Greece, while working at Demokritos and having been inspired by his previous work on polymerizations in organized thermotropic liquid crystalline media, Dr. Paleos extended his research to other more conveniently prepared organized systems. He investigated polymerization reactions at liquid-liquid interfaces and polymerizations of monomers assembled in micelles  or assembled and organized in vesicles . In conducting this work he was inspired by the investigations of Prof. H. Ringsdorf, as presented in his excellent review (H. Ringsdorf et al., J. Angew. Chem., Int. Ed. Engl. 1988, 27, 113-158). At that time, when these investigations were conducted, these molecular assemblies were characterized as colloidal. Now, based on their size they are also called nanoparticles. Therefore, colloid chemistry is bridged to the spectacularly advancing field of nanoscience-nanotechnology.
In the early eighties, Constantinos started investigating thermotropic liquid crystalline phases originating from Amphiphilic Molecules, which was a neglected area up to that time. In fact his first short note in Mol. Cryst. Liq. Cryst.  triggered great interest for the preparation and characterization of this type of thermotropic liquid crystals. Detailed characterization of these liquid crystalline materials was initiated in Strasbourg (1991-92) during his visiting professorship at the University of Strasbourg and continued the following years through a fruitful collaboration with Dr. A. Skoulios at CNRS. Dr. Skoulios is a great expert in the field of liquid crystalline characterization with X-ray crystallography. Numerous publications resulted from this joint effort, both of original research and reviews, triggering interest in the synthesis of amphiphilic molecules which self-assemble and organize forming thermotropic liquid crystals in the bulk and lyotropic liquid crystals when in water.
Hydrogen-bonded Liquid Crystals Obtained through Molecular Recognition
Following the first publication on “Hydrogen-bonded Liquid Crystals” by the Nobel Laureate J. M. Lehn in 1989 [J. Chem. Soc., Chem. Commun., 1989, 1868-1870], Dr. Paleos was among the first researchers around the world to start investigating the preparation and characterization of this type of liquid crystals resulting from the molecular recognition of complementary molecules through hydrogen bonding. A great number of original publications resulted, the majority of which was discussed in his highly cited reviews, in Angew. Chem., 1995  and Liquid Crystals, 2001 . In connection with this work, Molecular Recognition of Organized Molecular Assemblies, via hydrogen bonding in aqueous media, was also investigated .
Development of Functional and Multifunctional Dendritic Polymers
In the mid-nineties, Dr. Paleos entered the highly advancing field of Functional Dendritic Polymers in which he is intensively involved up to recent years [10-14]. Dendritic polymers, primarily due to their polyvalent properties, provide a diversity of products including:
- Liquid crystalline polymers based on symmetric dendrimers and non-symmetric hyperbranched polymers were prepared, which provided a diversity of liquid crystalline phases. The relevant publications were extensively cited.
- Alkylated dendritic polymers, either covalently or non-covalently bound to ceramics, forming Hybrid Materials. These materials act as “nanosponges” removing impurities from water under energy-saving conditions. Ultra-pure water is produced in which the remaining impurities are at the level of a few ppb, following filtration of water through hybrid material filtering modules. The latter are regenerated by washing with appropriate solvents. Patent applications in several countries were filed and granted, while several pertinent publications followed.
- Multifunctional dendritic derivatives had been intensively investigated as Drug Delivery Systems or transfection vectors for Gene Therapy in vitro experiments. Patent applications in several countries were filed and patents granted, while the results were disseminated in several publications. In this connection a dendritic-type semisynthetic carbohydrate, i.e. Hydroxyethyl starch (HES), was functionalized affording biodegradable drug carriers. Doxorubicin, an anticancer drug, was non-covalently attached to this carrier and the salt was subjected to in vitro experiments which proved very promising. These first results triggered increased interest on the synthesis and characterization of drugs based on this novel and biodegradable dendritic drug delivery system .
The last two activities led to establishing a spin-off Company, “DendriGen SA,” for commercial exploitation of the developed nanoparticles.
