Jinfeng Ren

Targeting mesoporous silica-encapsulated gold nanorods for chemo-photothermal therapy with near-infrared radiation

Mesoporous silica-encapsulated gold nanorods (GNRs@mSiO(2)) have great potential both in photothermal therapy and drug delivery. In this paper, we firstly developed GNRs@mSiO(2) as a synergistic therapy tool for delivery heat and drug to the tumorigenic region. We studied the ablation of tumor both in vitro and in vivo by the combination of photothermal therapy and chemotherapy using doxorubicin (DOX)-loaded GNRs@mSiO(2). Significantly greater cell killing was observed when A549 cells incubated with DOX-loaded GNRs@mSiO(2) were irradiated with near-infrared (NIR) illumination, attributable to both GNRs@mSiO(2)-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. We then performed in vivo therapy studies and observed a promising tumor treatment. Compared with chemotherapy or photothermal treatment alone, the combined treatment showed a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, the lower systematic toxicity of GNRs@mSiO(2) has been validated.

The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2

In this study, a dual-targeting drug delivery system based on PEGylated oxidized multi-walled carbon nanotubes (O-MWNTs) modified with angiopep-2 (O-MWNTs-PEG-ANG) was successfully developed for treatment of brain glioma. O-MWNTs can not only distribute in brains but also accumulate in tumors, and have ultrahigh surface area with remarkably high loading anticancer drug of doxorubicin (DOX), which was selected as drug carrier. Angiopep-2 can specifically combine to the low-density lipoprotein receptor-related protein (LRP) receptor overexpressed on the blood-brain barrier (BBB) and glioma cells, which was selected as targeting ligand. The cooperative dual-targeting to brain glioma by O-MWNTs-PEG-ANG was evaluated by intracellular tracking in vitro and fluorescence imaging in vivo, which demonstrated that the combination of O-MWNTs-PEG and angiopep-2 constituted an ideal dual-targeting drug delivery system. The anti-glioma effect of DOX-loaded O-MWNTs-PEG-ANG (DOX-O-MWNTs-PEG-ANG) was assessed by C6 cytotoxicity and median survival time of glioma bearing mice, which showed a better anti-glioma effect than DOX. The biological safety of O-MWNTs-PEG-ANG was evaluated by BCEC and C6 cytotoxicity, hematology analysis and CD68 immunohistochemical analysis, which proved O-MWNTs-PEG-ANG was good biocompatibility and low toxicity. The biological safety of DOX-O-MWNTs-PEG-ANG was evaluated by histopathological analysis, which suggested a lower cardiac toxicity than DOX. In conclusion, O-MWNTs-PEG-ANG is a promising dual-targeting carrier to deliver DOX for the treatment of brain tumor.

Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes.

Transferrin conjugated biodegradable polymersomes (Tf-PO) were exploited for efficient brain drug delivery, and its cellular internalization mechanisms were investigated. Tf-PO was prepared by a nanoprecipitation method with an average diameter of approximately 100 nm and a surface Tf molecule number per polymersome of approximately 35. It was demonstrated that the uptake of Tf-PO by bEnd.3 was mainly through a clathrin mediated energy-dependent endocytosis. Both the Golgi apparatus and lysosomes are involved in intracellular transport of Tf-PO. Thirty minutes after a 50mg/kg dose of Tf-PO or PO was injected into rats via the tail vein, fluorescent microscopy of brain coronal sections showed a higher accumulation of Tf-PO than PO in the cerebral cortex, the periventricular region of the lateral ventricle and the third ventricle. The brain delivery results proved that the blood-brain barrier (BBB) permeability surface area product (PS) and the percentage of injected dose per gram of brain (%ID/g brain) for Tf-PO were increased to 2.8-fold and 2.3-fold, respectively, as compared with those for PO. These results indicate that Tf-PO is a promising brain delivery carrier.

Enhanced intracellular delivery and chemotherapy for glioma rats by transferrin-conjugated biodegradable polymersomes loaded with doxorubicin.

