Zhenshu Zhu

Covalently Combining Carbon Nanotubes with Anticancer Agent: Preparation and Antitumor Activity

A multiwalled carbon nanotube (MWNT)-based drug delivery system was developed by covalently combining carbon nanotubes with the antitumor agent 10-hydroxycamptothecin (HCPT) using hydrophilic diaminotriethylene glycol as the spacer between nanotube and drug moieties. The surface functionalizations of the nanotube were carried out by enrichment of carboxylic groups with optimized oxidization treatment, followed by covalently linking hydrophilic diaminotriethylene glycol via amidation reaction, and then HCPT was chemically attached to carbon nanotubes through a cleavable ester linkage. It is demonstrated that the obtained MWNT-HCPT conjugates are superior in antitumor activity both in vitro and in vivo to clinical HCPT formulation. In vivo single photon emission computed tomography (SPECT) imaging and ex vivo gamma scintillation counting analyses reveal that MWNT-HCPT conjugates have relatively long blood circulation and high drug accumulation in the tumor site. These properties together with the enhanced cell uptake and multivalent presentation of HCPT on a single nanotube benefit substantially the antitumor effects and would boost significantly the applications of carbon nanotubes in the biomedicine field.

Paclitaxel-loaded poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) nanoparticles: Preparation and antitumor activity in vivo

Paclitaxel (PTX)-loaded poly(N-vinylpyrrolidone)-b-poly(epsilon-caprolactone) (PVP-b-PCL) nanoparticles with high drug payload were successfully prepared by a modified nano-precipitation method and characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and zeta potential. The satisfactory drug loading content (>25%) and high encapsulation efficiency (>85%) were achieved. The in vivo real-time biodistribution of PTX-loaded nanoparticles was investigated using near-infrared fluorescence (NIRF) imaging. The antitumor effect of PTX-loaded nanoparticles was evaluated, both, in vitro on three different cancer cell lines and in vivo on hepatic H22 tumor bearing mice model via intravenous administration (i.v.). It is found that PTX-loaded nanoparticles exhibit significant superior in vivo antitumor effect than the commercially available Taxol formulation by combining the tumor volumes and survival rates measurement, intravital positron emission tomography and computed tomography (PET/CT) imaging.

Resveratrol-loaded polymeric micelles protect cells from Aβ-induced oxidative stress

Resveratrol has been reported to protect several types of cells against beta-amyloid peptide (Abeta) toxicity by scavenging reactive oxygen species (ROS) and inactivating caspase-3. However, other studies found that long-term treatment with resveratrol inhibited cells by inducing ROS generation and activating caspase-3. In the current report, a 48-h incubation of resveratrol at the concentrations of 5 and 10 microM significantly attenuated the viability of PC12 cells and a 12-h pre-incubation of resveratrol did not protect PC12 cells against Abeta exposure (even further inhibited PC12 cells at the concentrations of 10 microM) by acting as a pro-oxidant. Due to the lipophilicity of resveratrol, resveratrol-loaded polymeric micelles basing on amphiphilic block copolymer were developed. Then, the effects of resveratrol-loaded polymeric micelles on the viability and Abeta protection of PC12 cells were investigated. At the equivalent concentrations of 5 and 10 microM resveratrol, a 48-h incubation of resveratrol-loaded nanoparticles did not show toxicity to cells, while 12-h pre-incubation of resveratrol-loaded nanoparticles protected PC12 cells from Abeta-induced damage in a dose dependent manner (1-10 microM) by attenuating intracellular oxidative stress and caspase-3 activity. Further investigations are absolutely needed to evaluate the feasibility and advantages of in vivo applications of resveratrol-loaded nanoparticles.

Nanospheres-Incorporated Implantable Hydrogel as a Trans-Tissue Drug Delivery System

The objective of this study is to investigate the anticancer efficacy of a drug delivery system comprised of gelatin hydrogel (jelly) containing cisplatin (CDDP)-loaded gelatin/poly(acrylic acid) nanoparticles by peritumoral implantation and to compare the treatment response between the implantation administration of the jelly and intravenous (i.v.) administration of the nanoparticles. It is found that the implantation of the jelly containing CDDP-loaded nanoparticles on tumor tissue exhibited significantly superior efficacy in impeding tumor growth and prolonging the lifetime of mice than that of i.v. injection of CDDP-loaded nanoparticles in a murine hepatoma H(22) cancer model. An in vivo biodistribution assay performed on tumor-bearing mice demonstrated that the jelly implant caused much higher concentration and retention of CDDP in tumor and lower CDDP accumulation in nontarget organs than that of i.v. injected nanoparticles. Immunohistochemical analysis demonstrated that the nanoparticles from the jelly can be distributed in tumor tissue not only by their diffusion but also by the vasculature in the implantation region into tumor interior, enabling CDDP to efficiently reach more viable cells of tumor compared with i.v. injected nanoparticles. Thus, nanoparticles for peritumoral chemotherapy are promising for higher treatment efficacy due to increased tumor-to-normal organ drug uptake ratios and improved drug penetration in tumors.

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.

