Abstract
Magnetic resonance imaging (MRI) is one of the most widely-used non-invasive clinical imaging tools, producing detailed anatomical images whilst avoiding side effects such as trauma or X-ray radiation exposure. In this article, a new approach to non-invasive monitoring of drug release from a delivery vehicle via MRI was developed, using pH-responsive Eudragit L100 and S100 fibres encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) and carmofur (a drug used in the treatment of colon cancer). Fibres were prepared by electrospinning, and found to be smooth and cylindrical with diameters of 645 ± 225 nm for L100 and 454 ± 133 nm for S100. The fibres exhibited pH responsive dissolution behaviour. Around the physiological pH range, clear pH-responsive proton relaxation rate changes due to matrix swelling/dissolution can be observed: r2 values of L100 fibres increase from 29.3 ± 8.3 to 69.8 ± 2.5 mM-1 s-1 over 3 h immersion in a pH 7.4 medium, and from 13.5 ± 2.0 mM-1 s-1 to 42.1 ± 3.0 mM-1 s-1 at pH 6.5. The r2 values of S100 fibres grow from 30.4 ± 4.4 to 64.7 ± 1.0 mM-1 s-1 at pH 7.4, but at pH 6.5, where the S100 fibres are not soluble, r2 remains very low (< 4 mM-1 s-1). These dramatic changes in relaxivity demonstrate that pH-responsive dissolution results in SPION release. In vitro drug release studies showed the formulations gave rapid release of carmofur at physiological pH values (pH 6.5 and 7.4), and acid stability studies revealed that they can protect the SPIONs from digestion in acid environments, giving the fibres potential for oral administration. Exploration of the relationship between relaxivity and carmofur release suggests a linear correlation (R2 > 0.94) between the two. Mathematical equations were developed to predict carmofur release in vitro, with very similar experimental and predicted release profiles obtained. Therefore, the formulations developed herein have the potential to be used for non-invasive monitoring of drug release in vivo, and could ultimately result in dramatic reductions to off-target side effects from interventions such as chemotherapy.
Highlights
By creating local magnetic field gradients, superparamagnetic iron oxide nanoparticles (SPIONs) can significantly decrease proton transverse relaxation times (T2), boosting signal contrast.[5,6] Their relatively low cytotoxicity and ability to be metabolized by normal biochemical pathways, alongside their unique magnetic properties, makes SPIONs useful for a range of biological applications, including hyperthermia and magnetic targeting.[7,8,9,10] For example, SPIONs have been explored for the targeted delivery of chemotherapeutics or for local temperature-induced apoptosis.[11]
TGA of the PVP-SPIONs (Fig. S1, Electronic supplementary information (ESI)†) revealed weight loss of 3.4 wt% between 40 and 170 1C, due to the removal of physisorbed water, and a weight loss of 6.2 wt% between 170 and 500 1C which can be attributed to the degradation of the PVP stabiliser
PVP-SPIONs and carmofur were encapsulated within pH-responsive Eudragit L100 or S100 nanofibres via electrospinning
Summary
By creating local magnetic field gradients, SPIONs can significantly decrease proton transverse relaxation times (T2), boosting signal contrast.[5,6] Their relatively low cytotoxicity and ability to be metabolized by normal biochemical pathways, alongside their unique magnetic properties, makes SPIONs useful for a range of biological applications, including hyperthermia and magnetic targeting.[7,8,9,10] For example, SPIONs have been explored for the targeted delivery of chemotherapeutics or for local temperature-induced apoptosis.[11]. In order to mimic the conditions encountered during oral delivery, where materials are likely to encounter a range of pH environments (gastric pH is highly acidic (pH 1.0–2.5), while the mean pH values in the proximal small intestine, colon and terminal ileum are 6.6, 7.0 and 7.5),[33] drug release experiments were carried out at different pHs. Initially, S100/Carmofur/SPION
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