Ruihan Tong

Gated magnetic mesoporous silica nanoparticles for intracellular enzyme-triggered drug delivery

The targeting drug release is significant to the anticancer treatment. In this context, the redox-responsive drug delivery has attracted most attention owing to the intracellular reductive environment, such as the high concentration of glutathione reductase in many cancer cells. Herein, a glutathione sensitive drug delivery nanoplatform was constructed by using core-shell mesoporous silica nanocomposite (Fe3O4@mSiO2) as carrier. By a simple silane coupling reaction, the glutathione cleavable diselenide linker has been prepared and grafted on to Fe3O4@mSiO2 to insure the encapsulation of anticancer drug doxorubicin. The detail release kinetics studies reveal the glutathione triggered drug release, which could be further adjusted by varying the amount of diselenide linker. To improve the tumor-targeting, folic acid was grafted. The cellular uptake and drug release investigation was carried out using HeLa (cervical cancer cell line) as the model cancer cell and L02 and HUVEC (human hepatic cell line and human umbilical vein endothelial cells, non-cancerous cell lines) as control, indicating the enhanced cytotoxicity toward HeLa cells that benefits from the fast endocytosis and enhanced cellular drug release owing to their overexpressing folic acid receptors and high concentration of glutathione. Associating with the magnetic targeting, these novel nanomaterials are expected to be promising in the potential application of tumor-targeting therapy.

NIR-sensitive UCNP@mSiO2 nanovehicles for on-demand drug release and photodynamic therapy

Nanocomposites have attracted the most attention for antitumor treatment. Here, we present a near-infrared (NIR) sensitive nanovehicle to reveal synergistic chemotherapy and photodynamic therapy (PDT). Upconverting nanoparticles (UCNP) NaYF4:Yb, Tm@NaYF4 were adopted as the core using a one-step coprecipitation method to realize the coating of the mesoporous silica shell and the doping of photosensitizer Hypocrellin A (HA). Furthermore, a UV light-cleavable 4-(2-carboxy-ethylsulfanylmethyl)-3-nitro-benzoic acid linker (CNBA) was synthesized and grafted outside as a “gate” to insure the encapsulation of the anticancer drug doxorubicin (DOX). Upon NIR irradiation, the UV light emission (derived from UCNP) can induce the break of the CNBA linker to make the “gate” open and cause drug release. Besides, the blue emission (450–470 nm) can excite HA to generate reactive oxygen (ROS) to achieve PDT. Owing to the nanoscale particle size (75 nm) and targeting transferrin (Tf) modification, these nanocomposites possess fast uptake by cancer cells (HeLa and MCF-7) and the enhanced cytotoxicity is derived from the synergistic effect of chemotherapy and PDT that would easily be controlled by the acting strength and time of NIR irradiation. Hence, the NIR light-sensitive nanocomposites are expected to be the promising and flexible platform for cancer treatment.

Enzyme and pH-responsive nanovehicles for intracellular drug release and photodynamic therapy

Currently, functional nanocomposites consisting of multiple therapy properties have attracted significant attention in the development of anticancer therapeutic agents. Herein, an enzyme and pH-responsive nanocomposite was constructed for sensitive intracellular drug release and photodynamic therapy (PDT). The nanocarrier, about 75 nm in size, is composed of an upconversion nanoparticle (UCNP, NaYF4:Yb,Er@NaYF4) core and mesoporous silica shell doped with chlorine e6 (Ce6) (UCNP@mSiO2-Ce6). Then, the sensitive linker succinic acid–glycine–phenylalanine–leucine–glycine (SGFLG) was prepared and grafted on to the nanovehicle to encapsulate the anticancer drug doxorubicin (DOX). The in vitro release kinetics was studied to reveal the sensitive DOX release, depending on the enzyme (cathepsin B) concentration and pH value. To further ensure the targeting of the tumor tissue, transferrin (Tf) was grafted, and then cellular uptake/release studies were carried out using HeLa as a model cancer cell and L02 (normal liver cell) as the control. The enhanced cytotoxicity towards HeLa over L02 cells is ascribed to the excess expression of Tf receptors, high concentration of cathepsin B, and the lower pH environment in cancer cells. In addition, under NIR irradiation, the visible light emission could excite Ce6 to generate reactive oxygen and to achieve PDT, which is associated with sensitive chemotherapy to further improve the specific cytotoxicity. The novel nanoplatform has potential application in cancer treatment.

