Preface Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 14 1161

Preface: Polymer Science and Polymer Therapeutics: Macromolecules, Dendrimers and Nanomedicine

Maria Micha-Screttas1 and Helmut Ringsdorf2

1Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas. Constantinou Ave.,

48, 11635, Athens, Greece, 2Institut für Organische Chemie, Universität Mainz, Duesbergweg 10-14, D-55099, Mainz,

Germany

1. HOW DOES SCIENCE DEVELOP?

“Two decisive aspects of the field of Science are tradition and innovation. Tradition is the basis, for it represents the accumulation of wisdom in the body of knowledge. To know what a subject is all about, and to control it, creates self-confidence, thus paving the way for innovation. Innovation is the adventure, because with challenge comes the risk of calling into question, or even losing, one’s own scientific identity which has been gained through tradition. Persisting in tradition without innovation, however, soon leads to linear thinking, to tiresome routine and the science of yesterday: The longing for new adventures withers and dies. On the other hand, intuition and pure innovation harbor the danger of superficiality. The sum of knowledge is immense and growing. Tradition and solid work are honored and admired. Nevertheless, science can be justified only by challenge and demands the willingness to give up long-held classical or traditional views in an attempt to discover new horizons” [1].

How does science genuinely develop? Today it is widely accepted that essential progress in science does not occur through the continuous collection of facts but by “revolutionary” processes that induce the replacement of existing models, or paradigms, by a new concept: a paradigm shift [2]. Paradigm shifts do not always have to be “revolutionary”, but they describe a stepwise development of science while linear thinking and a merely logical continuation of known facts and experiences do not lead necessarily to the next plateau of science: intelligence helps – but intuition and creativity are important parts of the game.

One of the most impressive examples for this is the development of Polymer Science and its fascinating variations during the last fifty years.

2. FROM MACROMOLECULES TO BIOLOGICAL SYSTEMS: A PARALLEL DEVELOPMENT OF AVENUES IN SCIENCE.

A paradigm shift marks the beginning of Macromolecular Chemistry, which then developed into Polymer Science almost as soon as it was born [3]. It was in the 1920s when Hermann Staudinger moved from his previous and considerable successes in low-molecular-weight organic chemistry (e.g. ketenes, ozonolysis, aliphatic diazo compounds, explosives, aromas, the Staudinger reaction) to macromolecules [4]. This was a step that needed vision and courage - unquestionably a paradigm shift. With his papers in the early 1920s e.g on “Polymerization” [5] and with the definition of macromolecules as primary-valence chain systems, Herman Staudinger marked the beginning of Macromolecular Chemistry. It took only a few years to convince or at least to quieten down the classical organic and colloid chemists, who had defined large molecules, polymers (multiples) as colloids and aggregates of small molecules. Industry did not care about this relatively short and stormy academic interlude : The field of synthetic macromolecules was developed systematically in many laboratories around the world, from the early 1930s onwards leading to fibres, plastics, and rubber as valuable materials in industry as well as for daily use. The “Plastic Age” was born.

But especially in connection with this particular issue of “Current Topics in Medicinal Chemistry” it is of course important to point out, that, alongside the chemistry of synthetic macromolecules, the science of biopolymers had already started to develop too at the beginning of the 20th century. Based on Emil Fischer’s investigations of sugars and aminoacids, Protein Chemistry emerged [6]: Thus Polymer Science and Bioscience developed in parallel: They were both already in full bloom when Staudinger received the Nobel Prize in 1953, “for his discoveries in the field of Macromolecular Chemistry” [7]. There is no better example of the parallelism of two scientific developments - and no director could have set the scene more perfectly - than the fact that Staudinger received the Nobel Prize in Chemistry in Stockholm [8] at the same time as Hans Adolf Krebs and Fritz Albert Lipmann [9] were awarded the Nobel Prize for Medicine for their work on enzymes and coenzymes as important biological macromolecules. It was probably even more like news from another planet for the synthetically oriented “Plastic Community” that in the same year J.D. Watson and F.H.Crick rang in molecular biology with their Nature articles on the DNA-model [10].

