Multifunctional and biodegradable polyphosphazenes for use as macromolecular anti-cancer drug carriers

Abstract

Using a living cationic polymerisation procedure we synthesised a series of multi-armed poly(organo)phosphazenes with controlled molecular weights and excellent aqueous solubility. The synthetic flexibility of polyphosphazenes was exploited in order to incorporate an acid-sensitive hydrazide linker to the polymer backbone, as well as tumour-targeting folic acid groups. We were then able to attach hydrophobic anti-cancer drug molecules via the pH labile linker and studied its pH-triggered release kinetics from the polymeric carrier. Although stable for short periods (several days) in an aqueous environment, the polymers were shown to degrade over longer periods (weeks) under simulated physiological conditions. Furthermore, the rate of degradation could be tailored through careful selection of substituents. These biodegradable, multi-functional polyphosphazenes represent promising candidates for use as macromolecular carriers for the tumour-targeted delivery of anti-cancer drugs.

Thermoresponsive Polyphosphazene‐Based Molecular Brushes by Living Cationic Polymerization

“…This was carried out firstly as it is expected to alter the hydrophobicity and rigidity of the polyphosphazenes backbone, and hence the properties of the polymers, but more importantly as it increases the spacing between the otherwise densely packed side chains (two chains per repeat unit for polymers 1‐4 ). Furthermore, the addition of amino acid ester units is known to enhance the rate of biodegradation of the polymers . It was observed from turbidity measurements (figure ), that despite the relatively low molar ratio of Jeffamine to ethyl valinate (25/75), the thermoresponsive properties of the resulting poly(organophosphazene) was predominately influenced by the Jeffamine used, suggesting that the ratio of ethylene oxide to propylene oxide has a significant impact on the thermosensitive properties of the resultant poly(organophosphazenes) and thus is an effective option to tailor these properties.…”

Photopolymerizable Porous Polyorganophosphazenes

“…The yield can certainly be improved by optimizing the technique. The method for this cationic polymerization was optimized by laboratory members [110]. The GPC-measurement performed confirmed that a high molecular weight polymer was produced as shown in Figure 4.10.…”

Branched Macromolecular Architectures for Degradable, Multifunctional Phosphorus‐Based Polymers

“…Investigations into amino acid substituted polyphosphazenes have shown degradation time‐frames ranging from a short half‐life of a few months for glycinate to years for valinate derivatives, due to the increased steric shielding of the phosphorus from hydrolytic attack . Furthermore, introducing hydrolysis sensitizing amino acid esters as co‐substituents represents a simple route to fine tune degradation rates . Amino acid units have also been shown to sensitize polyphosphazenes towards hydrolysis when used as spacers between the phosphorus and the organic substituents, that is replacing the ethyl ester with for example allyl groups for photochemical cross‐linking or water solubilizing groups (Figure ) .…”

“…Furthermore, post‐polymerization functionalization of the bifunctional polyphosphazene repeat unit offers a unique and facile route to multifunctional macromolecules. This has been utilized to attach mixed substituents to the polyphosphazene backbone, such as tumor‐specific targeting ligands in combination with cleavable drugs . Internal functional groups along the phosphazene backbone offer sites for drug conjugation without affecting the surface properties of the carriers, while peripheral functional groups can operate as targeting or solubilizing moieties.…”

“…Rapid, triggered payload release is followed by degradation of the carrier. Adapted with permission . Copyright 2011,The Royal Society of Chemistry.…”