Enzyme-responsive cell-penetrating peptide conjugated mesoporous silica quantum dot nanocarriers for controlled release of nucleus-targeted drug molecules and real-time intracellular fluorescence imaging of tumor cells.

Here, a set of novel and personalized nanocarriers are presented for controlled nucleus-targeted antitumor drug delivery and real-time imaging of intracellular drug molecule trafficking by integrating an enzyme activatable cell penetrating peptide (CPP) with mesoporous silica coated quantum dots nanoparticles. Upon loading of antitumor drug, doxorubicin (DOX) and further exposure to proteases in tumor cell environment, the enzymatic cleavage of peptide sequence activates oligocationic TAT residues on the QDs@mSiO2 surface and direct the DOX delivery into cellular nucleus. The systematic cell imaging and cytotoxicity studies confirm that the enzyme responsive DOX-loaded CPP-QDs@mSiO2 nanoparticles can selectively release DOX in the tumor cells with high cathepsin B enzyme expression and greatly facilitate DOX accumulation in targeted nucleus, thus exhibiting enhanced antitumor activity in these cells. As contrast, there is limited nuclear-targeted drug accumulation and lower tumor cytotoxicity observed in the cells without enzyme expression. More importantly, significant antitumor DOX accumulation and higher tumor inactivation is also found in the drug resistant tumor cells with targeted enzyme expression. Such simple and specific enzyme responsive mesoporous silica-QDs nanoconjugates provide great promise for rational design of targeted drug delivery into biological system, and may thus greatly facilitate the medical theranostics in the near future.

Li J ，Liu F ，Shao Q ，Min Y ，Costa M ，Yeow EK ，Xing B ... -  《-》

Enzyme-induced and tumor-targeted drug delivery system based on multifunctional mesoporous silica nanoparticles.

Cheng YJ ，Luo GF ，Zhu JY ，Xu XD ，Zeng X ，Cheng DB ，Li YM ，Wu Y ，Zhang XZ ，Zhuo RX ，He F ... -  《-》

Fluorescent carbon dot-gated multifunctional mesoporous silica nanocarriers for redox/enzyme dual-responsive targeted and controlled drug delivery and real-time bioimaging.

A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real-time bioimaging by combining a redox/enzyme dual-responsive disulfide-conjugated carbon dot with mesoporous silica nanoparticles (MSN-SS-CDHA). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CDHA). The as-prepared MSN-SS-CDHA exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CDHA with a diameter size of 3nm completely blocked the pore entrance of DOX-encapsulated MSN nanoparticles with a pore size of about 3nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual-responsive DOX-encapsulated MSN-SS-CDHA nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN-SS-CDHA-DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN-SH-DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN-SS-CD was also used as a control to investigate the ability of MSN-SS-CDHA to target A549 cells. The results obtained indicated that MSN-SS-CDHA possessed a higher cellular uptake through the CD44 receptor-mediated endocytosis compared with MSN-SS-CD in the A549 cells. Such specific redox/enzyme dual-responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of therapeutic reagents with real-time bioimaging, and may also facilitate the development of drug delivery systems for a number of clinical applications.

Wang Y ，Cui Y ，Zhao Y ，He B ，Shi X ，Di D ，Zhang Q ，Wang S ... -  《-》

Hybrid silica-coated Gd-Zn-Cu-In-S/ZnS bimodal quantum dots as an epithelial cell adhesion molecule targeted drug delivery and imaging system.

Dual-modal imaging probes based on fluorescence (FL) and magnetic resonance (MR) modalities have attracted great attention due to their ability to combine the target specificity and high penetration into body tissues. In this study, we developed a potent nanocarrier with an effective photoluminescent emission and MR imaging capacity to deliver the doxorubicin to breast cancer 4T1 cells. The nanocarrier was fabricated by coating of quantum dots (QDs) with mesoporous silica followed by amine functionalization of the silica surface. Then, the doxorubicin was loaded into the silica pores and biheterofunctional PEG was covalently bound to the surface of core-shell quantum dot mesoporous silica nanoparticles. In order to target the DOX-loaded nanoparticles, the EpCAM DNA aptamer was attached on the surface of the DOX-loaded PEGylated nanoparticles. The synthesized NPs were analyzed for their size distribution, morphology, zeta potential and magnetic susceptibility using HRTEM, SEM and VSM analysis. The QD-encapsulated mesoporous silica revealed spherical shapes with an average particle size of 100 nm. The maximum encapsulation efficacy of doxorubicin in the silica pores was 25%. The in vitro release assessment demonstrated the pH-sensitive release of doxorubicin from the designed formulations. The in vitro cytotoxicity assays indicated that the aptamer targeted nanoparticles showed greater cytotoxicity than both non-targeted NPs and free DOX toward 4T1 and MCF-7 cell lines. The in vivo studies in 4T1 tumor-bearing Balb/c mice demonstrated that EpCAM aptamer could specifically deliver the DOX-loaded nanoparticles into the tumor tissue and cause remarkable inhibition of tumor growth as compared to non-targeted formulation and free DOX. Moreover, the in vivo MR and fluorescent imaging in 4T1 tumor-bearing mice confirmed the accumulation and residence of targeted system in tumor tissue even 24 h post-injection. This work presents a novel system for preparing bimodal imaging theranostic NPs through hybridization of silica and magnetic-fluorescent quantum dots.

Akbarzadeh M ，Babaei M ，Abnous K ，Taghdisi SM ，Peivandi MT ，Ramezani M ，Alibolandi M ... -  《-》

Enzyme-responsive multifunctional magnetic nanoparticles for tumor intracellular drug delivery and imaging.

Enzyme-responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)-conjugated, enzyme-cleavable peptide precursors were covalently tethered onto the surface of uniform silica-coated magnetic nanoparticles through click chemistry. This enzyme-responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression.

Yang Y ，Aw J ，Chen K ，Liu F ，Padmanabhan P ，Hou Y ，Cheng Z ，Xing B ... -  《-》