Zi Gu

Enhanced effects of low molecular weight heparin intercalated with layered double hydroxide nanoparticles on rat vascular smooth muscle cells.

Surgical procedures to remove atherosclerotic lesions and restore blood flow also injure the artery wall, promoting vascular smooth muscle cell (SMC) phenotypic change, migration, proliferation, matrix production and ultimately, restenosis of the artery. Hence identification of effective anti-restenotic strategies is a high priority in cardiovascular research, and SMCs are a key target for intervention. This paper presents the in vitro study of layered double hydroxides (LDHs) as drug delivery system for an anti-restenotic drug (low molecular weight heparin, LMWH). The cytotoxicity tests showed that LDH itself had very limited toxicity at concentrations below 50 microg/mL over 6-day incubation. LDH nanoparticles loaded with LMWH (LMWH-LDHs) were prepared and tested on rat vascular SMCs. When conjugated to LDH particles, LMWH enhanced its ability to inhibit SMC proliferation and migration, with greater than above 60% reduction compared with the control (growth medium) over 3 or 7-day incubation. Cellular uptake studies showed that compared with LMWH alone, LMWH-LDH hybrids were internalized by SMCs more rapidly, and uptake was sustained over a longer time, possibly revealing the mechanisms underlying the enhanced biological function of LMWH-LDH. The results suggest the potential of LMWH-LDH as an efficient anti-restenotic drug for clinical application.

Pre-coating layered double hydroxide nanoparticles with albumin to improve colloidal stability and cellular uptake

One of the major challenges for nanoparticles to be used as a drug/gene delivery platform is their tendency to aggregate in electrolyte solution (physiological environment). The present work introduced the albumin pre-coating strategy that effectively prevented inorganic layered double hydroxide (LDH) nanoparticles with different sizes and interlayer anions from aggregation in phosphate buffer saline and cell culture medium solutions. We found that the key factors influencing the colloidal stability of albumin-coated LDHs included (1) the sequence and speed of reagent addition during the pre-coating process, (2) the albumin/LDH mass ratio, (3) the LDH particle size, and (4) anions intercalated in the LDH. Approximately, LDH nanoparticles with the size of 110 nm were well stabilised at the albumin/LDH mass ratio of 5 : 2 when LDH suspension was added into albumin solution dropwise with vigorous stirring. The albumin pre-coating also enhanced cellular uptake of LDH nanoparticles in Chinese hamster ovary cell culture. The configuration, affinity and adsorption isotherm of albumin on LDH nanoparticles were further investigated. The results in this work imply that the albumin-coating strategy is a potential method to prevent LDH nanoparticle aggregation in in vivo drug/gene delivery.

Antibody-targeted drug delivery to injured arteries using layered double hydroxide nanoparticles

Targeted local delivery of a nanoparticle-based, antibody-targeted, and low molecular weight heparin (LMWH) delivery system successfully reduces restenosis and thrombus formation in an animal model. An antibody recognizing cross-linked fibrin (XLF) D-dimer is successfully conjugated to layered double hydroxide nanoparticles. Use of the anti-XLF-conjugated LMWH-carrying layered double hydroxide nanoparticles shows successful targeting of the nanoparticles (red) to the injured artery wall (green), resulting in decreased neointimal thickening and thrombus formation.

Two-dimensional black phosphorus nanosheets for theranostic nanomedicine

The fast progress of theranostic nanomedicine has catalyzed the generation of diverse inorganic nanosystems with intrinsic multifunctionalities for versatile biomedical applications. However, these inorganic biomaterials suffer from the critical issue of low biodegradation rates and subsequently long-term accumulation-induced biosafety risk. Furthermore, the components of some inorganic nanosystems are not the necessary elements/components of the body, unavoidably causing immune response and inducing the toxic potential. The emergence of ultrathin two-dimensional black phosphorus (B.P.) nanosheets as a robust platform promises the clinical translation and biomedical applications of inorganic nanosystems based on their intriguing nature of easy biodegradation and single phosphorus composition, as necessarily required in vivo. This review summarizes and discusses the very recent developments and paradigms of ultrathin B.P. nanosheets in versatile biomedical applications, ranging from design/fabrication strategies, theranostic nanomedicine (PDT/PTT/chemotherapy, synergistic therapy and fluorescence/photoacoustic-based bio-imaging) to biosensing applications. The unique biological behavior and toxicity issue of these B.P. nanosheets are also discussed to guarantee their safe clinical translation. It is highly expected that the elaborately designed/engineered B.P. nanosheets will emerge as one of the most representative biodegradable inorganic nanosystems for versatile and immense biomedical applications to benefit the health of human beings.

Enhanced transcription and translation in clay hydrogel and implications for early life evolution

In most contemporary life forms, the confinement of cell membranes provides localized concentration and protection for biomolecules, leading to efficient biochemical reactions. Similarly, confinement may have also played an important role for prebiotic compartmentalization in early life evolution when the cell membrane had not yet formed. It remains an open question how biochemical reactions developed without the confinement of cell membranes. Here we mimic the confinement function of cells by creating a hydrogel made from geological clay minerals, which provides an efficient confinement environment for biomolecules. We also show that nucleic acids were concentrated in the clay hydrogel and were protected against nuclease, and that transcription and translation reactions were consistently enhanced. Taken together, our results support the importance of localized concentration and protection of biomolecules in early life evolution, and also implicate a clay hydrogel environment for biochemical reactions during early life evolution.

