Introduction to Polymers in Today's Biomedical Realm - ACS

Jul 8, 2013 - In Biomaterials Science, 2nd ed.; Ratner, B. D., ed.; Academic Press, Inc.: New York, 2004; pp 107− 115. There is no corresponding rec...
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Introduction to Polymers in Today’s Biomedical Realm Carmen Scholz*,1 and Jörg Kressler2 1Department

of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, Alabama 35899, United States 2Department of Chemistry, Martin Luther University Halle-Wittenberg, D-06099 Halle (Saale), Germany *E-mail: [email protected].

New synthetic polymers and polymer architectures contribute widely to the progress in pharmacy and biomedicine. This book consists of five sections that describe and discuss recent developments in biorelated polymers; specifically, the focus is on the following subject areas: i) Synthesis of new polymers for pharmacy and biomedicine, ii) Using polymers for modern therapeutic approaches, iii) Delivery of biomacromolecules, i.e., drugs as well as nucleic acids, iv) Polymers for tissue engineering, and v) Polymers for surfaces and sensors. All chapters were written by the world’s leading scientists in their respective fields. Research presented in these chapters demonstrates that these new polymers, new polymer architectures, and new polymer conjugates are well suited for demanding applications in biomedical diagnostics and therapies. Modern approaches to drug delivery systems, new scaffolds for tissue engineering, and surfaces for sensors or antimicrobial activity are discussed in detail. Novel strategies in polymer synthesis are presented, as e.g. the functionalization of dendrimers or hyperbranched polymers, exploiting the possibilities of ‘click’ chemistry for the synthesis of well-defined block and graft copolymers or bioconjugation, and introducing environmentally responsive polymer moieties. The characterization of these polymeric systems is a challenging © 2013 American Chemical Society In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

task in itself but becomes even more challenging when applying the in vitro and in vivo conditions that are relevant for pharmaceutical and biomedical applications.

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Introduction Research into Biorelated Polymers is one of the most active fields in chemistry, physics, and materials science as it is intimately related to the progress in medical and pharmaceutical research. In the past few years new concepts were developed and several books and review articles appeared (1–5). With an advanced genetic understanding of diseases and the development of genetic therapeutic approaches biopolymers became essential and an integral part of modern biomedical research (6, 7). Polymers can adopt manifold conformations, self-assemble into pre-determined structures, undergo stimuli-induced phase transitions or depolymerization steps and can act as probes. These characteristics together with their biocompatibility make them premier candidates for drug and gene delivery systems, for tissue engineering scaffolds, and for matrices for biomedical probes and many other biomedical applications (8–10). Research into Biorelated Polymers resides at the interface of chemistry, pharmacy, medicine and biology and it continues to attract attention from scientists in academia, industry, and government research laboratories. Polymers made their entry into the realm of biomedical materials quite spectacularly when it was discovered that World War II fighter pilots did not suffer adverse affects from plastic fragments from their aircraft canopies that were launched into their bodies after being hit. Later on, poly(methyl methacrylate) (Plexiglas) found ample application as replacement for damaged or diseased skull bones (11). Another example are artificial blood vessels which were made initially from poly(ethylene terephthalate) (Dacron) knitted into flexible tubes; the same material that is used in the textile industry. While one would suspect that the hydrophobic material would cause heavy blood clotting, the success (survival) rate was surprisingly high. A third example that illustrates the crucial need of polymers in the biomedical field was the lack of a suitable (polymeric) delivery system for the administration of penicillin. Since this antibiotic degraded very fast after in vivo injection, it had to be administrated every three hours. The first drug delivery formulation for penicillin consisted of beeswax and peanut oil, the so-called Romansky-formulation. With that, penicillin had to be injected only once a day. In recent years polymers have been tailored for specific biomedical and pharmaceutical applications starting with new and designed monomers and expanding to specific and controlled polymerizations that allow for tightly controlling molar masses and molar mass distributions. In addition, new polymerization techniques led to the production of new and well defined polymer architectures. This book provides five sections which focus on modern trends in biomedical and pharmaceutical polymers. 4 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

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• • • • •

Polymers with New Designs Modern Therapies Delivery of Biomacromolecules Tissue Engineering Surfaces and Sensors

This book was inspired by the 11th Biorelated Polymer Symposium that was held at the 243rd ACS meeting in March of 2012. The 20 chapters of this book provide detailed information on cutting edge research in the field of polymer science for biomedical and pharmaceutical applications. They are intended not only for polymer scientists but also for engineers and scientists working with polymers in life sciences.

