Branched Macromolecular Architectures for

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Branched Macromolecular Architectures for Degradable, Multifunctional PhosphorusBased Polymers Helena Henke, Oliver Brüggemann, Ian Teasdale* This feature article briefly highlights some of the recent advances in polymers in which phosphorus is an integral part of the backbone, with a focus on the preparation of functional, highly branched, soluble polymers. A comparison is made between the related families of materials polyphosphazenes, phosphazene/phosphorus-based dendrimers and polyphosphoesters. The work described herein shows this to be a rich and burgeoning field, rapidly catching up with organic chemistry in terms of the macromolecular synthetic control and variety of available macromolecular architectures, whilst offering unique property combinations not available with carbon backbones, such as tunable degradation rates, high multi valency and facile post-polymerization functionalization. As an example of their use in advanced applications, we highlight some investigations into their use as water-soluble drug carriers, whereby in particular the degradability in combination with multivalent nature has made them useful materials, as underlined by some of the recent studies in this area.

1. Introduction Control of macromolecular structure is of paramount importance for the design of modern advanced materials. Indeed, the advent of living polymerization and controlled radical polymerization can be regarded as the foundation of modern nanotechnology.[1] The preparation of ever more well-defined polymers is a central goal in modern macromolecular chemistry and in turn, increased control over macromolecular architecture and the development of polymers with diverse structures and properties. Meanwhile the view of branched polymers has changed from an unwanted side reaction to become a central strategy in the design of functional materials.[2] Today, a significant H. Henke, Prof. O. Brüggemann, Prof. I. Teasdale Institute of Polymer Chemistry Johannes Kepler University Linz Altenberger Straße 69, 4040 Linz, Austria E-mail: [email protected]

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number of three-dimensional macromolecular architectures are widely available, including highly branched polymers,[2] hyperbranched[3] and dendritic polymers,[4] star polymers[5,6] and macromolecular brushes[7] and many more.[8] Highly branched polymers find particular use as functional polymers and as nanocarriers due to their globular structure and high functional group density, as well as higher solubility and lower viscosity compared to their linear counterparts. Furthermore, unique characteristics are often observed, which cannot be obtained by linear polymers, for example the “dendritic effect’’, which describes the altered functional group behavior observed for dendrimers.[9] Thanks to decades of progress, organic polymer chemistry can now rely on a wide platform of reliable and facile methods for the preparation of well-defined polymers with a wide range of architectures and chemical functionalization. However, the chemistry of many inorganic polymers lags far behind,[10] despite the many unique properties that can potentially be achieved beyond the chemistry of carbon based polymers.[11] In this feature

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DOI: 10.1002/marc.201600644


Branched Macromolecular Architectures for Degradable, Multifunctional Phosphorus-Based Polymers

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article we highlight some recent efforts to address this for phosphorus-based polymers and to bring them up to the standards of structural control set for their carbon-based counterparts. Phosphorus-based polymers make up a diverse range of materials, including naturally occurring polymers, not least the high molecular weight polyphosphates DNA and RNA, carriers of the genetic information of all living organisms. Phosphorus can be included into macromolecules as pendant groups,[12] or into the main chain whereby phosphorus is then an integral part of the polymer backbone. Where the latter is the case, specifically designed chemistry is required for their poly merization, as opposed to simply adapting established techniques from organic polymer chemistry. Two of the most prominent phosphorus-based polymers containing phosphorus in the polymer backbone include polyphosphazenes and polyphosphoesters (Figure 1). Applications for both of these families of polymers are wide reaching,[13,14] including as non-halogenated alternatives to known flame retardants[15–18] and as fuel cell membranes,[19,20] as well as agents for catalysis, be it as macromolecular agents[21] or as ligands.[22,23] Of particular interest has been the application of such polymers in biomedical applications,[12,24,25] for example drug and vaccine delivery[26] as well as tissue engineering.[27] Research in phosphorus-containing polymers for a range of biomedical applications is partly driven by the pressing need for degradable polymers in this field. For example, while intricate molecular architectures can be readily prepared from controlled radical polymerizations and are available for sophisticated biomedical applications, the biopersistent nature of the aliphatic C-C backbone, means that they are not always suitable for certain uses. On the other hand, common degradable polymers such as polyesters do not always offer the required properties and ease of functionality.[28] As both polyphos phazenes and polyphosphoesters degrade inherently to metabolizable phosphates (plus ammonium salts for phosphazene), so long as the organic components are also non-toxic, these materials serve as a suitable platform for the design of safe synthetic biomaterials. The range of water-soluble polyphosphazenes and polyphosphoesters available mean they could potentially fulfil the requirement for water-soluble degradable polymers,[29] for example to complement biopersistent water soluble polymers such as polyethylene glycols[30–32] or

Figure 1. Structures of poly(organo)phosphazenes (left) and polyphosphoesters (right). R, R′ can be chosen from a wide range of organic substituents.

