Yong Hu

Preparation and evaluation of PEG–PCL nanoparticles for local tetradrine delivery

To establish a satisfactory delivery system for local delivery of Tetradrine (Tet), four kinds of core-shell nanoparticles were prepared from di-block copolymer of methoxy poly(ethylene glycol)-polycaprolactone (MePEG-PCL) and tri-block copolymer of polycaprolactone-poly(ethylene glycol)-polycaprolactone (PCL-PEG-PCL). The physiochemical traits of the four kinds of nanoparticles including morphology, particle size, zeta-potential, drug-loading content, stability, and in vitro release profile were studied. We also evaluated the four kinds of nanoparticles by in vitro cellular uptake experiment, cytotoxicity assay against LoVo cells, and biocmpatibility study. Histoculture Drug Response Assay (HDRA), a more predictive method usually used to evaluate chemosensitivity was firstly applied in our study to evaluate the antitumor potency of polymeric nanoparticles. The current study showed that all the four kinds of copolymers exhibited remarkable in vitro antitumor effects, especially in HDRA assay. The configuration and composition of the copolymers were important for the properties and functions of the nanoparticles. Nanoparticles prepared from the di-block copolymer with a particle size around 300nm and the hydrophobic composition about 80% was determined as the most effective drug carrier for further studies.

Cisplatin-loaded gelatin-poly(acrylic acid) nanoparticles: Synthesis, antitumor efficiency in vivo and penetration in tumors

Cisplatin (CDDP)-loaded gelatin-poly(acrylic acid) (GEL-PAA) nanoparticles were successfully prepared by polymerizing acrylic acid in the presence of gelatin in aqueous solution followed by incorporating CDDP into the formed GEL-PAA nanoparticles through polymer-metal complex formation of CDDP with carboxylic groups in the nanoparticles. The obtained nanoparticles had a spherical shape, with a mean size of about 100 nm, and high drug payload as well as stability. It is found that CDDP can be released from the nanoparticles in a sustained manner with a small initial burst release. In vitro cytotoxicity revealed that CDDP-loaded nanoparticles had similar cytotoxicity to free CDDP after 48 h co-incubation with human colorectal cancer cell line LoVo. In vivo antitumor activity indicated that the nanoparticle formulation was superior in anticancer effect to free CDDP on murine hepatic H22 tumor-bearing mice model through intraperitoneal (i.p.) administration and displayed a dose-dependent antitumor efficacy. Further, the penetration examination of the nanoparticles through tumor tissue revealed that the CDDP-loaded GEL-PAA nanoparticles could only affect the cells near the tumor vasculature after they entered into the tumor tissue.

Core/shell microspheres via coaxial electrohydrodynamic atomization for sequential and parallel release of drugs

Herein, it is demonstrated that coaxial electrohydrodynamic atomization can be used for the fabrication of microspheres with distinct core/shell structure. This allows the encapsulation of two different types of drugs in different compartments in one single step. In Group A, we prepared microspheres in which the core and the shell contain hydrophobic and hydrophilic drugs, respectively. In contrast, in Group B, the opposite is prepared. While the former can be achieved by using amphiphilic polymers in aqueous environment, the latter is difficult to be prepared. The release patterns of the two groups are significantly different. The release of drugs from Group A microspheres is rather sequential, whereas group B microspheres release drugs in a parallel (co-release) manner. Nevertheless, in both groups, we found that the release of drugs can be easily tailored by altering outer/inner flow ratios. These findings present the advantages and possible application of this multi-drug release system in chemotherapy. Moreover, cell culture experiments have been performed to testify the performances of different microspheres in cytotoxicity and cellular apoptosis in vitro.

