Novel, biodegradable, multi-arm polyphosphazenes for biomedical applications

In the first phase of this project we propose the design and synthesis of a series of novel materials based on polyphosphazenes, an extremely useful, but as yet structurally relatively undeveloped group of inorganic-organic polymers. We intend to prepare a series of polymers with tailored and novel architectures for this versatile and flexible group of polymers. In particular, we will look to utilize the recently developed living cationic polymerization method to prepare a series of multi-arm polymers based on polyphosphazenes, including star branched polymers, mixed arm star polymers, as well as core-cross linked micelles. Such structures are, however, of extreme importance for their application as macromolecular drug delivery agents, where polymer size and architecture are critical to biodistribution. We wish to build on these extremely promising preliminary studies to prepare a series of polyphosphazenes with tailored and novel architectures for this extremely useful and flexible group of polymers. It is expected that such materials could have a wide impact in the field of anticancer drug delivery, enhancing the tumour accumulation and reducing the severe side effects of anticancer agents. To this end, the second stage of the project will involve the conjugation and characterization of known and novel organometallic anti-cancer drugs to the functionalized polymeric carriers. This will include the preparation and coupling of state-of-the-art platinum and ruthenium drugs developed in the Keppler laboratories in Vienna. The third stage of the project will be carried out at the Medical University Vienna and will include testing of the in vitro anticancer activity and biocompatibility of the novel compounds, drug uptake and the intracellular distribution of the new polymer-conjugates. In vivo biodistribution and anticancer activity of the most promising drug candidates will then be carried out. We believe this fundamental research could have a great impact on the field of polymer therapeutics, producing a series of exciting new materials for intelligent, enhanced drug delivery applications.

The aim of this project was to develop degradable synthetic polymer carriers for anti-cancer drug delivery applications. In recent years it has been shown by many research groups that macromolecules can be used to improve the biodistribution of typical low molecular weight drugs, that is deliver a higher proportion of the drug to the required site. However, most standard (carbon-based) polymers are non-degradable in the required time frames, leading them to accumulate in the body. On the other hand, many biopolymers are difficult to synthesize and/or manipulate in the required manner. For this reason it was proposed to develop a series of drug carriers based on a much less known group of synthetic inorganic polymers, namely polyphosphazenes, which are polymers with a backbone of phosphorus and nitrogen. In this project, we showed that it was possible to make water soluble versions of these polymers with degradation rates tailored to the proposed application; that is stable for the drug delivery process, but degrading and eliminating from the body rapidly thereafter. A further significant success was the development of new polymerisation methods to be able to prepare the polyphosphazenes in a controlled and suitable manner, as would be required for such pharmaceutical applications. The new methods developed allow the size and shape of the polymers to be precisely tuned, a most important factor in determining the biodistribution of the carriers. This was previously not possible with this family of phosphorus based polymers. Separately, new platinum and ruthenium based drugs were designed, which could be coupled to the macromolecular carriers. The conjugates were designed to only release the drugs inside tumor cells, to potentially reduce side effects that may otherwise occur. Studies showed that the remarkably 30 fold increase in cell uptake of the conjugates compared with the small molecules, with the activity of the drugs also increasing in parallel. In vivo mouse tests were used to confirm the effectiveness of the newly prepared carriers in principal, although further optimization is required to develop these materials as clinical pharmaceuticals.