A brain drug delivery system for glioma chemotherapy based on transferrin-conjugated biodegradable polymersomes, Tf-PO-DOX, was made and evaluated with doxorubicin (DOX) as a model drug. Biodegradable polymersomes (PO) loaded with doxorubicin (DOX) were prepared by the nanoprecipitation method (PO-DOX) and then conjugated with transferrin (Tf) to yield Tf-PO-DOX with an average diameter of 107 nm and surface Tf molecule number per polymersome of approximately 35. Compared with PO-DOX and free DOX, Tf-PO-DOX demonstrated the strongest cytotoxicity against C6 glioma cells and the greatest intracellular delivery. It was shown in pharmacokinetic and brain distribution experiments that Tf-PO significantly enhanced brain delivery of DOX, especially the delivery of DOX into brain tumor cells. Pharmacodynamics results revealed a significant reduction of tumor volume and a significant increase of median survival time in the group of Tf-PO-DOX compared with those in saline control animals, animals treated with PO-DOX, and free DOX solution. By terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, Tf-PO-DOX could extensively make tumor cell apoptosis. These results indicated that Tf-PO-DOX could significantly enhance the intracellular delivery of DOX in glioma and the chemotherapeutic effect of DOX for glioma rats.

PEGylated poly(2-(dimethylamino) ethyl methacrylate)/DNA polyplex micelles decorated with phage-displayed TGN peptide for brain-targeted gene delivery

Phage-displayed TGN peptide-decorated polymeric micelle-like polyplexes based on pegylated poly(2-(dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) were prepared for efficient brain-targeted gene delivery. The diblock copolymers Methoxy-PEG-PDMAEMA and Maleimide-PEG-PDMAEMA were synthesized by the atom transfer radical polymerization method. The TGN ligand, a 12-amino acid peptide that could facilitate blood-brain barrier (BBB) targeting, was conjugated to the PEG terminus of the copolymer via a maleimide-mediated covalent binding procedure. TGN-PEG-PDMAEMA was complexed with plasmid DNA to yield polyplexes. The physiochemical properties of the polyplexes, such as morphology, particle size, zeta potential, cytotoxicity and DNA complex formation ability, were studied prior to the successful in vitro and in vivo transfection. The TGN-PEG-PDMAEMA/DNA polyplexes maintained their stable nano-size, were characterized by good condensation capacity and low toxicity and even provided higher cellular uptake than the unmodified polyplexes (PEG-PDMAEMA/DNA polyplexes). Confocal microscopy studies showed that the DNA of TGN-PEG-PDMAEMA/DNA polyplexes entered into the nuclei through the endosome/lysosome pathway. The transfection efficiency of TGN-modified polyplexes was higher than that of unmodified polyplexes both in vitro and in vivo. The results obtained from frozen sections indicated the widespread expression of an exogenous gene in the mouse brain after intravenous injection. Therefore, the results demonstrate that the TGN-decorated PEG-PDMAEMA developed in this study could be utilized as a potential vehicle for gene delivery to the brain.

Development of magnetic multiwalled carbon nanotubes combined with near-infrared radiation-assisted desorption for the determination of tissue distribution of doxorubicin liposome injects in rats.

For the first time, magnetic multiwalled carbon nanotubes (MWNTs) combined with near-infrared radiation-assisted desorption (NIRAD) was successfully developed for the determination of tissue distribution of doxorubicin liposome injects (DOXLI) in rats. The magnetic MWNTs nanomaterials were synthesized via a simple hydrothermal process. Magnetic Fe(3)O(4) beads, with average diameters of ca. 200 nm and narrow size distribution, were decorated along MWNTs to form octopus-like nanostructures. The hybrid nanocomposites provided an efficient way for the extraction and enrichment of doxorubicin (DOX) via π-π stacking of DOX molecules onto the polyaromatic surface of MWNTs. DOX adsorbed with magnetic MWNTs could be simply and rapidly isolated through a magnetic field. In addition, due to the near-infrared radiation (NIR) absorption property of MWNTs, irradiation with NIR laser was employed to induce photothermal conversion, which could trigger rapid DOX desorption from DOX-loaded magnetic MWNTs. Extraction conditions such as amount of magnetic MWNTs added, pH values, adsorption time, desorption solvent and NIR time were investigated and optimized. Method validations including linear range, detection limit, precision, and recovery were also studied. The results showed that the proposed method based on magnetic MWNTs coupled to NIRAD was a simple, rapid and high efficient approach for the analysis of DOXLI in rat tissues.

Perspectives on brain-targeting drug delivery systems.

