Ya Ding

Gold Nanoparticles for Nucleic Acid Delivery

Gold nanoparticles provide an attractive and applicable scaffold for delivery of nucleic acids. In this review, we focus on the use of covalent and noncovalent gold nanoparticle conjugates for applications in gene delivery and RNA-interference technologies. We also discuss challenges in nucleic acid delivery, including endosomal entrapment/escape and active delivery/presentation of nucleic acids in the cell.

Paclitaxel-loaded N-octyl-O-sulfate chitosan micelles for superior cancer therapeutic efficacy and overcoming drug resistance.

The nanoparticle-based drug delivery system holds great attraction to overcome or circumvent multidrug resistance (MDR) in cancer to date. In this work, a synthesized amphiphilic graft copolymer, N-octyl-O-sulfate chitosan (NOSC), and its paclitaxel (PTX)-encapsulated micelles (PTX-M) have been systematically investigated on the MDR reversal effect in vitro and in vivo as well as the mechanism of P-glycoprotein (P-gp) inhibition. NOSC in a wide concentration range even above the critical micelle concentration showed an effective effect on inhibiting P-gp-mediated PTX efflux, which was remarkably different from the surfactants and the Pluronic copolymers. Multiple mechanisms were involved in this effect of NOSC, such as stimulating P-gp ATPase, competitively impeding the binding of PTX with P-gp and reducing the fluidity of the cell membrane. PTX-M presented the highest cellular uptake and the lowest efflux rate of PTX, thereby yielding the optimal cytotoxicity on both the human hepatocellular liver carcinoma (HepG2) cells and the multidrug resistance HepG2 (HepG2-P) cells, which resulted from a combination of the inhibiting P-gp effect of NOSC and the bypassing P-gp action of the intact PTX-M. Additionally, PTX-M had superior blood persistence, tumor accumulation, and therapeutic efficacy after intravenous injection into the tumor-bearing mice. Furthermore, it was demonstrated that most of PTX-M as an intact form was delivered at the tumor site, which ensures the synergetic effect of NOSC micelles on drug delivery and P-gp inhibition. The aforementioned results suggested that NOSC micelles presented promising potential as an anticancer drug carrier for enhanced MDR cancer therapy.

The performance of thiol-terminated PEG-paclitaxel-conjugated gold nanoparticles

A series of thiol-terminated polyethylene glycol (PEG)-paclitaxel (PTX) derivatives are designed and synthesized to fabricate PTX-conjugated gold nanoparticles (PTX@GNPs) and improve their overall performance. By extending the molecular weight of PEG from 400 to 1000 Da, the optimized water solubility of the conjugate reaches 184 mg/mL, equal to 4.6 × 10(5) times that of PTX alone (0.4 μg/mL). High drug loading is obtained by eliminating the steric hindrance between PTX molecules on the surface of GNPs. The gold conjugate shows double simultaneous stimulation-induced drug release behavior in the presence of both esterase and high concentrations of glutathione. The synergic release characteristics of this conjugate results in significant performance improvements, including prolonged circulation due to high stability in vivo, targeted release of PTX inside tumor cells, and increased tumor cell killing efficiency. Improving the in vitro properties of the conjugate not only significantly enhances its therapeutic efficacy in a murine liver cancer model, but also allows drug-conjugated gold nanoparticles to be used as a promising nanoprodrug system in the cancer therapeutics.

Cysteine-grafted chitosan-mediated gold nanoparticle assembly: from nanochains to microcubes

Molecule-mediated nanoparticle assemblies were obtained by the rational design and modification of chitosan, and grafting it onto gold nanoparticles, providing a new way for combining the virtues of synthetic and biological polymers. Using thiolate-functionalized chitosan molecules as soft templates, gold nanoparticles were found to self-organize into 1D nanochains via specific molecular recognition, or assemble into 2D needle-like crystals and 3D flower clusters through conformational change of the template. Such clusters may further re-crystallize into gold single crystal microcubes by way of a simple dialysis method. The as-prepared nano- and microstructures were characterized and the mechanism for the gold nanoparticle assembly process and microcrystal formation was revealed. This work demonstrates a simple and novel approach for fabricating well defined gold nano- and microstructures through a controlled nanoparticle self-assembly process.