As far as the early biomedical application of macromolecules is concerned, synthetic Polymers and Biopolymers were used in parallel : Bone replacement materials, synthetic fibres as degradable and non-degradable surgical materials as well as plasma expanders (blood substitutes, especially polyvinylpyrollidone, PVP, during the second world war) were e.g., among the first ones to be applied ever in hospitals.

1162 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 14 Preface

3. MACROMOLECULES TO GARNISH: POLYMER SCIENCE AS A WELCOME INGREDIENT IN MATERIAL SCIENCE, SUPRAMOLECULAR CHEMISTRY AND NANOMEDICINE

The possibilities for synthetic macromolecules in the biomedical field changed drastically after the 1950s with the rapid development of modern biochemistry and biomedicine. In addition, molecular and cell biology, proteomics, and genetics led to far reaching paradigm shifts in the Life Science area. At the same time, in the field of synthetic chemistry intensive investigations about molecular recognition and molecular self-organization led to the development of molecular engineering [1] and thus to the evolution of Supramolecular Chemistry [11,12] opening doors in many directions. At the beginning Macromolecular chemistry was a field on the borderland between Chemistry and Physics. As Polymer Science it was already the midwife of Material Science and has therefore been fundamental for the development of our modern world. And now?

The enormous breadth of new materials with unusual properties offered by macromolecules (amphiphilic polymers, a wide variety of block copolymer systems, liquid crystalline polymers, H-bonding interactions etc.) made it possible that Macromolecular Science has long since become an essential part of many other modern areas of science, such as the chemistry and physics of supramolecular systems and supramolecular materials [12,13]. And then a little bit later the “Nanogames” appeared on the on the scene: Nanotechnology, Nanochemistry, Nanobiology, Nanoengineering, Nanomedicine etc, etc. Not a paradigm shift at he beginning but just a size definition of functional active units: colloidal metals, quantum dots, fullerenes, nanotubes, nanocapsules, block micelles, dendrimers etc.

Even if one remained a little bit skeptical, it has to be mentioned that coining the title “NANOMEDICINE” [14, 15] has had a very positive effect : it helped to overcome barriers between disciplines and scientists that, independent of many attempts to interact, still remained in their scientific boxes [16]. In the meantime the field has proved to be extremely successful in initiating steps across borders between Materials Science and Life Science.

When did macromolecules, when did Polymer Science step into Nanomedicine? Here again it is, from a science historical standpoint, interesting - and basically trivial - to note that polymers played from the beginning an important role in the “Nanogames”. Polymers just based on their molecular dimensions were “Nanosystems” before the word was coined. Polymeric pharmaceuticals were already established when Nanomedicine started to become popular. Macromolecular Science was no longer a stranger to the biosciences. The dawning area of polymer therapeutics [17] is a perfect example of science at the crossroads of different disciplines bridging gaps and growing on the interactive collaboration at the interfaces between physics, chemistry, biology, pharmacy and medicine [18]. Importantly many of the innovative polymer based therapeutics once dismissed as interesting but impractical scientific curiosities have now shown that they can satisfy the stringent requirements of industrial development and Regulatory Authority Approval [19].

4. Quo Vadis Nanomedicine ? THE BEST WAY TO PREDICT THE FUTURE IS TO INVENT IT [20]

“Current topics in Medicinal Chemistry” What does it mean? What does ‘current’ suggest? Looking up in an Oxford or Webster’s dictionary one finds the expected definitions (present, accepted, up-to-date, standard, etc.) but one also finds: “flow in a definite direction” and “a general tendency or drift”. Isn’t this in connection with this current volume a reason to ask: Quo Vadis Nanomedicine ?

4.1. From Macromolecules to Biological Assemblies

Would Mother Nature have used macromolecules to “develop” and “stabilize” life on our planet if she could have done the job with “more simple” small molecules only? Very unlikely! Although we do not know and will probably never know if she has even tried to do so before. It is a fact that Nature always makes use of “giant molecules” when it is a question of multifunctionality, that means when single molecules have to be used for very different functions. This is the concept of Nature to combine in a singular system viability and stability, surface recognition and specific local interaction, function dependent structural regulation and self-replication. Isn’t this an admirable inspiring concept of and for biomacromolecules? However : Isn’t this at the same time one of the basic arguments to believe in and to stick to Polymer Therapeutics and Macromolecular Drug Delivery Systems as an essential goal to develop Pharmaceuticals of the future?