Polymers with New Designs The development of new and designed monomers in the field of commercial mass plastics can be considered to be complete, but the synthesis of tailor-made monomers for biomedical application is only at its beginning. The unique advantage of polymers is their broad spectrum of chemical and physical properties, which can be exploited to complement and satisfy the broad spectrum of biomedical requirements. Challenging tasks for the future include stimuli-responsive polymer systems (responding to temperature, pH-value or pressure changes), chiral polymers for chiral recognition, tailored molar mass distributions that are not necessarily monodisperse, polyphilic polymers that carry additional functionalities and expand on the typical amphiphilic character, bioconjugate monomers and polymers, just to mention a few. This section describes important new synthetic routes that lead to tailor-made polymers for pharmaceutical and biomedical applications. New hyperbranched polyether-based lipids are presented, which might overcome some of the typical drawbacks of poly(ethylene glycol) (PEG), such as the lack of functional groups and non-biodegradability. An epoxide based monomer library is described including the monomers’ subsequent modification with biocompatibilizing moieties, such as cholesterol. New bioactive polymers with reduced toxicity based on poly(anhydride-esters) are discussed. These polymers can be employed as controlled drug delivery systems and can also be formulated into hydrogels, microspheres, and electrospun fibers. Hydrophilic and biodegradable linear polyesters based on glycerol and derivates of dicarboxylic acids can be synthesized by enzymatic polymerization. The grafting of fatty acids to these polymers yields materials that are similar to glycerides and find widespread pharmaceutical applications. Another example are poly(oxazoline)s which are an important class of biomedical polymers due to their structural similarities to peptides and the ease of tailoring their hydrophilicity. Similarly, synthetic poly(amino acid)s consisting of naturally occurring L-amino acids are inherently biocompatible. The polymer properties can be tailored by judiciously selecting the ratio of hydrophilic to hydrophobic L-amino acids and/or incorporating amino acids with functional groups. Typically, polymer aggregates or polymeric micelles loaded with 5 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

drugs are delivered to solid tumors via the enhanced permeation and retention effect. The stabilization of micelles under in vivo conditions can be achieved by electrostatic interactions as opposed to the classical covalent cross-linking of the core or the corona of micelles. Thus, the advantages of reversibility and maintained biodegradability are provided.

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Modern Therapies This section addresses completely new therapeutic approaches that have emerged over the last two decades to combat the most serious of illnesses. Most recently, stem cell therapies entered into medical practice and while stem cells could cure a multitude of medical problems, delivering them and maintaining their viability still presents a tremendous challenge. Closely related to stem cell therapy is the cancer stem cell hypothesis, which provides completely new dimensions for the development of anti-cancer therapeutics. Progress in this field is linked to nanomedicines based on functional polymers. Another long lasting battle is the fight against HIV: The synthesis of peptide – synthetic polymer conjugates, which impede the host cell entry and the fusion of the HIV-1 virus, is addressed with a series of PEGylated fusion inhibitors. Here, the power of controlled radical polymerization techniques combined with chemo-selective coupling reactions is demonstrated. Significant progress was achieved in the field of drug delivery to solid tumors, but active targeting remains the main problem for the clinical translation of these polymeric systems. The new technique of plasmonic photothermal therapy combined with heat shock targeting is introduced and discussed in detail.

