Shu-Ping Li

Synthesis of nanostructured methotrexate/hydroxyapatite: Morphology control, growth mechanism, and bioassay explore.

In this study, a new structure of methotrexate/hydroxyapatite (MTX/HAp) nanorods via a facile hydrothermal route was reported. The as-synthesized samples were then characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), thermogravimetric (TG) and differential scanning calorimetry (DSC) analysis. In order to explore the formation mechanism, the effects of reaction time, MTX concentrations and addition of ethylene glycol (PEG) were emphatically examined. The results indicated that, with the increase in reaction time, the fibrous nanoparticles turned to needle-like and then to rod-like. Our study also proved that reaction time of 12h was enough for the full-growth of the nanostructure. Drug-loading capacities (AIn) rose dramatically in the first 12h and reached a plateau afterwards. Importantly, MTX played a critical role in the longitudinal growth of MTX/HAp nanostructure and polyethylene glyco (PEG) was a good dispersing agent to improve the monodispersity. As expected, the functional agent of MTX was served as both the target anticancer drug loaded in HAp and effective complex agents to modify and control the morphologies of MTX/HAp. Lastly, in vitro bioassay tests gave us evidence that obvious tumor inhibition can be achieved when MTX was hybridized with HAp.

Au@SiO2 core-shell structure involved with methotrexate: Fabrication, biodegradation process and bioassay explore.

A new strategy is proposed to synthesize a kind of Au@SiO2 core-shell structure with methotrexate (MTX) loaded within it. Firstly, MTX molecules are attracted to the surface and vicinity of Au nanoparticles (NPs). Then the enriched MTX molecules on the surface of Au NPs have a good chance to be wrapped into the core-shell structure when SiO2 is uniformly deposited on the Au core. Secondly, the effect of Au amount and MTX content on the drug-loading capacity is emphatically studied and the result shows that core-shell structure plays a vital role in drug loading. In addition, the biodegradation process is also examined in phosphate buffer solution (PBS) at 37°C. The results show that the biodegradation of Au-MTX@SiO2 core-shell structure can be divided into two stages: the release of drug together with the fragmentation of core-shell structure and the subsequent dissolution of SiO2 layers. Lastly, in vitro bioassay tests give the evidence that obvious tumor inhibition can be achieved in presence of Au-MTX@SiO2 NPs even at low concentration and the efficacy can be greatly enhanced by the photothermal therapy on Au cores.

Novel morphology change of Au-Methotrexate conjugates: From nanochains to discrete nanoparticles

A novel morphology change of Au-methotrexate (Au-MTX) conjugates that could transform from nanochains to discrete nanoparticles was achieved by a simple, one-pot, and hydrothermal growth method. Herein, MTX was used efficiently as a complex-forming agent, reducing agent, capping agent, and importantly a targeting anticancer drug. The formation mechanism suggested a similarity with the molecular imprinting technology. The Au-MTX complex induced the MTX molecules to selectively adsorb on different crystal facets of gold nanoparticles (AuNPs) and then formed gold nanospheres. Moreover, the abundantly binding MTX molecules promoted directional alignment of these gold nanospheres to further form nanochains. More interestingly, the linear structures gradually changed into discrete nanoparticles by adding different amount of ethylene diamine tetra (methylene phosphonic acid) (EDTMPA) into the initial reaction solution, which likely arose from the strong electrostatic effect of the negatively charged phosphonic acid groups. Compared with the as-prepared nanochains, the resultant discrete nanoparticles showed almost equal drug loading capacity but with higher drug release control, colloidal stability, and in vitro anticancer activity.