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Helena Henke studied chemistry at the University of Vienna (Austria) with a diploma thesis on metal complexes as anticancer agents in the group of Bernhard Keppler and graduated with a Mag. rer. nat. in 2011. Her PhD studies brought her to the Johannes Kepler University Linz (Austria) where she is completing her PhD on the synthesis of polyphosphazenes with controlled dimensions and unique architectures and their application as nanomedicines under the guidance of Ian Teasdale. Oliver Brüggemann studied chemistry at the University of Hannover, Germany (1988–1994). During his doctorate, he worked with the Institute of Food Research in Reading, UK, (1996) and with the EPF Lausanne, Switzerland (1996–1997). After receiving his doctoral degree at the University of Hannover in 1997, he continued his research as a postdoc at the EPFL, and in the following at Lund University, Sweden. In 1999, he moved to Technical University of Berlin, where he finished his habilitation in technical chemistry in 2004. After two years at the polymer research department at BASF, Ludwigshafen, he was appointed as professor of chemical engineering at the Provadis School, located at the chemical park in Frankfurt-Hoechst. Since 2007, he is professor and chair for polymer chemistry at Johannes Kepler University Linz, Austria. Ian Teasdale completed his PhD in chemistry in 2008 at the University of Manchester (UK) working on the synthesis of high performance polyaryletherketones, under the guidance of Prof. Michael L. Turner. A postdoc position at the Institute of Polymer Chemistry at the Johannes Kepler University Linz (Austria) was followed by assistant professorship in polymer chemistry. He was recently promoted to associate professor at the same university where he is currently interested in synthetic polymer chemistry with a particular research focus on polyphosphazene synthesis and their use as degradable polymers, as well as their application in biomedical applications drug delivery and tissue engineering.

polyvinylpyrrolidone.[33] In this regard, water-soluble, multifunctional polymers with controlled, especially branched structures,[4,34,35] are of special interest therapeutic applications,[36] whereby polymeric carriers which are fully degradable to small molecules are of paramount importance.[37] In the second half of this article we

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Figure 2. Scheme for the post-polymerization substitution of poly(dichlorophosphazenes).

highlight the application of such degradable, multifunctional polymers in drug delivery.

2. Synthesis 2.1. Polyphosphazenes Poly(dichlorophosphazene) [NPCl2]n, the primary precursor to polyphosphazenes, is highly reactive and thus under anhydrous conditions can be readily substituted with a wide range of organic nucleophiles leading to poly(organo) phosphazenes.[13] This facile post-polymerization substitution (Figure 2), also referred to as macrosubstitution,[38] expedites the preparation of polymers not only with very differing properties but a uniquely high multivalency due to the two substitutable chlorine atoms per repeat unit. High molecular weight [NPCl2]n is traditionally synthesized via thermal ring opening polymerization of hexachlorocyclotriphosphazene [NPCl2]3 at 250 °C under vacuum[38] or in solution[39,40] and can be prepared on an industrial scale.[38] Although some catalysts lower the initiation temperature of [NPCl2]3, including Lewis acids such as AlCl3[41] and BCl3,[42] there is a small temperature window for initiation, above which uncontrolled branching and cross-linking occur, in part due to randomized Cl cleavage along the polymer chain.[43] Furthermore, the extent of polymerization is difficult to control, resulting in polymers with broad molecular weight

distributions.[44] Investigations into an ambient temperature ring opening polymerization via trialkylsilylated phosphazene cations, together with bulky carborane counterions[45] has been shown to lead to full conversion at room temperature[45,46] possibly leading to better control over the ring-opening polymerization [NPCl2]n,[47] although the accessibility of the initiators is limited.[48] The development of a room temperature poly merization of trichloro(trimethylsilyl)phosphoranimine (Cl3PNSi(CH3)3) has provided much needed control over the synthesis of [NPCl2]n to achieve not only polymers with narrow polydispersities, but also to gain access to block polymers and more advanced structures.[10,32,49–52] The most frequently used initiator for the polymerization of the monomer Cl3PNSi(CH3)3 to [NPCl2]n is PCl5.[49,53] The reaction of 2:1 equivalents of PCl5 to Cl3PNSi(CH3)3 leads to the formation of [Cl3PNPCl3]+ [PCl6]−. The cationic species [Cl3PNPCl3]+ can react with further equivalents of Cl3PNSi(CH3)3 in a living cationic polymerization with the number of repeat units determined by the further equivalents of monomer added.[46,54] Narrow dispersities (Đ) can be attained for shorter chains n