Poly(phosphonate)s: versatile polymers for biomedical applications
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Abstract
Chapter 1 gives a general introduction into the field of poly(phosphoester)s (PPEs). First, an introduction into the use of polymers in biomedical science is given, discussing the fundamental requirements for solvable polymers to be used in the human body. Afterwards, the more sophisticated properties of stimuli-responsive “smart” materials are discussed. Afterwards, the current “gold standard”, PEG, is introduced to determine the base for its success and its drawbacks, highlighting the need for complementary alternatives. The first part of the chapter closes with benefits and disadvantages of a selected few promising alternatives for PEG. Afterwards, a short introduction of phosphorus, concerning its omnipresence and importance in nature, is given.
Chapter 2 presents the synthesis and characterization of PPns carrying different alkyl side chains. Three novel cyclic monomers for the ring-opening polymerization (ROP) are introduced. The polymerization is promoted by the organocatalysts (DBU) and (TBD), proceeds with high control over molecular weight and produces polymers with narrow molecular weight distributions even at full monomer conversion. The polymers with methyl-, ethyl- and i-propyl- side chains are soluble in water without a temperature-dependent phase separation. Polymers with n-butyl side chains exhibit decreased solubility in water, concentration-dependent cloud point temperatures, and show increased toxicity against HeLa cells.
Chapter 3 presents the ROP of a cyclohexyl-substituted monomer. Homopolymers with good control over molecular weight and rather narrow molecular weight distributions are produced. The homopolymer exhibits a glass transition 60 °C higher compared to all previously reported poly(phosphonate)s. Copolymerization with the water-soluble 2-isopropyl-2-oxo-1,3,2-dioxaphospholane (iPrPPn) produces water-soluble, well-defined copolymers.
Chapter 4 presents the design of random poly(phosphonate) copolymers with either high solubility in water or a finely tunable hydrophilic-to-hydrophobic phase transition upon heating (“LCST”). Polymerization via ROP provides high control over molecular weight, copolymer composition, and produces polymers with narrow molecular weight distributions. The phase separation temperature can be adjusted in water and depends mainly on the copolymer composition.
Chapter 5 presents a collaborative work with Prof. Dr. M Kelland from the University of Stavanger, Norway. The ability of PPn copolymers presented in Chapter 3 and Chapter 4 to inhibit gas hydrate formation is evaluated. All of the copolymers give better KHI activity than tests with no additive. However, none of the PPns give lower onset temperatures than the benchmark, poly(N-vinyl caprolactam), a well-known commercial KHI.
Chapter 6 presents the first simple coacervates made from temperature-induced phase separation of aqueous PPn terpolymer solutions. In order to finely tune the balance of hydrophilic and hydrophobic side-chains, functional pendant groups for further modifications are randomly distributed over the whole chain. These functional terpolymers spontaneously phase separate into a polymer rich coacervate phase in water upon heating above the LCST, providing an elegant method to prepare degradable and non-toxic carrier system.
Chapter 7 first presents well-defined degradable PPns with adjustable UCST. The pre-copolymers obtained by ROP are turned into thermoresponsive polymers by thiol-ene modification to introduce pendant carboxylic acids. By this means non-cell-toxic, degradable polymers exhibiting UCST behavior in water are produced. After a thorough investigation of the UCST behavior, block copolymers with PEG as a non-responsive water-soluble block are synthesized via the macroinitiator route.
Chapter 8 presents a cooperative study with Johanna Simon from our group to investigate the influence of surface properties of PPn-coated nanocarriers. The focus is put especially on the protein adsorption behavior of carriers modified with PPns of different hydrophilicity to control the “stealth” properties. We combine the precision of ROP with the grafting-onto process to obtain nanocarriers with precise control over the surface hydrophilicity. We present that the overall protein amount is unchanged in spite of the different hydrophilicity of the investigated surfaces.