Influence of Different Solvents on the Property of Methotrexate/Layered Double Hydroxides

Methotrexate (MTX) was intercalated into the layered double hydroxides (LDHs) by the coprecipitation method to form MTX/LDHs nanocompounds, the effect of different solvents, i.e. water, mixture of ethanol and water, mixture of polyethylene glycol-400/4000 (PEG-400/4000) and water, on the properties of MTX/LDHs nanocompounds has been exam- ined carefully. The nanocompounds were then characterized by X-ray diffraction (XRD), Fourier transform infrared spec- troscopy (FTIR), transmission electron/micrograph (TEM), atomic force microscopy (AFM), thermogravimetry/differential scanning calorimetry (TG-DSC) and UV-visible diffuse spectroscopy (UV-vis). XRD and FTIR investigations demonstrated the successful intercalation of MTX anions as a declining monolayer into the interlayer of LDHs and the interlayer spacing changed accordingly with the variation in the kind of solvents. We thought that the addition of ethanol and PEG just changed the growth environment, especially the property of interlayer water in MTX/LDHs compounds and the hypothesis has been proved by the analysis of TG-DSC. There is no intercalation of PEG molecular into the LDHs interlayers from all the charac- terization. Compared with the product prepared in other solvents, the particles obtained in the mixture of PEG-400 and water exhibited round plates with the best monodispersity and the most regular morphology. The mechanism how PEG-400 mole- cules influence the formation of MTX/LDHs nanocompounds is described emphatically: non-ionized PEG-400 molecules will form chain-like structures due to the assembly in water, and the growth of nanocompounds is strictly limited in these structures. Due to the inhibition effect of PEG-400, further agglomeration will be forbidden; as a result the monodispersity will be improved. But when the molecular chain of PEG is too long (i.e. PEG-4000), it goes against the growth of nanocom- pounds on the contrary. The in vitro release experiment has been carried out in phosphate buffer solution at the pH value of 7.4, and the result revealed that the release property of MTX/LDHs can be well described by parabolic diffusion equation, or the release mechanism is mainly belongs to drug diffusion. The work reported here will help to establish a general method for the synthesis of drug/LDH nanocompounds with regular morphology and perfect dispersion properties. Keywords layered double hydroxides; polyethylene glycol; uniform particles; in vitro release

Methotrexate intercalated calcium carbonate nanostructures: Synthesis, phase transformation and bioassay study

The formation and stabilization of amorphous calcium carbonate (ACC) is an active area of research owing to the presence of stable ACC in various biogenic minerals. In this paper, the synthesis of calcium carbonate (CaCO3) under the participation of methotrexate (MTX) via a facile gas diffusion route was reported. The results indicated that the addition of MTX can result in the phase transformation of CaCO3, and then two kinds of hybrids, i.e., MTX-vaterite and stable MTX-ACC came into being. Interestingly, the functional agent MTX served as both the target anticancer drug loaded and effective complexation agents to modify and control the morphology of final samples. The examination of MTX-ACC biodegradation process revealed that the collapse of MTX-ACC nanoparticles was due to the synergistic effect of drug release and the phase transformation. Finally, our study also proved that MTX-ACC exhibited the most excellent suppressing function on the viability of cancer cells, especially after long-time duration.

Synthesis of Au yolk/LDH shell nanoparticles as anticancer vehicles

In this paper, anticancer drug methotrexate (MTX) is applied as a coupling agent to fabricate Au@SiO2 core–shell structures for the first time. Then, a novel kind of Au yolk/LDH shell nanoparticles is obtained by using Au@SiO2 as the template. Finally, the in vitro cytotoxicity is examined and the result indicates that the yolk/shell nanovehicles loaded with MTX exhibit superior anticancer efficacy, compared to the free drug.

Methotrexate intercalated layered double hydroxides with the mediation of surfactants: Mechanism exploration and bioassay study.

Methotrexatum intercalated layered double hydroxides (MTX/LDHs) hybrids were synthesized by the co-precipitation method and three kinds of nonionic surfactants with different hydrocarbon chain lengths were used. The resulting hybrids were then characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM). XRD and FTIR investigations manifest the successful intercalation of MTX anions into the interlayer of LDHs. TEM graphs indicate that the morphology of the hybrids changes with the variation of the chain length of the surfactants, i.e., the particles synthesized using polyethylene glycol (PEG-7) present regular disc morphology with good monodispersity, while samples with the mediation of alkyl polyglycoside (APG-14) are heavily aggregated and samples with the addition of polyvinylpyrrolidone (PVP-10) exhibit irregular branches. Furthermore, the release and bioassay experiments show that monodisperse MTX/LDHs present good controlled-release and are more efficient in the suppression of the tumor cells.