Curcumin delivery by methoxy polyethylene glycol–poly(caprolactone) nanoparticles inhibits the growth of C6 glioma cells

As a potential anticancer agent, curcumin (Cum) has been reported for its chemopreventive and chemotherapeutic activity in a series of cancers through influencing cell cycle arrest, differentiation, apoptosis, etc. Therefore, the potential activity against various cancers of Cum raises the possibility of its application as a novel model drug in nanoparticle-based delivery systems. The current study reported a spherical core-shell structure curcumin-loaded nanoparticle (Cum-np) formed by amphilic methoxy polyethylene glycol-poly(caprolactone) (mPEG-PCL) block copolymers. Characterization tests indicated that Cum was incorporated into mPEG-PCL-based nanoparticles with high encapsulation efficiency due to its lipophilicity. The incorporated Cum could be released from Cum-np in a sustained manner. Cum was effectively transported into the cells by nanoparticles through endocytosis and localized around the nuclei in the cytoplasms. In vitro studies proved that the cytotoxicity of Cum-np would be pro-apoptosis effect against rat C6 glioma cell line in a dose-dependent manner. The present results suggest that Cum-np could be a potential useful chemotherapeutic formulation for malignant glioma therapy. Moreover, the development of traditional Chinese medicine with nanoscale drug formation warrants more intensive research for its clinical applications.

In situ formation of chitosan–gold hybrid hydrogel and its application for drug delivery

A novel chitosan-gold (CS-Au) hybrid hydrogel was developed from chitosan and chloroauric acid in aqueous solution. Its physiochemical characteristics, including UV absorption, structure, morphology, swelling properties were studied. The CS-Au hybrid hydrogel exhibited an excellent water-absorbing property and could be applied as a drug delivery system for anticancer drug: doxorubicin (DOX) due to its high equilibrium water swelling content. The drug loading and release experiments elicited an efficient drug loading content and sustained drug release pattern. Moreover, DOX released from hydrogel which itself had no cytotoxicity was biological active similar as the free DOX, but lower cytotoxicity due to its controllable release. All proved it an ideal local drug delivery system indicating a promising potential future in medical or pharmaceutical area.

Enhanced cytotoxicity and activation of ROS-dependent c-Jun NH2-terminal kinase and caspase-3 by low doses of tetrandrine-loaded nanoparticles in Lovo cells – A possible Trojan strategy against cancer

Tetrandrine (Tet), a bis-benzylisoquinoline alkaloid, has recently been reported as a novel anti-cancer agent in vitro and in vivo by inducing apoptosis with the formation of reactive oxygen species (ROS) and the activation of ROS-dependent c-Jun NH(2)-terminal kinase (JNK) and caspase-3. However, application of Tet is limited for its insolubility. Accumulated evidences raise the possibility of developing nanoscale delivery systems of Trojan strategy with improved solubility, stability and cytotoxicity of lipophilic Tet. Here, we reported first a simple way to produce Tet-loaded nanoparticles based on amphiphilic block copolymer. The controlled release pattern of Tet-loaded nanoparticles (Tet-np) was characterized by in vitro release experiments. Cytotoxicity tests proved anti-tumor effect of Tet-np against Lovo cells. Moreover, doses of Tet-np during lower concentrations (1-8 microg/ml) led to more cell inhibition than equivalent doses of free Tet did (1-8 microg/ml). It was further presented that the higher uptake efficiency, more reactive oxygen species (ROS) generation, and the stronger activation of ROS-dependent c-Jun NH(2)-terminal kinase (JNK) and caspase-3 were induced by the equivalent dose of Tet delivered by nanoparticles. Although the present results suggested that Tet-np could be a potential useful chemotherapeutic tool, intensive researches are still warranted.

Synthesis and application of strawberry-like Fe3O4-Au nanoparticles as CT-MR dual-modality contrast agents in accurate detection of the progressive liver disease