Monodisperse Au–Fe2C Janus Nanoparticles: An Attractive Multifunctional Material for Triple-Modal Imaging-Guided Tumor Photothermal Therapy

Imaging-guided photothermal therapy (PTT) by combination of imaging and PTT has been emerging as a promising therapeutic method for precision therapy. However, the development of multicomponent nanoplatforms with stable structures for both PTT and multiple-model imaging remains a great challenge. Herein, we synthesized monodisperse Au-Fe2C Janus nanoparticles (JNPs) of 12 nm, which are multifunctional entities for cancer theranostics. Due to the broad absorption in the near-infrared range, Au-Fe2C JNPs showed a significant photothermal effect with a 30.2% calculated photothermal transduction efficiency under 808 nm laser irradiation in vitro. Owing to their excellent optical and magnetic properties, Au-Fe2C JNPs were demonstrated to be advantageous agents for triple-modal magnetic resonance imaging (MRI)/multispectral photoacoustic tomography (MSOT)/computed tomography (CT) both in vitro and in vivo. We found that Au-Fe2C JNPs conjugated with the affibody (Au-Fe2C-ZHER2:342) have more accumulation and deeper penetration in tumor sites than nontargeting JNPs (Au-Fe2C-PEG) in vivo. Meanwhile, our results verified that Au-Fe2C-ZHER2:342 JNPs can selectively target tumor cells with low cytotoxicity and ablate tumor tissues effectively in a mouse model. In summary, monodisperse Au-Fe2C JNPs, used as a multifunctional nanoplatform, allow the combination of multiple-model imaging techniques and high therapeutic efficacy and have great potential for precision theranostic nanomedicines.

Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy

Hybrid drug delivery system containing both organic and inorganic nanocarriers is expected to achieve its complementary advantages for the aim of improving the performance of antineoplastic drugs in tumor therapy. Here we report the use of liposomes and gold nanoparticles to construct a liposome with a hybrid Cluster Bomb structure and discuss its unique multi-order drug release property for liver tumor treatment. A very simple method is used for the hybrid liposome preparation and involves mixing two solutions containing liposomes loaded with either non-covalent or covalent Paclitaxel (PTX, namely free PTX or PTX-conjugated GNPs, respectively) by different ratio of volume (25:75, 50:50, 25:75, v/v). Various mixed liposomes were tested to determine the optimal conditions for maximum drug delivery. The optimized liposome was then tested using xenograft Heps tumor-bearing mice and showed the best efficacy for chemotherapeutic inhibition of tumor at PTX liposome: PTX-conjugated GNP liposome of 25:75 ratio (v/v). This system allows for simple and easy preparation while providing a more accurate site- and time-release mode for tumor treatment using antitumor drugs.

The enhanced longevity and liver targetability of Paclitaxel by hybrid liposomes encapsulating Paclitaxel-conjugated gold nanoparticles

Organic and inorganic drug delivery systems both demonstrate their own advantages and challenges in practical applications. Combining these two drug delivery strategies in one system is expected to solve their current issues and achieve desirable functions. In this paper, gold nanoparticles (GNPs) and liposomes have been chosen as the model systems to construct a hybrid system and investigate its performance for the tumor therapy of Paclitaxel (PTX). The thiol-terminated polyethylene glycol (PEG400)-PTX derivative has been covalently modified on the surface of GNPs, followed by the encapsulation of PTX-conjugated GNPs (PTX-PEG400@GNPs) in liposomes. The hybrid liposomes solve the solubility and stability problems of gold conjugates and show high drug loading capacity. In vitro PTX release from the hybrid system maintains the similar sustained behavior demonstrated in its conjugates. Under the protection of a biocompatible liposome shell, encapsulated PTX shows enhanced circulation longevity and liver targetability compared to Taxol(®) and PTX-PEG400@GNPs suspension in the pharmacokinetic and biodistribution studies. These indicate that encapsulating drug-conjugated inorganic nanoparticles inside organic carriers maintains the superiority of both vehicles and improves the performance of hybrid systems. Although these attributes of hybrid liposomes lead to a better therapeutic capacity in a murine liver cancer model than that of the comparison groups, it shows no significant difference from Taxol(®) and conjugate suspension. This result could be due to the delayed and sustained drug release from the system. However, it indicates the promising potential for these hybrid liposomes will allow further construction of a compound preparation with improved performance that is based on their enhanced longevity and liver targetability of Paclitaxel.