A novel platform designed by Au core/inorganic shell structure conjugated onto MTX/LDH for chemo-photothermal therapy.

A novel platform making up of methotrexate intercalated layered double hydroxide (MTX/LDH) hybrid doped with gold nanoparticles (NPs) may have great potential both in chemo-photothermal therapy and the simultaneous drug delivery. In this paper, a promising platform of Au@PDDA-MTX/LDH was developed for anti-tumor drug delivery and synergistic therapy. Firstly, Au NPs were coated using Layer-by-Layer (LbL) technology by alternate deposition of poly (diallyldimethylammonium chloride) (PDDA) and MTX molecules, and then the resulting core-shell structures (named as Au@PDDA-MTX) were directly conjugated onto the surface of MTX/LDH hybrid by electrostatic attraction to afford Au@PDDA-MTX/LDH NPs. Here MTX was used as both the agent for surface modification and the anti-tumor drug for chemotherapy. The platform of Au@PDDA-MTX/LDH NPs not only had a high drug-loading capacity, but also showed excellent colloidal stability and interesting pH-responsive release profile. In vitro drug release studies demonstrated that MTX released from Au@PDDA-MTX/LDH was relatively slow under normal physiological pH, but it was enhanced significantly at a weak acidic pH value. Furthermore, the combined treatment of cancer cells by using Au@PDDA-MTX/LDH for synergistic hyperthermia ablation and chemotherapy was demonstrated to exhibit higher therapeutic efficacy than either single treatment alone, underscoring the great potential of the platform for cancer therapy.

Induction of Au-methotrexate conjugates by sugar molecules: production, assembly mechanism, and bioassay studies

Au-methotrexate (Au-MTX) conjugates induced by sugar molecules were produced by a simple, one-pot, hydrothermal growth method. Herein, the Au(III)-MTX complexes were used as the precursors to form Au-MTX conjugates. Addition of different types of sugar molecules with abundant hydroxyl groups resulted in the formation of Au-MTX conjugates featuring distinct characteristics that could be explained by the diverse capping mechanisms of sugar molecules. That is, the instant-capping mechanism of glucose favored the generation of peanut-like Au-MTX conjugates with high colloidal stability while the post-capping mechanism of dextran and sucrose resulted in the production of Au-MTX conjugates featuring excellent near-infrared (NIR) optical properties with a long-wavelength plasmon resonance near 630-760 nm. Moreover, in vitro bioassays showed that cancer cell viabilities upon incubation with free MTX, Au-MTX conjugates doped with glucose, dextran and sucrose for 48 h were 74.6%, 55.0%, 62.0%, and 63.1%, respectively. Glucose-doped Au-MTX conjugates exhibited a higher anticancer activity than those doped with dextran and sucrose, therefore potentially presenting a promising treatment platform for anticancer therapy. Based on the present study, this work may provide the first example of using biocompatible sugars as regulating agents to effectively guide the shape and assembly behavior of Au-MTX conjugates. Potentially, the synergistic strategy of drug molecules and sugar molecules may offer the possibility to create more gold-based nanocarriers with new shapes and beneficial features for advanced anticancer therapy.

Synthesis of nanostructured calcium carbonate/methotrexate@silica and its application in cancer therapy

Biomedical applications of nontoxic amorphous calcium carbonate (ACC) have mainly been restricted because of its aqueous instability. Herein, we report the successful synthesis of highly stable ACC–methotrexate (MTX)@SiO2 nanospheres in vitro for use in cancer therapy. Further, vaterite–MTX@SiO2 nanospheres were also prepared for comparison. In our synthesis procedure, ACC–MTX and vaterite–MTX were firstly prepared at different pH values, and then SiO2 layers were subsequently deposited by the well-known Stober method. The results indicated that the special structure of ACC–MTX@SiO2 presents better controlled-release and results in efficient death of cancer cells, thus showing its great potential as a desirable chemotherapeutic system for cancer therapy.