Abstract
Following the huge clinical success of drug-eluting vascular stents, there is a significant interest in the development of drug-eluting stents for other applications, such as the treatment of gastrointestinal (GI) cancers. Central to this process is understanding how particular drugs are released from stent coatings, which to a large extent is controlled by drug-polymer interactions. Therefore, in this study we investigated the release of docetaxel (DTX) from a selection of non-degradable polymer films. DTX-polymer films were prepared at various loadings (1, 5 and 10% w/w) using three commercially available polymers including poly(dimethylsiloxane) (PSi), poly (ethylene-co-vinyl acetate) (PEVA) and Chronosil polyurethane (PU). The formulations were characterised using different techniques such as photoacoustic Fourier-transform infrared (PA-FTIR) spectrophotometry, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The effect of DTX on the mechanical properties of the films, in-vitro release, and degradation tests were also assessed. For all polymers and DTX loadings, the drug was found to disperse homogenously without crystallisation within the polymer matrix. While no specific interactions were observed between DTX and PSi or PEVA, hydrogen-bonding appeared to be present between DTX and PU, which resulted in a concentration-dependent decrease in the Young’s moduli of the films due to disruption of inter-polymeric molecular interactions. In addition, the DTX-PU interactions were found to modulate drug release, providing near-linear release over 30 days, which was accompanied by a significant reduction in degradation products. The results indicate that DTX-loaded PU films are excellent candidates for drug-eluting stents for the treatment of oesophageal cancer.
Highlights
A recent report from the Global Burden of Disease Cancer Collaboration highlighted oesophageal cancer as the 11th most common type of cancer by the number of incidents in both sexes globally [1]
Whilst no significant differences between the paclitaxel eluting stent and uncoated control stents were found, this study provided the basis for further testing of drug-eluting stents (DESs) in oesophageal cancer clinical studies
DTX therapy is associated with systemic side effects such as neurotoxicity, musculoskeletal toxicity and neutropenia, cumulative fluid retention and peripheral neuropathy caused by prolonged infusion of DTX, and severe hypersensitivity reactions and hyperlipidemia caused by polysorbate 80
Summary
A recent report from the Global Burden of Disease Cancer Collaboration highlighted oesophageal cancer as the 11th most common type of cancer by the number of incidents in both sexes globally [1]. DTX therapy is associated with systemic side effects such as neurotoxicity, musculoskeletal toxicity and neutropenia, cumulative fluid retention and peripheral neuropathy caused by prolonged infusion of DTX, and severe hypersensitivity reactions and hyperlipidemia caused by polysorbate 80 Considering these drawbacks, recent and extensive effort has been focused on the development of less toxic formulations that avoid the use of polysorbate 80 and provide more targeted drug delivery [48]. DESs provide a unique opportunity to deliver therapeutics, such as DTX, locally from a polymer coating to the target tissue, whilst minimising systemic toxicities. In this study we assessed a selection of clinically relevant non-biodegradable polymers (poly(dimethylsiloxane) (PSi), PEVA and Chronosil polyurethane (PU)) to prepare DTX-loaded films as potential DES covering materials for localized delivery of DTX to the oesophagus lumen. The performance of the different polymer compositions was determined using various analytical techniques to allow selection of the most appropriate DTX-polymer combination based on physical characteristics and release behaviour
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