Dual-stimuli responsive hyaluronic acid-conjugated mesoporous silica for targeted delivery to CD44-overexpressing cancer cells.

In this paper, a redox and enzyme dual-stimuli responsive delivery system (MSN-SS-HA) based on mesoporous silica nanoparticles (MSN) for targeted drug delivery has been developed, in which hyaluronic acid (HA) was conjugated on the surface of silica by cleavable disulfide (SS) bonds. HA possesses many attractive features, including acting as a targeting ligand and simultaneously a capping agent to achieve targeted and controlled drug release, prolonging the blood circulation time, and increasing the physiological stability and biocompatibility of MSN. The anticancer drug doxorubicin (DOX) was chosen as a model drug. In vitro drug release profiles showed that the release of DOX was markedly restricted in pH 7.4 and pH 5.0 phosphate buffer solution (PBS), while it was significantly accelerated upon the addition of glutathione (GSH)/hyaluronidases (HAase). In addition, the release was further accelerated in the presence of both GSH and HAase. Confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) showed that MSN-SS-HA exhibited a higher cellular uptake via cluster of differentiation antigen-44 (CD44) receptor-mediated endocytosis compared with thiol (SH)-functionalized MSN (MSN-SH) in CD44 receptor over-expressed in human HCT-116 cells. The DOX-loaded MSN-SS-HA was more cytotoxic against HCT-116 cells than NIH-3T3 (CD44 receptor-negative) cells due to the enhanced cellular uptake of MSN-SS-HA. This paper describes the development of an effective method for using a single substance as multi-functional material for MSN to simultaneously regulate drug release and achieve targeted delivery.

Zhao Q ，Liu J ，Zhu W ，Sun C ，Di D ，Zhang Y ，Wang P ，Wang Z ，Wang S ... -  《-》

Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells.

Yu M ，Jambhrunkar S ，Thorn P ，Chen J ，Gu W ，Yu C ... -  《-》

Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery.

Zhao Q ，Geng H ，Wang Y ，Gao Y ，Huang J ，Wang Y ，Zhang J ，Wang S ... -  《-》

Multifunctional mesoporous silica nanoparticles modified with tumor-shedable hyaluronic acid as carriers for doxorubicin.

In this paper, a CD44-targeted and redox-responsive drug delivery system based on mesoporous silica nanoparticles (MSNs) was synthesized by conjugating tumor-shedable hyaluronic acid (HA) on the surface of MSNs via disulfide bonds. Doxorubicin hydrochloride (DOX·HCl) was physically encapsulated into HA modified MSNs (MSNs/SS/HA@DOX) as a model drug. MSNs/SS/HA@DOX (40nm) had a high drug loading (14.1%) and redox-responsive drug release property. The cellular uptake behaviors of MSNs/SS/HA@DOX by HeLa and LO2 cells were evaluated by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM). MSNs/SS/HA@DOX exhibited higher cellular uptake efficacy via CD44-mediated endocytosis by HeLa cells (CD44 over-expressed cells) than by LO2 cells (CD44 deficient cells). The in vitro cytotoxicity assay demonstrated that MSNs/SS/HA@DOX exhibited higher cytotoxicity to HeLa cells than to LO2 cells. These results indicated that MSNs/SS/HA@DOX might be promising as a multifunctional drug delivery system to improve the anti-tumor efficacy of chemotherapeutic drugs.

Zhang J ，Sun Y ，Tian B ，Li K ，Wang L ，Liang Y ，Han J ... -  《-》

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 ... -  《-》