Gold Nanoparticle-Based Drug Delivery Platform for Antineoplastic Chemotherapy

Gold nanoparticles (AuNPs) have demonstrated increasingly wide applications in drug delivery due to their unique physicochemical and optical properties as well as low toxicity. Compared to the organic nanocarriers for therapeutic agents, AuNPs have shown superior performance as drug delivery vectors, including the inert nature, well-developed synthesis strategies, tunable size, and flexible and easy surface modification with various chemical and biological molecules. In this review, we emphasize on the applications of AuNPs in the aspect of improving pharmaceutical property and therapeutic efficacy of drugs, especially those covalently and noncovalently connected to the surface of AuNPs. Acting as a solid core to link drugs and their derivatives, AuNPs provide the nano-prodrug system with compressed size, high loading efficiency, three-dimension structure, and enhanced cellular uptake capability. With the intensive and systematical investigation of the drug-connected AuNPs, several important issues will become the hot but emergent topics for future research in this field, such as the toxicity in live human subjects, ultimate destination, and possible pathways and mechanisms for their absorption, circulation, distribution, metabolism, and excretion.

Glutathione-mediated drug release from Tiopronin-conjugated gold nanoparticles for acute liver injury therapy.

Tiopronin-conjugated gold nanoparticles (TPN@GNPs), with glutathione (GSH)-responsive drug release property, were developed for acute liver injury therapy. The TPN@GNPs were prepared using a one-pot synthesis method and characterized by UV-vis and transmission electronic microscopy methods. The TPN@GNPs displayed typical surface plasmon resonance of nanogold with a narrow size distribution (ca. 2 nm). The in vitro drug release profiles of the conjugates indicated that TPN@GNPs were able to release TPN in a sustained fashion for 4 h at a simulated intracellular level of GSH. pH values or ionic strengths of the release media had no obvious influence on TPN release from the surface of nanoparticles. The pharmacokinetic studies in rats showed that the TPN@GNPs had longer MRT (7.71 h) than TPN (3.96 h), indicating sustained release pattern of TPN@GNPs in vivo. The sustained release of TPN at the relative high GSH concentration could ameliorate the instability of TPN and enable the drug release in the target cells. Although the IC50 value of TPN@GNPs with TPN/AuCl4(-) of 3:1 (mol/mol) showed slight increase in comparison with that of the free TPN in HepG2 cells (1.26±1.07 vs. 1.73±1.16 mg/mL), the TPN@GNPs displayed better effects over TPN in the treatment of acute liver injury in vivo. In a liver injury mice model induced by CCl4, the histological analysis showed both the TPN@GNPs and free TPN group could repair the liver injury. In addition, the biochemical parameters showed TPN@GNPs could reduced the aminotransferase to a lower level compared with TPN, which might be due to the sustained drug release and passive liver targeting properties of TPN@GNPs. It demonstrated that gold nanoparticle-based drug delivery system allowed smart functions and superior properties by taking advantages of the unique small size effects and surface chemical properties.

One-step pyrolysis method for the synthesis of highly efficient 3D hollow carbon nanostructure supported metallic catalysts

By using a one-step pyrolysis method, porous hollow carbon nanosphere supported PtRu catalysts are synthesized from the metallic salt-adsorbed hollow polymer (i.e. chitosan) nanosphere complex. The hollow polymer structure acts as both the template and the carbon precursor for the hollow structure fabrication, provides sites for dispersing metallic precursors and subsequent nucleation centers for catalyst deposition in the pyrolysis process. TEM, XRD, and XPS measurements show that formation of metallic nanoparticles and carbon support occurs simultaneously in the pyrolysis process, the resultant carbon nanospheres have porous hollow core-shell structure, and the loaded catalyst has high PtRu alloying degree. In addition, the present approach allows us to finely adjust the loading and bulk composition of PtRu particles by changing the concentration and atomic ratio of the metallic solutions for salt adsorption, and the particle size of PtRu can be well controlled to less than 10 nm. Electrochemical results show that the prepared catalyst (with 18.5%wt Pt and the atomic ratio of Pt/Ru = 1:1) shows high electrochemical activity and stability toward the oxidation of methanol, even outperforming the commercial PtRu/XC-72 (JM) catalyst. This excellent performance could be due to the unique structure of carbon nanostructure and the pyrolysis-method-induced high stability and alloying degree of the loaded metallic catalysts.