In his Nobel Prize contribution [21] Aaron Kluge describes the decisive role of macromolecules in all biological processes of living cells: “These macromolecules do not of course function in isolation but often interact to form ordered aggregates or macromolecular complexes, sometimes so distinctive in form and function as to deserve the name of organelles”. Of course he was referring to nucleic acid-protein complexes - no mention of synthetic macromolecules. Naturally - it was 1982. But today? In the age of proteomics, hybrid structures (organic, inorganic, synthetic, etc), self-organization and self-association, supramolecular systems, modern colloid chemistry and enormous synthetic possibilities, all the prerequisites are actually in place to start to play similar games with synthetic systems [7, p. 1068]. Nanomedicine is not a matter of rhetoric anymore [17-19, 22-25].

4.2. Nanomedicine - a Step Towards Pharmaceuticals of the Future

Now, at the beginning of the 21st century, we are witnessing a paradigm shift in medical practice. The use of macromolecules in medicine is not new - natural polymers have been used as herbal remedies for several millennia but now modern Pharmacology, Toxicology and Molecular Cell Biology have learned to define more vigorously the molecular basis of their action. This is at the same time a perfect base for synthetic nanopharmaceuticals. Thus the concept of macromolecules as

Preface Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 14 1163

pharmacologically active compounds necessitates the close, long-term collaboration of macromolecular science with membrane and cell biology, with pharmacy, pharmacology, and medicine. It is certainly only a matter of time before pharmaceuticals are required not only to affect cells and tissues specifically, but to also exhibit specific behavior in the cytoplasm of the cell: a defined interaction with the plethora of membranes and cell organelles.

The more we know about the interaction of natural and synthetic macromolecules with cell membranes and cell organelles, and the better we understand endosomal and lysosomal systems and the processes of intracellular transport of novel macromolecules, the closer we will come to an understanding that will allow the development of disease-specific macromolecules. Here, too, the close and mutually planned collaboration between macromolecules science, membrane and molecular biology, and pharmacy and pharmacology is required. It is a question of the synthesis of macromolecules based on biological rationale. That should not put an end to the pure joy of synthesizing novel macromolecules for the sake of synthesis, but this approach belongs - and this is said without deprecation - to classical macromolecule science. It is foreseeable that attention will be focussed more and more on bioactive compounds in the form of polymeric therapeutics in order to be able to fulfil the plethora of increasingly stringent demands on the pharmaceuticals of the future. As already mentioned before, not without reason has Mother Nature always made use of macromolecules when it was a matter e.g. of viability, stability, recognition and regulation .

When a field suddenly becomes fashionable, it is important to keep perspective and most importantly distinguish the science fact from science fiction. During the last 10 years gene therapy and more lately stem cell therapy (embryonic, adult) have gained growth as the most modern and most promising, Nevertheless, one has to realize that really fascinating scientific facts whose application is pushed too fast - something very “normal” for our frequently sensation-oriented scientific society - often hold back older concepts and basic investigations in the field. It is hardly necessary to state once more that basic research and applied research are brother and sister and cannot be separated but they certainly grow differently. Within our often shareholder value driven research tendencies, basic research sometimes seems to lose if an application is not visible right away, and this influences research funding in our modern world! But especially in medicinal chemistry the step from brilliant ideas and basic concepts to successful application in clinics takes time. In this respect one has to realize that, in the above-mentioned field of gene therapy and antisense therapy, the problems in developing their technologies were as much underestimated as their fast application-oriented possibilities were overestimated.

4.3. Dendrimers in Nanomedicine : Hype or Reality?

The explosive development of macromolecular chemistry, has led to the synthesis of a multitude of linear, branched and cross linked polymeric compounds. Basically every compound that is needed, and basically every surface property that is desired, can be synthesized. Particularly dramatic growth has been observed in the field of random hyperbranched polymers, dendrigraft polymers and dendrimer-like polymers [28-32].

