In vitro and in vivo chemo-phototherapy of magnetic TiO2 drug delivery system formed by pH-sensitive coordination bond.

To achieve tumor-specific delivery of doxorubicin, TiO2@Fe3O4/PEI/delivery of doxorubicin conjugates were designed and synthesized. Fe3O4 could act as magnetically responsive carriers and enhance the visible light photodynamic activities of TiO2 Delivery of doxorubicin was conjugated via coordination bond. The drug release rate at pH 5.2 was much faster than that at pH 7.4, due to pH-sensitive coordination bond. Besides, TiO2@Fe3O4/PEI/delivery of doxorubicin showed high antitumor efficacy combining with phototherapy, good bio-safety, higher cellular uptake with an external magnetic field, and less toxicity in vitro and in vivo. These results suggested that TiO2@Fe3O4/PEI/delivery of doxorubicin may be promising for high tumor treatment efficacy with minimal side effects in future.

A multi-functional nanoplatform for tumor synergistic phototherapy.

Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.

Enhancement of cytotoxicity of artemisinin toward cancer cells by transferrin-mediated carbon nanotubes nanoparticles.

Artemisinin (ART) is a kind of drug with an endoperoxide bridge which tends to react with Fe(2+) to generate radicals for killing cancer cells. However, simultaneous delivery of hydrophobic ART and Fe(2+) ions into cancer cells remains a major challenge. In this study, a multi-functional tumor-targeting drug delivery system employing hyaluronic acid-derivatized multi-walled carbon nanotubes (HA-MWCNTs) as drug carriers, transferrin (Tf) as targeting ligand and ART as a model drug for cancer treatment was constructed. This delivery system (HA-MWCNTs/Tf@ART) not only retained optical property of MWCNTs and cytotoxicity of ART but also demonstrated synergistic anti-tumor effect using ART and Tf. Compared with free ART, remarkably enhanced anti-tumor efficacy of this drug vehicle was realized both in cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of ART and co-delivery of Tf and ART analogs. HA-MWCNTs/Tf@ART with laser irradiation demonstrated the highest inhibition effect compared to the other groups. This result may provide a new way of using promising natural drugs for cancer therapy.

Near-infrared-triggered in situ hybrid hydrogel system for synergistic cancer therapy.

As one of the most frequently used chemotherapeutic drugs, doxorubicin (DOX) is accompanied by low accumulation in tumors and severe dose-limiting side effects with systemic administration, which limits its therapeutic index. In this work, a novel and injectable in situ photo-sensitive inorganic/organic hybrid hydrogel as a localized drug-delivery system was examined. It explored poly(ethylene glycol) double acrylates (PEGDA) as a polymeric matrix, DOX as a model drug, a TiO2@MWCNT nanocomposite as the photoinitiator and photosensitizer-photothermal agent for tumor therapy possessing a multi-mechanism using a single NIR laser. Briefly, a PEGDA solution containing DOX and TiO2@MWCNTs was injected into a tumor and rapidly gelled in vivo via a photo-crosslinking action triggered by a NIR laser. DOX release from the DOX/TiO2@MWCNTs/PEGDA hydrogel was sustained and long-lasting, over 10 days, indicating that the PEGDA gel acted as a drug depot. Simultaneously, a NIR laser light was adopted which can be absorbed and converted into reactive oxygen species (ROS) or local hyperthermia by TiO2@MWCNTs, leading to tumor cell death. This DOX/TiO2@MWCNTs/PEGDA hydrogel exhibited remarkable anti-proliferative activities against MCF-7 cancer cells in vitro. Experiments in vivo showed that a single intratumoral injection of this hydrogel with 808 nm laser irradiation was the most effective among all DOX formulations in the tumor-bearing mice models. There was a relatively small DOX distribution in normal tissues and much lower systemic toxicity than the control group (DOX-only). In general, it is believed that the novel photo-sensitive hybrid hydrogel system prepared in this study can afford high drug-loading, sustained and stable drug release, as well as repeated phototherapy of the tumor with the administration of a single dose.

Transferrin-mediated fullerenes nanoparticles as Fe(2+)-dependent drug vehicles for synergistic anti-tumor efficacy.

Artesunate (AS) is an iron-dependent drug, which has been used extensively as anti-malarial drugs worldwide with no obvious side effects. Recently, studies have shown that AS also possess profound cytotoxicity against tumor cells. However, simultaneous delivery of hydrophobic AS and Fe(2+) into tumor cells remains a major challenge. Herein, we report a new kind of active-targeting preparations which could not only specially target to tumor cells but also synchronously transfer AS and irons into tumor tissue. In this study, hyaluronic acid (HA) was grafted onto fullerene to get a water-soluble biomaterial (HA-C60) with excellent biocompatibility, and then combined with transferrin (Tf) to obtain a multi-functional drug delivery system (HA-C60-Tf) with significant tumor-targeting efficacy and powerful photodynamic therapy capacity. Finally, AS was adsorbed on HA-C60-Tf with a high loading efficacy of 162.4% (weight ratio of AS: HA-C60-Tf). Compared with free AS, remarkably enhanced antitumor efficacy of AS-loaded HA-C60-Tf nanoparticles was realized both in a cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of AS in tumor and activated mechanism by co-delivery of Tf and AS analogs. Furthermore, with laser irradiation in vivo, the relative tumor volume (V/V0) of HA-C60-Tf/AS declined by half, from 1.72 ± 0.12 to 0.84 ± 0.07, suggesting a new way with multi-mechanism for tumor treatment was developed.