UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, 5 Cutcombe Road, London, SE5 9RX, UK.
Dalton Trans. 2018 Feb 27;47(9):3166-3177. doi: 10.1039/c7dt03729e.
The potential of the layered gadolinium hydroxide (LGdH) [Gd(OH)]Cl·yHO (LGdH-Cl) for simultaneous drug delivery and magnetic resonance imaging was explored in this work. Three non-steroidal anti-inflammatory drugs (diclofenac [dic], ibuprofen [ibu], and naproxen [nap]) were intercalated into LGdH-Cl for the first time, using three different routes (ion exchange intercalation, coprecipitation, and exfoliation-self-assembly). X-ray diffraction, elemental microanalysis and IR spectroscopy confirmed successful incorporation of the drug into the interlayer spaces of the LGdH in all cases. From a comparison of the guest anion sizes and interlayer spacings, the active ingredients are believed to adopt intertwined bilayer configurations between the LGdH layers. The materials prepared by coprecipitation in general have noticeably higher drug loadings than those produced by ion exchange or self-assembly, as a result of the incorporation of some neutral drug into the composites. The LGdH-drug intercalates are stable at neutral pH, but rapidly degrade in acidic conditions to free Gd into solution. While LGdH-nap releases its drug loading into solution very rapidly (within ca. 1.5 h) at pH 7.4, LGdH-dic shows sustained release over 4 h, and LGdH-ibu extends this to 24 h. The latter composites therefore can be incorporated into enteric-coated tablets to provide sustained release in the small intestine. The drug intercalates are highly biocompatible and retain the proton relaxivity properties of the parent LGdH-Cl, with the materials most promising for use as negative contrast agents in MRI. Overall, the LGdH-drug intercalation compounds appear to have great potential for use in theranostic applications.
本工作探索了层状氢氧化钆（LGdH）[Gd(OH)]Cl·yH2O（LGdH-Cl）在药物输送和磁共振成像（MRI）的联合应用中的潜力。三种非甾体抗炎药（双氯芬酸[dic]、布洛芬[ibu]和萘普生[nap]）首次被插层进入 LGdH-Cl，采用了三种不同的途径（离子交换插层、共沉淀和剥离-自组装）。X 射线衍射、元素微分析和红外光谱证实了药物在所有情况下都成功地进入了 LGdH 的层间空间。从客体阴离子尺寸和层间距的比较来看，活性成分被认为在 LGdH 层之间采用了交错双层结构。一般来说，共沉淀法制备的材料具有明显更高的药物负载量，这是由于一些中性药物被掺入复合材料中。LGdH-药物插层在中性 pH 值下是稳定的，但在酸性条件下迅速降解，将 Gd 释放到溶液中。虽然 LGdH-nap 在 pH 7.4 时非常迅速地将其药物负载释放到溶液中（约 1.5 h 内），但 LGdH-dic 则在 4 h 内持续释放，LGdH-ibu 将其延长至 24 h。因此，后者的复合材料可以被纳入肠溶片剂中，以在小肠中提供持续释放。药物插层具有高度的生物相容性，并保留了母体 LGdH-Cl 的质子弛豫率特性，这些材料最有希望作为 MRI 的阴性对比剂。总的来说，LGdH-药物插层化合物在治疗诊断应用中具有很大的应用潜力。
