Facile synthesis of lactoferrin conjugated ultra small large pore silica nanoparticles for the treatment of glioblastoma.

The blood brain barrier (BBB) and blood tumour barrier (BTB) remain a major roadblock for delivering therapies to treat brain cancer. Amongst brain cancers, glioblastoma (GBM) is notoriously difficult to treat due to the challenge of delivering chemotherapeutic drugs across the BBB and into the tumour microenvironment. Consequently, GBM has high rates of tumour recurrence. Currently, limited numbers of chemotherapies are available that can cross the BBB to treat GBM. Nanomedicine is an attractive solution for treating GBM as it can augment drug penetration across the BBB and into the heterogeneous tumour site. However, very few nanomedicines exist that can easily overcome both the BBB and BTB owing to difficulty in synthesizing nanoparticles that meet the small size and surface functionality restrictions. In this study, we have developed for the first-time, a room temperature protocol to synthesise ultra-small size with large pore silica nanoparticles (USLP, size ∼30 nm, pore size >7 nm) with the ability to load high concentrations of chemotherapeutic drugs and conjugate a targeting moiety to their surface. The nanoparticles were conjugated with lactoferrin (>80 kDa), whose receptors are overexpressed by both the BBB and GBM, to achieve additional active targeting. Lactoferrin conjugated USLP (USLP-Lf) were loaded with doxorubicin - a chemotherapy agent that is known to be highly effective against GBM in vitro but cannot permeate the BBB. USLP-Lf were able to selectively permeate the BBB in vitro, and were effectively taken up by glioblastoma U87 cells. When compared to the uncoated USLP-NPs, the coating with lactoferrin significantly improved penetration of USLP into U87 tumour spheroids (after 12 hours at 100 µm distance, RFU value 19.58 vs. 49.16 respectively). Moreover, this USLP-Lf based delivery platform improved the efficacy of doxorubicin-mediated apoptosis of GBM cells in both 2D and 3D models. Collectively, our new nano-platform has the potential to overcome both the BBB and BTB to treat GBM more effectively.

Openwork@Dendritic Mesoporous Silica Nanoparticles for Lactate Depletion and Tumor Microenvironment Regulation.

The direct depletion of lactate accumulated in the tumor microenvironment holds promise for cancer therapy but remains challenging. Herein, we report a one-pot synthesis of openwork@ dendritic mesoporous silica nanoparticles (ODMSNs) to address this problem. ODMSNs self-assembled through a time-resolved lamellar growth mechanism feature an openworked core and a dendritic shell, both constructed by silica nanosheets of ≈3 nm. With a large pore size, high surface area and pore volume, ODMSNs exhibited a high loading capacity (>0.7 g g-1 ) of lactate oxidase (LOX) and enabled intratumoral lactate depletion by >99.9 %, leading to anti-angiogenesis, down-regulation of vascular endothelial growth factor, and increased tumor hypoxia. The latter event facilitates the activation of a co-delivered prodrug for enhancing anti-tumor and anti-metastasis efficacy. This study provides an innovative nano-delivery system and demonstrates the first example of direct lactate-depletion-enabled chemotherapy.

Enhanced Solubility, Permeability and Anticancer Activity of Vorinostat Using Tailored Mesoporous Silica Nanoparticles.

Suberoylanilide hydroxamic acid (SAHA) or vorinostat (VOR) is a potent inhibitor of class I histone deacetylases (HDACs) that is approved for the treatment of cutaneous T-cell lymphoma. However, it has the intrinsic limitations of low water solubility and low permeability which reduces its clinical potential especially when given orally. Packaging of drugs within ordered mesoporous silica nanoparticles (MSNs) is an emerging strategy for increasing drug solubility and permeability of BCS (Biopharmaceutical Classification System) class II and IV drugs. In this study, we encapsulated vorinostat within MSNs modified with different functional groups, and assessed its solubility, permeability and anti-cancer efficacy in vitro. Compared to free drug, the solubility of vorinostat was enhanced 2.6-fold upon encapsulation in pristine MSNs (MCM-41-VOR). Solubility was further enhanced when MSNs were modified with silanes having amino (3.9 fold) or phosphonate (4.3 fold) terminal functional groups. Moreover, permeability of vorinostat into Caco-2 human colon cancer cells was significantly enhanced for MSN-based formulations, particularly MSNs modified with amino functional group (MCM-41-NH2-VOR) where it was enhanced ~4 fold. Compared to free drug, vorinostat encapsulated within amino-modified MSNs robustly induced histone hyperacetylation and expression of established histone deacetylase inhibitor (HDACi)-target genes, and induced extensive apoptosis in HCT116 colon cancer cells. Similar effects were observed on apoptosis induction in HH cutaneous T-cell lymphoma cells. Thus, encapsulation of the BCS class IV molecule vorinostat within MSNs represents an effective strategy for improving its solubility, permeability and anti-tumour activity.

Asymmetric Silica Nanoparticles with Tunable Head-Tail Structures Enhance Hemocompatibility and Maturation of Immune Cells.

Asymmetric mesoporous silica nanoparticles (MSNs) with controllable head-tail structures have been successfully synthesized. The head particle type is tunable (solid or porous), and the tail has dendritic large pores. The tail length and tail coverage on head particles are adjustable. Compared to spherical silica nanoparticles with a solid structure (Stöber spheres) or large-pore symmetrical MSNs with fully covered tails, asymmetrical head-tail MSNs (HTMSNs) show superior hemocompatibility due to reduced membrane deformation of red blood cells and decreased level of reactive oxygen species. Moreover, compared to Stöber spheres, asymmetrical HTMSNs exhibit a higher level of uptake and in vitro maturation of immune cells including dendritic cells and macrophage. This study has provided a new family of nanocarriers with potential applications in vaccine development and immunotherapy.

Mesoporous Magnesium Oxide Hollow Spheres as Superior Arsenite Adsorbent: Synthesis and Adsorption Behavior.

Arsenic contamination in natural water has posed a significant threat to global health due to its toxicity and carcinogenity. Adsorption technology is an easy and flexible method for arsenic removal with high efficiency. In this Article, we demonstrated the synthesis of mesoporous MgO hollow spheres (MgO-HS) and their application as high performance arsenite (As(III)) adsorbent. MgO-HS with uniform particle size (∼180 nm), high specific surface area (175 m(2) g(-1)), and distinguished mesopores (9.5 nm in size) have been prepared by hard-templating approach using mesoporous hollow carbon spheres as templates. An ultrahigh maximum As(III) adsorption capacity (Qmax) of 892 mg g(-1) was achieved in batch As(III) removal study. Adsorption kinetic study demonstrated that MgO-HS could enable As(III) adsorption 6 times faster as a commercial MgO adsorbent. The ultrahigh adsorption capacity and faster adsorption kinetics were attributed to the unique structure and morphology of MgO-HS that enabled fast transformation into a flower-like porous structure composed of ultrathin Mg(OH)2 nanosheets. This in situ formed structure provided abundant and highly accessible hydroxyl groups, which enhanced the adsorption performance toward As(III). The outstanding As(III) removal capability of MgO-HS showed their great promise as highly efficient adsorbents for As(III) sequestration from contaminated water.

Biphasic Synthesis of Large-Pore and Well-Dispersed Benzene Bridged Mesoporous Organosilica Nanoparticles for Intracellular Protein Delivery.

Large pore (4.6-7.6 nm) and well-dispersed benzene bridged mesoporous organosilica nanoparticles with uniform particle size of ≈50 nm are prepared via a biphasic approach. They can be directly used as nanocarriers without surface modification for the intracellular delivery of therapeutic proteins.