Manganese-based layered double hydroxide nanoparticles as a T1-MRI contrast agent with ultrasensitive pH response and high relaxivity

Recently, Mn(II)-containing nanoparticles have been explored widely as an attractive alternative to Gd(III)-based T1 -weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn-based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5-7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH-ultrasensitive Mn-based layered double hydroxide (Mn-LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm-1 s-1 at pH 5.0 and 6.82 mm-1 s-1 at pH 7.0 vs 1.16 mm-1 s-1 at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn-LDH, as demonstrated by extended X-ray absorption fine structure. Further in vivo imaging reveals that Mn-LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn-doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment.

Crosslinking to enhance colloidal stability and redispersity of layered double hydroxide nanoparticles

This article introduces a strategy for stabilizing and redispersing layered double hydroxide (LDH) nanoparticles by crosslinking bovine serum albumin (BSA) coated onto the surface. The strategy involves optimization of the amount of the crosslinking agent glutaraldehyde (GTA) to achieve minimal aggregation and ready redispersion. LDH nanoparticles were prepared by co-precipitation and hydrothermal treatment, with subsequent BSA coating at the BSA/LDH mass ratio of 5:2. BSA coated onto LDH nanoparticles was crosslinked with different amounts of GTA. Aggregation studies using dilution assays, dynamic light scattering, and zeta potential analysis indicated that severe aggregation at lower LDH nanoparticle concentrations can be prevented by proper crosslinking of BSA with GTA. The GTA-crosslinked BSA-coated nanoparticles showed excellent redispersity compared to the non-crosslinked nanoparticles. In vitro cytotoxicity and cell uptake were found to be minimally affected by GTA-crosslinking. The new strategy therefore provides a much more effective method for the prevention of LDH nanoparticle aggregation and improved LDH nanoparticle redispersion for use in a wide variety of bio-applications in vitro and in vivo.

Efficient drug delivery using SiO2-layered double hydroxide nanocomposites

MgAl-layered double hydroxide (MgAl-LDH) nanoparticles have great potentials in drug and siRNA delivery. In this work, we used a nanodot-coating strategy to prepare SiO2 dot-coated layered double hydroxide (SiO2@MgAl-LDH) nanocomposites with good dispersibility and controllable size for drug delivery. The optimal SiO2@MgAl-LDH nanocomposite was obtained by adjusting synthetic parameters including the mass ratio of MgAl-LDH to SiO2, the mixing temperature and time. The optimal SiO2@MgAl-LDH nanocomposite was shown to have SiO2 nanodots (10-15nm in diameter) evenly deposited on the surface of MgAl-LDHs (110nm in diameter) with the plate-like morphology and the average hydrodynamic diameter of 170nm. We further employed SiO2@MgAl-LDH nanocomposite as a nanocarrier to deliver methotrexate (MTX), a chemotherapy drug, to the human osteosarcoma cell (U2OS) and found that MTX delivered by SiO2@MgAl-LDH nanocomposite apparently inhibited the U2OS cell growth.

Aggregation of layered double hydroxide nanoparticles in the presence of heparin: towards highly stable delivery systems

The effect of heparin adsorption on the colloidal stability of layered double hydroxide particles as potential drug delivery agents was studied in aqueous suspensions. The lamellar structures were prepared by the co-precipitation method and composed of magnesium(II) and aluminium(III) mixed hydroxide as the layers and carbonate anions between the layers. Stable and positively charged particles were observed at low heparin concentrations and low ionic strengths where the surface charge was only partially neutralized by the oppositely charged natural polyelectrolyte adsorbed on the surface. Increasing the heparin dose resulted in charge neutralization and subsequent charge reversal at appropriate doses. The particles aggregated rapidly in the absence of sufficient surface charge, however, remarkably stable dispersions were obtained when the particles were completely covered by heparin. The latter coating process gave rise to two-times higher surface charge density in magnitude and about 20-times higher critical coagulation concentration than for the bare particles. The significant stabilization effect due to the heparin-coating resulted from repulsive interparticle forces of electrostatic and steric origin. On the basis of these findings, efficient delivery systems can be designed where the colloid stability of the carrier particles is enhanced by coating with a biocompatible polyelectrolyte.

Influence of hydrothermal treatment on physicochemical properties and drug release of anti-inflammatory drugs of intercalated layered double hydroxide nanoparticles.

The synthesis method of layered double hydroxides (LDHs) determines nanoparticles’ performance in biomedical applications. In this study, hydrothermal treatment as an important synthesis technique has been examined for its influence on the physicochemical properties and the drug release rate from drug-containing LDHs. We synthesised MgAl–LDHs intercalated with non-steroidal anti-inflammatory drugs (i.e., naproxen, diclofenac and ibuprofen) using a co-precipitation method with or without hydrothermal treatment (150 °C, 4 h). After being hydrothermally treated, LDH–drug crystallites increased in particle size and crystallinity, but did not change in the interlayer anion orientation, gallery height and chemical composition. The drug release patterns of all studied LDH–drug hybrids were biphasic and sustained. LDHs loaded with diclofenac had a quicker drug release rate compared with those with naproxen and ibuprofen, and the drug release from the hydrothermally-treated LDH–drug was slower than the freshly precipitated LDH–drug. These results suggest that the drug release of LDH–drugs is influenced by the crystallite size of LDHs, which can be controlled by hydrothermal treatment, as well as by the drug molecular physicochemical properties.