Dendrimers with their unique properties of monodispersity, their well defined “cascade structure” and the wide variation of surface characteristics, peptide hybrids, and degradable and non-degradable systems have opened additional possibilities for the biopharmaceutical and biomedical fields. The first reviews already describe the medical interest in such highly structure and multifunctional polymers [31,32]. The breakthroughs for dendritic and highly branched systems in the field of pharmacy and pharmacology are certainly not yet here, but the chances have always been and still are. Dendritic polymers with their regular and well defined macromolecular structure which can further be chemically modified at either the core or the shell are full of potential and future. This issue of “Current Topics in Medicinal Chemistry” is exactly devoted to this topic and rightly so.

4.4. Wit is the Finder

One of the most optimistic views for the development and enhance of Polymer Science in the Biomedical field was already published in 1959. In his Nobel Lecture, J. Lederburg [26,27] paid an extravagant compliment to synthetic polymer chemists when he said : “If the ingenuity and craftsmanship so successfully directed at the fabrication of organic polymers for the practical needs of mankind were to be concentrated on the problem of constructing a self-replicating assembly along these lines I predict that the construction of an artificial molecule having the essential function of primitive life would fall within the grasp of our current knowledge of organic chemistry”. What a tribute to polymer chemistry, what a trust in us - and J. Lederberg did not even know the words : Nanomedicine and Nanotechnology.

If in science we only try to reach the goals we can think of, we only reach what any intellectual scientist could reach - interesting linearly approached results, but not breakthroughs, no paradigm shifts. For the development of science, intelligence is helpful, but intuition and creativity are most important. In other words or as the famous physicist and philosopher Georg Christoph Lichtenberg already phrased it so wonderfully in 1779: “The wit is the finder, intelligence is the observer”.

REFERENCES

[1] Ringsdorf, H.; Schlarb, B.; Venzmer, J. Molecular Architecture and Function of Polymeric Oriented Systems: Models for the Study of Organization, Surface Recognition, and Dynamics of Biomembranes. Angew. Chem. Int. Ed. 1988, 27, 113-158.

[2] Kuhn, T.S. The Structure of Scientific Revolutions; 2nd ed., University of Chicago: Chicago, 1970. [3] Movawetz, H. Polymers:The Origin and Growth of a Science; Wiley Interscience: New York, 1985. [4] Staudinger, H. From Organic Chemistry to Macromolecules. A Scientific Autobiography Based on the Original Papers; Wiley Inc.: New York, 1985;

Translated from “Arbeitserinnerungen”; Hüthig Verlag: Heidelberg, 1961. [5] Staudinger, H. Über Polymerization (On Polymerization). Ber. Dtsch. Chem. Ges. 1920, 53, 1073.

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[6] Tauford. C.; Reynolds, J.; Protein Chemists bypass the Colloid/Macromolecule Debate. Ambix 1999, 46, 33-51. [7] Ringsdorf, H. Hermann Staudinger and the Future of Polymer Research Jubilees - Beloved Occasions for Cultural Piety. Angew. Chem. Int. Ed. 2004,

43, 1064-1076. [8] In the issue of “Chemical and Engineering News”, of January, 11, 1954 the award of the Nobel Prize of 1953 is described under ‘The Cover: Nobel

Ceremony Honors Chemists”: Chem. Eng.News, 1954, 32, 162-163. [9] Hans Adolf Krebs (1900-1981). Professor of Biochemistry at Oxford University; areas of research : biochemistry, metabolic energetics, elucidation of

the urea cycle and the citric acid cycle, which was named after him (Krebscycle)] and Fritz Albert Lipmann [Fritz Albert Lipmann (1899-1986), Professor of Biochemistry at Harvard University; areas of research: coenzyme A and its central role in energy trnsfer in cells, energetics of metabolic processes, cellular synthesis of peptides.

[10] Watson, J.D.; Crick, F.H. C. Molecular Structure of Nucleic Acids. A Structure for Deoxyribose Nucleic Acid. Nature, 1953, 171, 737-38. (b) Watson, J.D.; Crick, F.H. C, Genetical Implications of the Structure of Deoxyribonucleic Acid. 1953, 171, 964-967.

