Redox stimuli-responsive hollow mesoporous silica nanocarriers for targeted drug delivery in cancer therapy.

In order to specifically deliver drugs into cancer cells with targeted recognition and controlled release, biocompatible hollow mesoporous silica nanocarriers with tumor-targeting and glutathione-responsive release dual properties were developed. These multifunctional nanocarriers were fabricated by anchoring transferrin on the surface of hollow mesoporous silica nanoparticles through disulfide bond conjugation, which could be cleaved in the presence of glutathione. In this case, transferrin acted as the gatekeeper to control the drug release, and as a tumor-targeting agent to improve drug accumulation at the tumor site simultaneously. The detailed investigations indicate that the anticancer drug (doxorubicin) release from the nanocarriers was strongly dependent on the concentration of glutathione. The capacity of the nanocarriers to selectively deliver doxorubicin to the tumor cells was demonstrated in vitro and in vivo. The doxorubicin-loaded nanocarriers showed enhanced inhibition of tumor growth and minimal side-effects in vivo compared to free doxorubicin. These redox stimuli-responsive nanocarriers that achieved a combination of tumor targeting and controlled drug release provide a promising platform for efficient cancer therapies.

Tumor-Targeting Multifunctional Rattle-Type Theranostic Nanoparticles for MRI/NIRF Bimodal Imaging and Delivery of Hydrophobic Drugs.

The development of theranostic systems capable of diagnosis, therapy, and target specificity is considerably significant for accomplishing personalized medicine. Here, a multifunctional rattle-type nanoparticle (MRTN) as an effective biological bimodal imaging and tumor-targeting delivery system is fabricated, and an enhanced loading ability of hydrophobic anticancer drug (paclitaxel) is also realized. The rattle structure with hydrophobic Fe3 O4 as the inner core and mesoporous silica as the shell is obtained by one-step templates removal process, and the size of interstitial hollow space can be easily adjusted. The Fe3 O4 core with hydrophobic poly(tert-butyl acrylate) (PTBA) chains on the surface is not only used as a magnetic resonance imaging (MRI) agent, but contributes to improving hydrophobic drug loading amount. Transferrin (Tf) and a near-infrared fluorescent dye (Cy 7) are successfully modified on the surface of the nanorattle to increase the ability of near-infrared fluorescence (NIRF) imaging and tumor-targeting specificity. In vivo studies show the selective accumulation of MRTN in tumor tissues by Tf-receptor-mediated endocytosis. More importantly, paclitaxel-loaded MRTN shows sustained release character and higher cytotoxicity than the free paclitaxel. This theranostic nanoparticle as an effective MRI/NIRF bimodal imaging probe and drug delivery system shows great potential in cancer diagnosis and therapy.

The strategy to improve gene transfection efficiency and biocompatibility of hyperbranched PAMAM with the cooperation of PEGylated hyperbranched PAMAM.

As a promising non-viral gene vector, cationic polyamidoamine (PAMAM) dendrimer could form complexes with negative charged DNA to mediate efficient gene delivery in vitro and in vivo. However, complicated synthesis technology and potential cytotoxicity limited their application in clinical translational researches. Hyperbranched polyamidoamine (h-PAMAM), which could be synthesized by a simpler one-pot method, has similar properties with PAMAM, and PEGylation modification of h-PAMAM has been used to reduce cytotoxicity. Here we prepared gene delivery system with h-PAMAM and h-PAMAM derivative h-PAMAM-g-PEG, respectively and found that the viability of cells with h-PAMAM-g-PEG was quite higher in comparison with cells with unmodified h-PAMAM. However, gene delivery efficiency was lower with h-PAMAM-g-PEG. Then we used mixture composed of h-PAMAM and h-PAMAM-g-PEG and such composition was designed to reduce cytotoxicity while maintaining high transfection efficiency. Our results indicated that this mixture system of h-PAMAM and h-PAMAM-g-PEG achieved higher transfection efficiency and lower cytotoxicity compared with h-PAMAM-only system.

Redox- and temperature-controlled drug release from hollow mesoporous silica nanoparticles.

A controlled drug-delivery system has been developed based on mesoporous silica nanoparticles that deliver anticancer drugs into cancer cells with minimized side effects. The copolymer of two oligo(ethylene glycol) macromonomers cross-linked by the disulfide linker N,N'-bis(acryloyl)cystamine is used to cap hollow mesoporous silica nanoparticles (HMSNs) to form a core/shell structure. The HMSN core is applied as a drug storage unit for its high drug loading capability, whereas the polymer shell is employed as a switch owing to its redox/temperature dual responses. The release behavior in vitro of doxorubicin demonstrated that the loaded drugs could be released rapidly at higher temperature or in the presence of glutathione (GSH). Thus, the dual-stimulus polymer shell exhibiting a volume phase transition temperature higher than 37 °C can effectively avoid drug leakage in the bloodstream owing to the swollen state of the shell. Once internalized into cells, the carriers shed the polymer shell because of cleavage of the disulfide bonds by GSH, which results in the release of the loaded drugs in cytosol. This work may prove to be a significant development in on-demand drug release systems for cancer therapy.