Delivery of Biomacromecules When considering the delivery of biologically active molecules the focus is moving from small drug molecules to macromolecules that actively interfere with cell biology, such as therapeutic proteins, DNA and RNA. The enhanced delivery of siRNA using polycationic structures in combination with the reduced toxicity of the carrier is a research focus discussed here. Poly(aspartamide)s with aminoethylene units in the side chains are designed to improve siRNA transfection based on: i) accelerated endosomal escape, and ii) stable siRNA complexation. Dendrimers are discussed for RNAi (RNA interference) delivery, a technique closely related to the process of gene silencing. Dendrimers of higher generations are of particular interest due to the high density of functional groups on their surface. Furthermore, alternatives for the PEGylation of proteins are discussed. PEG has some major drawbacks that are caused by its non-degradability even under in vivo conditions. Thus, technologies other than PEGylation are introduced, such as HESylation (conjugation with hydroxyethyl starch), Polysialylation, PASylation (coupling with polysialic acid) and Xten (fusion of a protein with an unstructured polypeptide) technologies. Polymer physics is utilized for biomedical applications when typical phase separation phenomena of polymers in solution are employed to control the affinity between 6 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

receptors and adhesion peptides. These phase transitions (UCST and LCST) can be controlled by the polymer architecture, specifically via the functional groups attached to thermo-responsive polymers.

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Tissue Engineering Tissue engineering is an extraordinarily active and fast growing area in medical research. Researchers strive to re-grow and replace tissue and potentially entire organs that were lost to disease or trauma. Major progress has been made in the area of cell biology, but cells need a support system if they are expected to develop into functional tissue or even an organ. These scaffolds can be produced from synthetic as well as naturally occurring polymers and they provide the mechanical properties, including shape persistence and the adhesion sites for growing cells. This section presents different examples for polymeric scaffold materials. Porous hydogel spheres are described for the treatment of peripheral arterial disease; different polymer constructs are studied for their ability to promote angiogenesis. New cellulose derivates with mitogenic/angiogenic and osteogenic activity are introduced as potential scaffold materials for bone regeneration; here, the cellulose was sulfated to different degrees and the bioactivity varied strongly with the degree of sulfation as studied by interactions with various growth factors. Another natural polymer, silk, is discussed as scaffold material for applications in cartilage and also bone tissue regeneration. Silk fibroin has potentially bioactive properties such as promotion of cell adhesion and cell proliferation, and it supports metabolic activity. Technologies for the production of special scaffolds such as non-woven nets, sponges, and hydrogels are explained. A new aspect is the ability of these materials to support the osteogenic differentiation of stem cells for regenerative medicine therapy.

Surfaces and Sensors The interface between any synthetic or natural polymer and a living system is the most crucial area; this is the only surface that the living system “sees” and to the physical and chemical properties of which it will respond. The success of a biomedically relevant polymer, that can be a drug delivery system, implant, temporary deposit etc., depends primarily on its interaction with the living system it targets. Hence, polymer surfaces garner a lot of attention and can be designed to elicit very different responses, which range from “biological invisibility” to direct interaction, such as recognition or biocidal activity. Numerous reports focus on the functionalization of polymer surfaces in order to render them biocompatible. Yet, polymer surfaces are also the breeding ground for harmful microorganisms. Therefore, it is not only important to develop techniques that make surface biocompatible, it is equally important to develop the chemistries that render surfaces biocidal. Polymers that carry alkylammonium groups belong to a class of materials that effectively contact-kill pathogenic bacteria. Especially polyurethanes can be tailored for these purposes since the broad variety of soft and hard segments together with the tuning of hydrophilic/hydrophobic properties 7 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

can be utilized. Also, cationic amphiphilic copolymers containing different methacrylates are employed to fight drug-resistant bacterial infections. On the other hand, the tailoring of polymer surfaces is a very important facet in the design and generation of biosensors. The ability of sugar-decorated chips to discriminate between different viral strains and to detect viruses with an extremely high sensitivity is described here.

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Conclusion This book demonstrates that research in the field of new polymers for pharmaceutical and biomedical applications is a very active research endeavor and it is also intimately related to the progress achieved by the medical sciences over the last years. Progress in polymer synthetic techniques such as controlled polymerizations, ‘click’ chemistry or enzymatic polymerizations was immediately adopted by the pharmaceutical and medical sciences. Equally, new polymer architectures such as dendrimers and hyperbranched polymers have been introduced for biomedical applications and the bioconjugation of synthetic polymers with drugs and proteins led to break-through therapies. Thus, progress in medicine was in part enabled by advances made in polymer science.

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