[11] Lehn, J.M. Supramolecular Chemistry: Concepts and Perspectives; VCH: New York, 1995. [12] Lehn, J.M. Supramolecular Polymer Chemistry: Scope and Perspectives. In Ciferri, A. (Ed.) Supramolecular Polymers; Marcel Dekker: New York;

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underlying pathophysiology of disease. The ultimate goal is improved quality of life. The nanoscale is still varied and discussed but it normally includes 1-100nm. Also of relevance are nano-interactions within the framework of a larger device.

[15] Adcock, H. Using Nanotechnology to Improve Drug Therapy :What is all the Fuss About? Pharmaceut. J. 2003, 271, 362. [16] b) Nanomedicine : Grounds for Optimism. Lancet 2003, 362, 673. [17] Ringsdorf, H.; Duncan, R. Drug Delivery - Yesterday and Today. In Polymers in Drug Delivery. Uchegbu, I. F.; Schatzlein, A. G.; Eds.; CRC Press:

Boca Raton, 2006. See also Ref. [7], page 1073 (ref. 29). [18] Duncan, R. The Dawning Era of Polymer Therapeutics, Nat. Rev. Drug Discov. 2003, 2, 347-360. [19] Haag, R.; Kratz, F. Polymer Therapeutics: Concepts and Applications. Angew. Chem. Int. Ed. 2006, 45, 1198-1215. [20] Polymer Therapeutics I. Adv. Polym. Sci. 2005, Vol. 192; Satchi-Fainaso, R.; Duncan, R.; Eds. b) Polymer Therapeutics II. Adv. Polym. Sci. 2005, Vol.

193; Satchi-Fainaso, R.; Duncan, R.; Eds. “The best way to predict the future is to invent it” Richard Feynman. [21] a) Klug, A. From Macromolecules to Biological Assemblies. In Nobel Lectures Chemistry, 1981-1990. Frängsmyc, A.G.; Malström, B.G.; Eds.; 1992,

p. 77. b) Klug, A. Angew. Chem. Int. Ed. 1983, 22, 565-582. [22] Nanomedicine : A Matter of Rhetoric? Nat. Mater. 2006, 5, 243. [23] European Governments Urged to Ramp Up Funding for Nanomedicine R and D. NanoBiotech News, 2006, 2-3. [24] Ferrari, M. Cancer Nanotechnology: Opportunities and Challenges, Nat. Rev. Cancer 2005, 5, 161-171. [25] Duncan, R. Targeting and Intracellular Delivery of Drugs. In Encyclopedia of Molecular Cell Biology and Molecular Medicine; Meyers, R.A.; (Ed.);

Wiley-VCH, Weinheim, Germany, 2005; pp. 163-204. [26] Lederberg, J. Nobel Prize Lecture. Science, 1959, 131, 209. [27] Movawetz, H. also cites J. Lederberg’s mental leap in his book on the history of Polymer Science : Movawetz, H. Polymers:The Origin and Growth of

a Science; Wiley Interscience: New York, 1985; p. 213. [28] Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. A New Class of Polymers-Starburst-Dendritic

Macromolecules. Polym. J. 1985, 17, 117-132. [29] Hawker, C. J.; Fréchet, J. M. J. Preparation of Polymers with Controlled Molecular Architecture. A New Convergent Approach to Dendritic

Macromolecules. J. Am. Chem. Soc. 1990, 112, 7638-7647. [30] Newkome, G. R.; Moorfield, C. N.; Vögtle, F. Dendritic Molecules: Concepts, Syntheses, Perspectives; VCH Publishers, Inc.: N.Y. 1996; pp. 1-261. [31] Duncan, R.; Izzo, L. Dendrimer Biocompatibility and Toxicity. Adv. Drug Deliv. Rev. 2005, 57, 2215-2237. [32] Sideratou, Z.; Tziveleka, L.-A.; Kontoyianni, C.; Tsiourvas, D.; Paleos. C. M. Design of Functional Dendritic Polymers for Application as Drug and

Gene Delivery Systems. Gene Ther. Mol. Biol. 2006, 10A, 71-94.

Helmut Ringsdorf

Institut für Organische Chemie,

Universität Mainz,

Duesbergweg 10-14,

D-55099, Mainz,

Germany,

Tel: +49(0)6131 39-22402

Fax: +49 (0)6131 39-23145

E-mail: ringsdorf@uni-mainz.de