Near-infrared light-mediated DOX-UCNPs@mHTiO2 nanocomposite for chemo/photodynamic therapy and imaging

Recently, incorporating multiple components into one nanoplatform for anticancer theranostics has attracted most attention. Herein, a rattle-structured nanocomposite by using UCNPs (NaYF4:Yb,Tm@NaYF4) as core coated with hollow mesoporous TiO2 (UCNPs@mHTiO2) was constructed as the nanocarrier. First, UCNPs@SiO2@TiO2 was prepared, by a selective etching method to remove SiO2 shell, to make sure the hollow mesoporous structure and high surface area (347m2g-1) of UCNPs@mHTiO2. Under near-infrared (NIR) light irradiation, the UV emission can excite TiO2 to produce ROS and to realize photodynamic therapy (PDT). In addition, the hollow structure offers space to store antitumor drug molecules (doxorubicin, DOX) and this nanocomposite also exhibits the improved DOX release in mildly acidic environment, which could greatly promote chemotherapy efficiency. Moreover, the luminescence resonance energy transfer (LRET) from UCNPs to DOX, owing to the effective distance restricted by the cavity, can be used to monitor the intercellular drug release kinetics. HeLa cells were used as the model cancer cells and the detailed cell experiments show the enhanced cytotoxicity, ascribing to the synergistic effect of chemotherapy and PDT. Therefore, the novel multifunctional nanocomposite, combining with chemotherapy, PDT, and imaging, should be a potential candidate in anticancer field.

Enzyme-sensitive magnetic core–shell nanocomposites for triggered drug release

Fe3O4@mSiO2 (magnetic Fe3O4 core coated by a mesoporous silica shell) nanoparticles were successfully synthesized as a carrier. The anti-cancer drug doxorubicin (DOX) and chlorambucil (Chl) were used as the model cargo. After the drug-loading, a sodium hyaluronic acid (HA) cross-linked gel was adopted to coat the outside of the Fe3O4@mSiO2 nanoparticles as a layer (named as drug–Fe3O4@mSiO2–HA) to prevent drug pervasion. The detailed release kinetics were investigated, revealing the sensitive release triggered by hyaluronidase (HAase), a major enzyme which is rich in the tumor microenvironment, which can degrade the HA shell to induce the enzyme sensitive drug release. Moreover, there are some HA receptors in many tumor areas, associating with magnetic targets to further ensure the specific targeted drug delivery. With these improved performances, these smart multifunctional nanocomposites are expected to possess potential applications in the biopharmaceutical for cancer therapy.

DOX-UCNPs@mSiO2–TiO2 nanocomposites for near-infrared photocontrolled chemo/photodynamic therapy

Currently, incorporating multiple therapeutic functions into one nanostructure has attracted more and more attention for the development of efficient anticancer agents. In this study, a uniform core–shell UCNPs@mSiO2 nanocomposite was prepared as the carrier to develop the NIR light-controlled chemotherapy associated with photodynamic therapy (PDT). In view of the novel UV emission, the semiconductor photosensitizer TiO2 was exploited due to its high efficiency and chemical stability. The host modification method was used to integrate TiO2 doping and mesoporous structure, which can store anticancer drug molecules (doxorubicin, DOX). To improve the utilization of emission, a photolabile o-nitrobenzyl derivative was incorporated to form a sensitive linker (NB linker) as a “gate” to make sure the few leak. Upon NIR irradiation, the UV emission can not only excite TiO2 to produce reactive oxygen species (ROS), but also induce the breaking of NB linker as well as drug release. The NIR-triggered performances were further demonstrated by the cell experiment using HeLa cells as the model cancer cell. The synergistic effect of chemotherapy and PDT induces enhanced cytotoxicity, which is more powerful than their simple effects added together. Therefore, the novel NIR light-controlled double-therapeutic nanocomposite should be a potential candidate for anticancer agents.