Polymers as Tools in Medicine

Multifunctional Polyphosphazenes for Drug Delivery and Tissue Engineering

  • Fig. 1: Degradable multifunctional polyphosphazenes tailored for (left) drug delivery and (right) tissue engineering applications.Fig. 1: Degradable multifunctional polyphosphazenes tailored for (left) drug delivery and (right) tissue engineering applications.
  • Fig. 1: Degradable multifunctional polyphosphazenes tailored for (left) drug delivery and (right) tissue engineering applications.
  • Fig. 2: Schematic structures of polymers 1 with a glycine spacer, 3 with a valine spacer and 5 without any amino acid moieties (a). Degradation profiles of polymer 1 (∆), 3 (Ο) and polymer 5 () at pH 5. The release of phosphate was quantitatively determined by UV-Vis analysis (b). Used with permission from [9] (a) and [7] (b).
  • Fig. 3: Design of crosslinked porous networks based on photoinitiated thiol-ene click reactions of ene-functionalized polyphosphazenes with polythiols in the absence (polymer 2) or presence (polymers 3-5) of additional divinyl components. Lower right corner: resulting exemplary disc shaped scaffold. Used with permission from [9].

The Institute of Polymer Chemistry at the Johannes Kepler University Linz focuses its research mainly on the synthesis and characterization of functional polymers for applications in skin care formulations, in catalysis, or in chromatography. This also includes works on the development of biomimetic materials like DNA strands based on artificial backbones or stimuli-responsive capsules using renewable resources such as silk proteins. Industrial aspects of polymers and plastics, such as degradation effects during polymer processing or the immobilization of stabilisers in polyolefines, are also covered.

Individual Polymer Design for Specific Purposes
In a number of projects, functional polymers are synthesized to be utilized in medical applications, such as drug delivery, controlled substance release and tissue engineering. At the institute, for these purposes polyphosphazenes are often chosen as the polymer basis, with their backbones only consisting of alternating phosphorous and nitrogen atoms in the main chain in combination with carbon-based substituents. Polyphosphazenes are a unique and versatile class of macromolecules allowing tailor-made design for medical and pharmaceutical applications [1,2], flame retardants, or polymeric electrolytes for fuel cells and batteries. These special polymers appear either in form of thermoplastic fibers and membranes, high performance elastomers, hydrogels, soluble linear or non-soluble crosslinked macromolecules. Depending on the side-group substituents, polyphosphazenes can also be rendered bioerodible, undergoing hydrolytic degradation to biologically benign small molecules.

In the approaches presented here polyphosphazenes are synthesized mainly via living cationic polymerization allowing the control of their molecular weight and polydispersity. These polymers are developed to be used as drug carriers [3-5] or crosslinked scaffolds for cell cultivation. Figure 1 demonstrates the similarities in the design of these polymers leading, however, to different applications. It is shown that these polyphosphazenes may be equipped with a wide range of functionalities.

They may be tailored individually by attaching for example selected drug molecules, additional targeting groups, solubility modifiers, fluorescent labels, crosslinkable and/or other chemical functionalities to the backbones. By this means, highly complex macromolecules can be designed, e.g., for drug delivery in cancer treatment, allowing the targeted release of the pharmaceutical agent in the vicinity of the tumor (fig. 1, left). In this example, the enhanced permeability and retention (EPR) effect allows the accumulation of the drug-polymer conjugate in the tumor tissue [6], and a carefully designed pH sensitive linker leads to a triggered intracellular release of the active agent.

Alternatively, polyphosphazenes functionalized with photoreactive moieties, may, after crosslinking, be used as scaffolds allowing cells to grow in a governed way, leading to the generation of new tissue, which can be implanted later (fig. 1, right).

Polymer Degradation with Chemically Based Timers
Alongside the versatility of these macromolecules, another major advantage of polyphosphazenes, either linear or crosslinked, is their ability to hydrolytically degrade after fulfilling their tasks [5,7]. Polyphosphazenes degrade into harmless phosphates and ammonia salts. Together with the relatively small side arms, these molecules may easily be excreted from the body, avoiding a permanent presence and a continuous, thus, potentially hazardous accumulation of polymers in the bloodstream or the tissues. Importantly, the degradation rate of the polyphosphazenes can also be tailored, depending on the number and type of functional groups linked to the chains. For instance, after using additional amino acid spacers such as glycine or valine between the polyphosphazene backbone and water solubilizing side arms (fig. 2a), the degradation profiles could be altered significantly. This could be observed by determination of the release of phosphate as one significant degradation product via UV-Vis spectroscopy (fig. 2b). With glycine as spacer, the degradation rate was highest, compared to valine, which still increased the rate compared to an amino acid free polyphosphazene.

Click-reactions for the Generation of 3-D Polymer Scaffolds
Polyphosphazene based scaffolds for tissue engineering can be achieved via photochemical crosslinking [8], to give 3-D matrices which are stable during the interaction with cells and their aqueous environment. For this purpose, polyphosphazene chains coupled with vinyl functionalities may be interconnected in the presence of polythiols by UV initiated thiol-ene click reactions (fig. 3, polymer 2). The hydrophobicity of the polyphosphazene network can be readily altered using additional divinyl components to provide optimum interaction with living cells (fig. 3, polymers 3-5). Pores are generated by the use of sodium chloride crystals as a porogen during crosslinking, which can simply be washed out after obtaining the porous 3-D matrices. An exemplary disc shaped scaffold is shown in Figure 3 (right lower corner).

In a number of biocompatibility tests it could be demonstrated that the polymers do not show any significant toxicity towards the cells. Furthermore, cell adhesion and proliferation is observed to be comparable to classic scaffolds such as collagen based materials, but with the added ease of functionalization of these synthetic materials. Further optimization of these systems is currently underway.

Overall, it can be stated the polyphosphazenes presented here are highly promising candidates for drug delivery and tissue engineering applications, which demand a unique combination of precise structural control, adaptability and tailored bioerodibility.

[1] Allcock H.R. and Morozowich N.L.: Polym. Chem. 3, 578-590 (2012)
[2] M. Deng et al.: Soft Matter 6, 3119-3132 (2010)
[3] I. Teasdale and O. Brüggemann: Polymers 5, 161-187 (2013)
[4] I. Teasdale et al.: Mon. Chem. 143, 355-360 (2012)
[5] I. Teasdale et al.: Polym. Chem. 2, 828-834 (2011)
[6] Y. Matsumura and H.Maeda: Cancer Res. 46, 6387-6392 (1986)
[7] S. Wilfert et al.: J. Polym. Sci., Part A: Polym. Chem. 52, 287-294 (2014)
[8] S. Wilfert, T. Aigner, A. Iturmendi, R. Forstner, M. Rigau, F. Hildner, E. Oberbauer, G. Olawale, B. Husar, R. Liska, K. R. Schröder, O. Brüggemann, I. Teasdale: submitted (2014)
[9] S. Wilfert: Dissertation: Novel and functional polyphosphazenes for biomedical applications, Johannes Kepler University Linz, 2014.




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