Functional and Multifunctional Liposomes - Cell Modelling - Drug Delivery Systems
The expertise in the development of synthetic vesicles already from the eighties, led Dr. Paleos to start working in 2000 towards the development of Multifunctional Liposomes aiming at their application as drug delivery systems or as biological cell models [15-19]. Also a comparative evaluation of multifunctional liposomes vs. multifunctional dendritic derivatives as drug delivery systems was undertaken.
Within the objective of developing drug delivery systems, Dr. Paleos extended his work from molecular recognition of complementary molecules to the recognition of self-assembled nanoparticles. Thus, he investigated liposome-liposome and liposome-dendritic polymer interactions. A mechanism for the interaction of these nanoparticles has been proposed aiming at modelling cell-cell and cell-drug interactions in drug delivery. These investigations were published and reviewed in several prestigious journals [15-19].
A significant outcome of the work dealing with liposome-liposome interactions led to proposing a working hypothesis regarding the origin of eukaryotes (Journal of Molecular Recognition 2007, Langmuir 2011, and Accounts of Chemical Research 2014). Thus, based on the results of complementary liposome interactions, it was hypothesized [20,21] that eukaryotes, which exhibit a multicompartment character, might have originated from the symbiotic association of prokaryotes.
Molecular Transporters: Functional Liposomes and Dendritic Polymers
Within the framework of his investigations on drug delivery, Dr. Paleos has undertaken research on decorating the surface of liposomes or dendritic polymers aiming to the development of molecular transporters . The guanidinium moiety facilitates cell membrane transport, while the triphenylphosphonium cation directs the latter nanoparticles to mitochondria. These phosphonium derivatives are characterized as second generation transporters. For the guanidinium functionalized transporters, he proposed a novel multi-step mechanism for membrane penetration [23,24]. Several original publications and reviews in prestigious journals have resulted from this continuing effort.
In the last years, due to his interest on the origin of living cells, Dr. Paleos has experienced a great satisfaction realizing that his early research involvement, on organized polymerization in liquid crystalline media, and on the structure and properties of amphiphilic-type liquid crystals, is related in some way to the issue of the Origin of Life [D. W. Deamer, Chem. Soc. Rev. 41, 5375-5379 (2012)]. According to this investigation, polymerization of mononucleotides to RNA-type polymers took place, in the absence of catalyst, in liquid crystalline media during the prebiotic era.
Further to focusing to Nanochemistry and Supramolecular Chemistry as described above, Dr. Paleos also worked in topics of conventional chemistry including synthetic and mechanistic organic chemistry, polymer modification, nitroxide stable free radicals chemistry.
1. C. M. Paleos and M. M. Labes*, Polymerization of a Nematic Liquid Crystal Monomer, Mol. Cryst. Liq. Cryst., 11, 385 (1970).
2. C. M. Paleos*, N. M. Karayiannis and M. M. Labes, Reduction of 2,2,2,6 Tetramethyl-piperidine Nitroxide Radical via Complex Formation with Copper (II) Perchlorate, Chem. Comm., 195 (1970).
3. C. M. Paleos* and P. Dais, A Ready Reduction of Some Nitroxide Free Radicals with Ascorbic Acid, Chem. Comm., 345 (1977).
4. C. M. Paleos, Polymerization of Micelle Forming Monomers, in "Polymerization in Organized Media" Editor: C. M. Paleos, Gordon and Breach Publishers, New York, Philadelphia, p. 183, 1992.
5. C. M. Paleos, Polymerization in Vesicular Media, in "Polymerization in Organized Media", Editor: C. M. Paleos, Gordon and Breach Publishers, New York, Philadelphia, p. 283, 1992.
6. C. M. Paleos, Thermotropic Liquid Crystals Derived from Amphiphilic Mesogens, Mol. Cryst. Liq. Cryst., 243, 159 (1994).
7. C. M. Paleos*, D. Tsiourvas, Thermotropic Liquid Crystals Formed by Intermolecular Hydrogen Bonding Interaction, Angew. Chem. Intern. Engl. Ed., 34, 1696 (1995).