Development of non-invasive assay for the accurate diagnosis of progressive liver diseases (e.g., fatty liver and hepatocellular carcinoma (HCC)) is of great clinical significance and remains to be a big challenge. Herein, we reported the synthesis of strawberry-like Fe3O4-Au hybrid nanoparticles at room temperature that simultaneously exhibited fluorescence, enhanced X-ray attenuation, and magnetic properties. The results of in vitro fluorescence assay showed that the nanoparticles had significant photo-stability and could avoid the endosome degradation in cells. The in vivo imaging of normal mice demonstrated that the Fe3O4-Au nanoparticles provided 34.61-fold contrast enhancement under magnetic resonance (MR) guidance 15 min post the administration. Computed tomography (CT) measurements showed that the highest Hounsfield Unit (HU) was 174 at 30 min post the injection of Fe3O4-Au nanoparticles. In vivo performance of the Fe3O4-Au nanoparticles was further evaluated in rat models bearing three different liver diseases. For the fatty liver model, nearly homogeneous contrast enhancement was observed under both MR (highest contrast ratio 47.33) and CT (from 19 HU to 72 HU) guidances without the occurrences of focal nodules or dysfunction. For the cirrhotic liver and HCC, pronounced enhancement under MR and CT guidance could be seen in liver parenchyma with highlighted lesions after Fe3O4-Au injection. Furthermore, pathological, hematological and biochemical analysis revealed the absence of acute and chronic toxicity, confirming the biocompatibility of our platform for in vivo applications. Collectively, These Fe3O4-Au nanoparticles showed great promise as a candidate for multi-modality bio-imaging.

X-ray CT guided fault-free photothermal ablation of metastatic lymph nodes with ultrafine HER-2 targeting W18O49 nanoparticles.

Designing high accuracy in the diagnosing and fault-freely eliminating lymphatic metastasis of breast malignancy, to avoid the invasiveness and complications caused by traditional assays, is of great therapeutic importance. To this end, theranostic W18O49 nanoparticles targeting to human epidermal growth receptor 2 (HER-2) over-expressed breast malignancy were synthesized via polyol method. By taking advantage of their high X-ray attenuating and photothermotherapy potency, lymph nodes in the mice bearing HER-2 positive metastasis could be clearly distinguished under CT guidance and selectively eliminated by laser ablation. The therapeutic efficacy was further confirmed by the significantly extended survival period. These finding evidenced the potential of these nanoparticles for imaging guided photothermal ablation of HER-2 positive breast malignancy.

Hollow chitosan–silica nanospheres for doxorubicin delivery to cancer cells with enhanced antitumor effect in vivo

Here we report the synthesis of hybrid hollow chitosan–silica nanospheres (CS–Silica NPs) with chitosan–polyacrylic acid (CS–PAA) nanoparticles as the template and doxorubicin (DOX) delivery based on CS–Silica NPs. The morphology and the microstructure of CS–Silica NPs were characterized by field emission scanning electron microscopy (FESEM) and X-ray photoelectron spectroscopy (XPS). The confocal laser scanning microscopy (CLSM) and flow cytometry experiments showed that the cellular uptake of the DOX-loaded CS–Silica NPs was time dependent. In addition, cellular internalization and intracellular distribution of DOX-loaded CS–Silica NPs indicated that the DOX was mainly distributed in the cell nucleus while the carriers were primarily located in the cytoplasm. In vivo antitumor response indicated that the DOX loaded CS–Silica hybrid hollow nanospheres exhibited superior antitumor effect over the free drugin vivo, which might be ascribable to the enhanced cellular uptake efficiency and the effective delivery of drug to the cell nucleus.

Surface-Potential-Regulated Transmembrane and Cytotoxicity of Chitosan/Gold Hybrid Nanospheres

Chitosan-gold hybrid nanospheres with varying surface zeta potentials were designed as a model system to investigate cell internalization. Gold nanoparticle was selected as optical marker to facilitate the visualization of the hybrid polymeric nanosphere internalization course and the localization in the cell by dark-field optical microscopy and transmission electron microscopy. It is found that surface potential has significant biological implications in the transmembrane efficiency, intracellular fate, and cytotoxicity of the hybrid nanospheres. Compared to those with lower surface potential, the spheres with higher surface potential show a faster cell uptake and enhance the nucleus targeting. However, too high a surface potential may destabilize the cell membrane and induce cell damage as well as cytotoxicity. These finding can help us to design suitable drug or gene nanocarriers with low cytotoxicity and high delivering ability.