Layered terbium hydroxides for simultaneous drug delivery and imaging

Layered rare-earth hydroxides have begun to gather increasing attention as potential theranostic platforms owing to their extensive intercalation chemistry combined with magnetic and fluorescent properties. In this work, the potential of layered terbium hydroxide (LTbH) as a platform for simultaneous drug delivery and fluorescence imaging was evaluated. LTbH-Cl ([Tb2(OH)5]Cl·yH2O) was loaded with three nonsteroidal anti-inflammatory drugs (diclofenac, ibuprofen, and naproxen) via ion-exchange. Drug release studies in phosphate buffered saline (pH = 7.4) revealed all three formulations release their drug cargo rapidly over the course of approximately 5 hours. In addition, solid state fluorescence studies indicated that fluorescence intensity is strongly dependent on the identity of the guest anion. It was postulated that this feature may be used to track the extent of drug release from the formulation, which was subsequently successfully demonstrated for the ibuprofen loaded LTbH. Overall, LTbH exhibits good biocompatibility, high drug loading, and a strong, guest-dependent fluorescence signal, all of which are desirable qualities for theranostic applications

Layered rare-earth hydroxides as multi-modal medical imaging probes: particle size optimisation and compositional exploration

Recently, layered rare-earth hydroxides (LRHs) have received growing attention in the field of theranostics. We have previously reported the hydrothermal synthesis of layered terbium hydroxide (LTbH), which exhibited high biocompatibility, reversible uptake of a range of model drugs, and release-sensitive phosphorescence. Despite these favourable properties, LTbH particles produced by the reported method suffered from poor size-uniformity (670 ± 564 nm), and are thus not suitable for therapeutic applications. To ameliorate this issue, we first derive an optimised hydrothermal synthesis method to generate LTbH particles with a high degree of homogeneity and reproducibility, within a size range appropriate for in vivo applications (152 ± 59 nm, n = 6). Subsequently, we apply this optimised method to synthesise a selected range of LRH materials (R = Pr, Nd, Gd, Dy, Er, Yb), four of which produced particles with an average size under 200 nm (Pr, Nd, Gd, and Dy) without the need for further optimisation. Finally, we incorporate Gd and Tb into LRHs in varying molar ratios (1 : 3, 1 : 1, and 3 : 1) and assess the combined magnetic relaxivity and phosphorescence properties of the resultant LRH materials. The lead formulation, LGd1.41Tb0.59H, was demonstrated to significantly shorten the T2 relaxation time of water (r2 = 52.06 mM−1 s−1), in addition to exhibiting a strong phosphorescence signal (over twice that of the other LRH formulations, including previously reported LTbH), therefore holding great promise as a potential multi-modal medical imaging probe

Biocompatible hydroxy double salts as delivery matrices for non-steroidal anti-inflammatory and anti-epileptic drugs

We recently reported the synthesis of two novel biocompatible hydroxy double salts (HDS), [Mg2Zn3(OH)8]Cl2·3.4H2O (MgZn-Cl) and [Fe2.4Zn2.6(OH)8]Cl2·2H2O (FeZn-Cl) (J. Mater. Chem. B 2016, 4, 5789) and showed them to be suitable for the loading and sustained release of naproxen. Here we build on these findings and report the intercalation, storage stability, biocompatibility and drug release properties of MgZn-Cl and FeZn-Cl loaded with diclofenac, ibuprofen, and valproate. All three active pharmaceutical ingredients could be successfully intercalated into both HDS by ion exchange. An increase in interlayer space from ca. 8 Å to 18.5–27 Å was observed after intercalation, consistent with the replacement of the initial chloride ion with the larger drug anions. Confirmation of successful intercalation was provided by IR spectroscopy, elemental microanalysis, and thermogravimetric analysis. 1H NMR revealed that the structural integrity of the drug ions is not affected by intercalation. Drug release studies were performed in conditions representative of the gastrointestinal tract, and showed that the solubility of the drug ions controls the fate of the HDS in an acidic environment. The valproate intercalates dissolved completely within two hours at pH 1.0, whereas the other drug-loaded HDS freed some of their drug payload in the acidic media and the rest at pH 6.8. The HDS are further found to be biocompatible in an in vitro cell viability test, and to remain stable upon storage for 5 years