Enhanced Neuroprotective Effects of Resveratrol Delivered by Nanoparticles on Hydrogen Peroxide-Induced Oxidative Stress in Rat Cortical Cell Culture

Resveratrol (RES) has recently been reported as a potential antioxidant in treatment of ischemia/reperfusion injury through attenuating oxidative stress and apoptosis. However, application of RES is limited for its insolubility and short half-time. Latest evidence raises the possibility of developing nanoparticle-based delivery systems with improved solubility, stability and cytotoxicity of lipophilic drug. Here, we reported first a simple way to produce RES-loaded nanoparticles (RES-NPs) based on poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) polymer and further evaluated the protective effect of RES-NPs on hydrogen peroxide-induced oxidative stress and apoptosis in rat cortical cell culture. The controlled release pattern of RES-loaded nanoparticles was characterized by in vitro release experiments. Cytotoxicity tests proved cytocompatibility of these nanoparticles with neurons. Shown by coumarin-6 loaded nanoparticles, the uptake of nanoparticles by neurons was considered through endocytosis, which could lead to higher uptake efficiency at lower concentration. Thereby, the hypothesis is raised that RES-NPs could demonstrate enhanced neuroprotection compared to an equivalent dose of free RES at lower concentration, especially. It was further supported by enhanced reduction of LDH release, elimination of ROS and MDA, and attenuation of apoptosis signal (ratio of Bax/Bcl-2, activation of caspase-3). RES-NPs could be a potential treatment needing intensive research for ischemia/reperfusion related disorder including stroke.

Tumor Accumulation, Penetration, and Antitumor Response of Cisplatin-Loaded Gelatin/Poly(acrylic acid) Nanoparticles

In this report, the cisplatin (CDDP)-loaded gelatin/poly(acrylic acid) (GEL-PAA) nanoparticles with a spherical shape and drug loading content of 24.6% were prepared. In vivo near-infrared fluorescence (NIRF) imaging and ex vivo gamma scintillation counting analyses reveal that CDDP-loaded GEL-PAA nanoparticles have prominent passive tumor-targeting ability and the nontarget nanoparticles can be readily excreted from the body. Further, it is demonstrated that the CDDP-loaded nanoparticles have the ability to penetrate the tumor after their extravasation through the leaky vessels and distribute in a distance of about 20 μm from the vessels at 24 h postinjection. The in vivo antitumor responses reveal that the nanoparticle formulation exhibits significantly superior in vivo antitumor effect than free CDDP by the comparison of tumor volume and the examinations of cell apoptosis and proliferation in tumor tissues through proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl-transferase-mediated nick end labeling (TUNEL) methods.

Structure-Dependent cis/trans Isomerization of Tetraphenylethene Derivatives: Consequences for Aggregation-Induced Emission.

The isomerization and optical properties of the cis and trans isomers of tetraphenylethene (TPE) derivatives with aggregation-induced emission (AIEgens) have been sparsely explored. We have now observed the tautomerization-induced isomerization of a hydroxy-substituted derivative, TPETH-OH, under acidic but not under basic conditions. Replacing the proton of the hydroxy group in TPETH-OH with an alkyl group leads to the formation of TPETH-MAL, for which the pure cis and trans isomers were obtained and characterized by HPLC analysis and NMR spectroscopy. Importantly, cis-TPETH-MAL emits yellow fluorescence in DMSO at -20 °C whereas trans-TPETH-MAL shows red fluorescence under the same conditions. Moreover, the geometry of cis- and trans-TPETH-MAL remains unchanged when they undergo thiol-ene reactions to form cis- and trans-TPETH-cRGD, respectively. Collectively, our findings improve our fundamental understanding of the cis/trans isomerization and photophysical properties of TPE derivatives, which will guide further AIEgen design for various applications.

Fluorescent Micelles Based on Star Amphiphilic Copolymer with a Porphyrin Core for Bioimaging and Drug Delivery

Star-shaped poly(ε-caprolactone)-b-poly(ethylene oxide) amphiphilic copolymer with a tetrakis-(4-aminophenyl)-terminated porphyrin core was synthesized. Paclitaxel (PTX)-loaded polymeric micelles were prepared by the self-assembly of the star copolymer and in situ encapsulation of PTX. The fluorescent characteristic of the porphyrin moiety allowed the cellular uptake and biodistribution of the PTX-loaded micelles to be monitored by fluorescent imaging. The PTX-loaded micelles can be readily internalized by cancer cells and have a slightly higher cytotoxicity than clinic PTX injection Taxol. In vivo real-time fluorescent imaging revealed that the micelles could accumulate at tumor site via the blood circulation in tumor-bearing mice. In vivo antitumor efficacy examinations indicated that the PTX-loaded micelles had significantly superior efficacy in impeding tumor growth than Taxol and low toxicity to the living mice.

Enhanced in vitro and in vivo therapeutic efficacy of codrug-loaded nanoparticles against liver cancer.

Paclitaxel (Ptx), one of the most widely used anticancer agents, has demonstrated extraordinary activities against a variety of solid tumors. However, the therapeutic response of Ptx is often associated with severe side effects caused by its nonspecific cytotoxic effects and special solvents (Cremophor EL®). The current study reports the stable controlled release of Ptx/tetrandrine (Tet)-coloaded nanoparticles by amphilic methoxy poly(ethylene glycol)–poly(caprolactone) block copolymers. There were three significant findings. Firstly, Tet could effectively stabilize Ptx-loaded nanoparticles with the coencapsulation of Tet and Ptx. The influence of different Ptx/Tet feeding ratios on the size and loading efficiency of the nanoparticles was also explored. Secondly, the encapsulation of Tet and Ptx into nanoparticles retains the synergistic anticancer efficiency of Tet and Ptx against mice hepatoma H22 cells. Thirdly, in the in vivo evaluation, intratumoral administration was adopted to increase the site-specific delivery. Ptx/Tet nanoparticles, when delivered intratumorally, exhibited significantly improved antitumor efficacy; moreover, they substantially increased the overall survival in an established H22-transplanted mice model. Further investigation into the anticancer mechanisms of this nanodelivery system is under active consideration as a part of this ongoing research. The results suggest that Ptx/Tet-coloaded nanoparticles could be a potential useful chemotherapeutic formulation for liver cancer therapy.