8. C. M. Paleos* and D. Tsiourvas, Supramolecular Hydrogen-bonded Liquid Crystals, Liq. Cryst., 28, 1127 (2001).
9. C. M. Paleos* and D. Tsiourvas, Molecular Recognition of Organized Assemblies via Hydrogen Bonding in Aqueous Media, Advanced Materials, 9, 695 (1997).
10. C. M. Paleos*, D. Tsiourvas and Zili Sideratou, Molecular Engineering of Dendritic Polymers and their application as Drug and Gene Delivery Systems, Molecular Pharmaceutics, 4, 169 (2007).
11. C. M. Paleos*, L-A Tziveleka, Z. Sideratou and D. Tsiourvas, Gene Delivery Using Functional Dendritic Polymers, Expert Opinion on Drug Delivery, 6,27-38(2009).
12. M. Arkas, D. Tsiourvas and C. M. Paleos*, Functional Dendritic Polymers for the Development of Hybrid Materials for Water Purification, Macrom. Mater. Eng., 295, 883(2010).
13. C. M. Paleos*, D. Tsiourvas, Z. Sideratou and L.-A. Tziveleka, Drug Delivery Employing Multifunctional Dendrimers and Hyperbranched Polymers, Expert Opinion on Drug Delivery, 7, 1387 (2010).
14. C. M. Paleos*, D. Tsiourvas and Z. Sideratou, Triphenylphosphonium Decorated Liposomes and Dendritic Polymers: Prospective Second Generation Drug Delivery Systems for Targeting Mitochondria, Molecular Pharmaceutics, 13, 2233 (2016).
15. C. M. Paleos*, Z. Sideratou and D. Tsiourvas,Drug Delivery Systems based on Hydroxyethyl Starch, Bioconjugate Chemistry, 28, 1611 (2017).
16. C. M. Paleos*, Z. Sideratou and D. Tsiourvas, Molecular Recognition of Complementary Liposomes is Modelling Cell-Cell Recognition, ChemBioChem., 2,305 (2001).
17. C. M. Paleos*, D. Tsiourvas and Z. Sideratou, Interaction of Vesicles: Adhesion, Fusion and Multicompartment Systems Formation, ChemBioChem, 11, 510 (2011).
18. C. M. Paleos*, D. Tsiourvas and Z. Sideratou, Multicompartment Lipid-based Systems prepared from Vesicles Interactions, Langmuir, 28, 2337 (2012).
19. C. M. Paleos*, D. Tsiourvas, Z. Sideratou and A. Pantos, Formation of Artificial Multicompartment Vesosome and Dendrosome as Prospected Drug and Gene Delivery Carriers, J. Controlled Release, 170,141 (2013).
20. C. M. Paleos* and A. Pantos, Molecular Recognition and Organizational and Polyvalent Effects in Vesicles Induce the Formation of Artificial Multicompartment Cells as Model Systems of Eukaryotes, Acc. Chem. Res., 47, 475, (2014).
21. C. M. Paleos*, Organization and compartmentalization by lipid membranes promote reactions related to the origin of cellular life, Astrobiology, 19, 547 (2018).
22. C, M. Paleos*, D. Tsiourvas and Z. Sideratou, Triphenylphosphonium Decorated Liposomes and Dendritic Polymers: Prospective Second Generation Drug Delivery Systems for Targeting Mitochondria, Molecular Pharmaceutics, 13, 2233 (2016).
23. Pantos, I. Tsogas and C. M. Paleos*, Guanidinium Group: A Versatile Moiety inducing Transport and Multicompartmentalization in Complementary Membranes, BBA-Biomembranes, 1778,811 (2008).
24. T. A. Theodossiou, A. Pantos, I. Tsogas and C. M. Paleos*, Guanidinylated Dendritic Molecular Transporters: Prospective Drug Delivery Systems and Application in Cell Transfection, ChemMedChem, 3, 1635-1643 (2008).