Hyaluronic acid-capped compact silica-supported mesoporous titania nanoparticles for ligand-directed delivery of doxorubicin.

Mesoporous titania nanoparticles (MTN), owing to their high surface area to volume ratio and tunable pore sizes, appear capable of delivering sizable amounts of drug payloads, and hence, show considerable promise as drug delivery candidates in cancer therapy. We designed silica-supported MTN (MTNst) coated with hyaluronic acid (HA) to effectively deliver doxorubicin (DOX) for breast cancer therapy. The HA coating served a dual purpose of stabilizing the payload in the carriers as well as actively targeting the nanodevices to CD44 receptors. The so-formed HA-coated MTNst carrying DOX (HA/DOX-MTNst) had spheroid particles with a considerable drug-loading capacity and showed significantly superior in vitro cytotoxicity against MDA-MB-231 cells as compared to free DOX. HA/DOX-MTNst markedly improved the cellular uptake of DOX in an apparently CD44 receptor-dependent manner, and increased the number of apoptotic cells as compared to free DOX. These nanoplatforms accumulated in large quantities in the tumors of MDA-MB-231 xenograft tumor-bearing mice, where they significantly enhanced the inhibition of tumor growth compared to that observed with free DOX with no signs of acute toxicity. Based on these excellent results, we deduced that HA/DOX-MTNst could be successfully used for targeted breast cancer therapy. STATEMENT OF SIGNIFICANCE: This is the first study to use silica-supported mesoporous titania nanoparticles (MTNst) for doxorubicin (DOX) delivery to treat breast cancer, which exhibited effective and enhanced in vitro and in vivo apoptosis and tumor growth inhibition. Solid silica was used to support the mesoporous TiO2 resulting in MTNst, which efficiently incorporated a high DOX payload. The hyaluronic acid (HA) coating over the MTNst surface served a dual purpose of first, stabilizing DOX inside the MTNst (capping agent), and second, directing the nanoplatform device to CD44 receptors that are highly expressed in MDA-MB-231 cells (targeting ligand). The NPs exhibited highly efficacious in vitro tumor-cell killing and excellent in vivo tumor regression, highlighting the enormous promise of this system for breast cancer therapy.

Gupta B ，Poudel BK ，Ruttala HB ，Regmi S ，Pathak S ，Gautam M ，Jin SG ，Jeong JH ，Choi HG ，Ku SK ，Yong CS ，Kim JO ... -  《-》

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 ... -  《-》

Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy.

In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA-DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA-DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer. Combination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer.

Liu Y ，Qiao L ，Zhang S ，Wan G ，Chen B ，Zhou P ，Zhang N ，Wang Y ... -  《-》

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 mesoporous silica nanoparticles for tumor cells and mitochondria multistage-targeted drug delivery.

Naz S ，Wang M ，Han Y ，Hu B ，Teng L ，Zhou J ，Zhang H ，Chen J ... -  《-》