Due to the presence of the blood-brain barrier, there is limited drug access into the brain. In order to overcome this challenge, various strategies have been developed to enhance penetration of drugs into the brain. Of these, the most frequently used are pharmacological technologies or comparable methods being developed for brain-targeting drug delivery using receptor- or adsorptive- or transporter-mediated transcytosis and the nose-to-brain route. It goes without saying that exploration of Brain-targeting drug delivery systems has created another potential option for the treatment of central nervous system diseases. In addition to above methods, other technologies for brain-targeting drug delivery (e.g. chemical delivery systems, prodrugs, pharmacological disruption of the BBB and inhibition of drug efflux by P-glycoprotein) are also summarized in this review.

Monodisperse magnetites anchored onto carbon nanotubes: a platform for cell imaging, magnetic manipulation and enhanced photothermal treatment of tumors

In this paper, a facile solvothermal synthesis method was developed to prepare monodisperse magnetites anchored onto multi-walled carbon nanotubes (MWNTs). The pristine MWNTs were treated with a mixture of concentrated sulfuric and nitric acids. The oxidized MWNTs (o-MWNTs) had abundant carboxylic groups on the surface, which have a strong ability to chelate metal ions like Fe3+. The obtained MWNTs-Fe3O4 nanomaterials allowed π-π stacking of fluorescein isothiocyanate (FITC) to monitor inside living cancer cells by fluorescence imaging. Cells labeled with MWNTs-Fe3O4 nanomaterials could be efficiently manipulated by a magnetic field due to the large magnetic moment of the iron oxide domain in the nanocomposites. The MWNTs-Fe3O4 nanomaterials have been demonstrated to be effective for in vivo photothermal treatment of tumors using mice implanted with human U87 tumors as a model.

Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer.

The intractability of non-small cell lung cancer (NSCLC) to multimodality treatments plays a large part in its extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for selective induction of apoptosis in cancer cells; however, many NSCLC cell lines are resistant to TRAIL-induced apoptosis. The therapeutic effect can be restored by treatments combining TRAIL with chemotherapeutic agents. Actinomycin D (ActD) can sensitize NSCLC cells to TRAIL-induced apoptosis by upregulation of death receptor 4 (DR4) or 5 (DR5). However, the use of ActD has significant drawbacks due to the side effects that result from its nonspecific biodistribution in vivo. In addition, the short half-life of TRAIL in serum also limits the antitumor effect of treatments combining TRAIL and ActD. In this study, we designed a combination treatment of long-circulating TRAIL liposomes and ActD liposomes with the aim of resolving these problems. The combination of TRAIL liposomes and ActD liposomes had a synergistic cytotoxic effect against A-549 cells. The mechanism behind this combination treatment includes both increased expression of DR5 and caspase activation. Moreover, systemic administration of the combination of TRAIL liposomes and ActD liposomes suppressed both tumor formation and growth of established subcutaneous NSCLC xenografts in nude mice, inducing apoptosis without causing significant general toxicity. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which TRAIL liposomes are safely combined with ActD liposomes.

A novel combination of TRAIL and doxorubicin enhances antitumor effect based on passive tumor-targeting of liposomes

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anticancer agent for non-small cell lung cancer (NSCLC). However, approximately half of NSCLC cell lines are highly resistant to TRAIL. Doxorubicin (DOX) can sensitize NSCLC cells to TRAIL-induced apoptosis, indicating the possibility of combination therapy. Unfortunately, the therapeutic effect of a DOX and TRAIL combination is limited by multiple factors including the short serum half-life of TRAIL, poor compliance and application difficulty in the clinic, chronic DOX-induced cardiac toxicity, and the multidrug resistance (MDR) property of NSCLC cells. To solve such problems, we developed the combination of TRAIL liposomes (TRAIL-LP) and DOX liposomes (DOX-LP). An in vitro cytotoxicity study indicated that DOX-LP sensitized the NSCLC cell line A-549 to TRAIL-LP-induced apoptosis. Furthermore, this combination therapy of TRAIL-LP and DOX-LP displayed a stronger antitumor effect on NSCLC in xenografted mice when compared with free drugs or liposomal drugs alone. Therefore, the TRAIL-LP and DOX-LP combination therapy has excellent potential to become a new therapeutic approach for patients with advanced NSCLC.