Biocompatible hydroxy double salts as delivery matrices for non-steroidal anti-inflammatory and anti-epileptic drugs

We recently reported the synthesis of two novel biocompatible hydroxy double salts (HDS), [Mg2Zn3(OH)8]Cl2·3.4H2O (MgZn-Cl) and [Fe2.4Zn2.6(OH)8]Cl2·2H2O (FeZn-Cl) (J. Mater. Chem. B 2016, 4, 5789) and showed them to be suitable for the loading and sustained release of naproxen. Here we build on these findings and report the intercalation, storage stability, biocompatibility and drug release properties of MgZn-Cl and FeZn-Cl loaded with diclofenac, ibuprofen, and valproate. All three active pharmaceutical ingredients could be successfully intercalated into both HDS by ion exchange. An increase in interlayer space from ca. 8 Å to 18.5–27 Å was observed after intercalation, consistent with the replacement of the initial chloride ion with the larger drug anions. Confirmation of successful intercalation was provided by IR spectroscopy, elemental microanalysis, and thermogravimetric analysis. 1H NMR revealed that the structural integrity of the drug ions is not affected by intercalation. Drug release studies were performed in conditions representative of the gastrointestinal tract, and showed that the solubility of the drug ions controls the fate of the HDS in an acidic environment. The valproate intercalates dissolved completely within two hours at pH 1.0, whereas the other drug-loaded HDS freed some of their drug payload in the acidic media and the rest at pH 6.8. The HDS are further found to be biocompatible in an in vitro cell viability test, and to remain stable upon storage for 5 years

Solid lipid nanoparticles self-assembled from spray dried microparticles

We report the self-assembly of drug-loaded solid lipid nanoparticles (SLNs) from spray dried microparticles comprising poly(vinylpyrrolidone) (PVP) loaded with glyceryl tristearate (GTS) and either indomethacin (IMC) or 5-fluorouracil (5-FU). When the spray dried microparticles are added to water, the PVP matrix dissolves and the GTS and drug self-assemble into SLNs. The SLNs provide a non-toxic delivery platform for both hydrophobic (IMC) and hydrophilic (5-FU) drugs. They show extended release profiles over more than 24 h, and in permeation studies the drug cargo is seen to accumulate inside cancer cells. This overcomes major issues with achieving local intestinal delivery of these active ingredients, in that IMC permeates well and thus will enter the systemic circulation and potentially lead to side effects, while 5-FU remains in the lumen of the small intestine and will be secreted without having any therapeutic benefit. The SLN formulations are as effective as the pure drugs in terms of their ability to induce cell death. Our approach represents a new and simple route to the fabrication of SLNs: by assembling these from spray-dried microparticles on demand, we can circumvent the low storage stability which plagues SLN formulations

Layered double hydroxide-based nanomaterials for biomedical applications

Against the backdrop of increased public health awareness, inorganic nanomaterials have been widely explored as promising nanoagents for various kinds of biomedical applications. Layered double hydroxides (LDHs), with versatile physicochemical advantages including excellent biocompatibility, pH-sensitive biodegradability, highly tunable chemical composition and structure, and ease of composite formation with other materials, have shown great promise in biomedical applications. In this review, we comprehensively summarize the recent advances in LDH-based nanomaterials for biomedical applications. Firstly, the material categories and advantages of LDH-based nanomaterials are discussed. The preparation and surface modification of LDH-based nanomaterials, including pristine LDHs, LDH-based nanocomposites and LDH-derived nanomaterials, are then described. Thereafter, we systematically describe the great potential of LDHs in biomedical applications including drug/gene delivery, bioimaging diagnosis, cancer therapy, biosensing, tissue engineering, and anti-bacteria. Finally, on the basis of the current state of the art, we conclude with insights on the remaining challenges and future prospects in this rapidly emerging field