Mesoporous Biodegradable Magnesium Phosphate-Citrate Nanocarriers Amplify Methotrexate Anticancer Activity in HeLa Cells.

We present the synthesis of amorphous, mesoporous, colloidal magnesium phosphate-citrate nanoparticles (MPCs) from biogenic precursors, resulting in a biocompatible and biodegradable nanocarrier that amplifies the action of the anticancer drug methotrexate (MTX). Synthesis conditions were gradually tuned to investigate the influence of the chelating agent citric acid on the colloidal stability and the mesoporosity of the obtained nanoparticles. With optimized synthesis conditions, a large BET surface area of 560 m2/g was achieved. We demonstrate the potential of these biocompatible and biodegradable mesoporous MPCs as a drug delivery system. Lipid-coated MPCs were used to load the fluorescent dye calcein and the chemotherapeutic agent MTX into the mesopores. In vitro experiments show very low premature release of the cargo but efficient stimuli-responsive release in an environment of pH 5.5, in which MPCs degrade. Lipid-coated MPCs are taken up by cancer cells and are nontoxic up to concentrations of 100 µg/mL. When loaded with MTX serving as a representative model drug for in vitro studies, MPCs induced efficient cell death with an IC50 value of 1.1 µg/mL. Compared to free MTX, its delivery with MPCs enhances its efficiency by an order of magnitude. In summary, we have developed a biodegradable nanomaterial synthesized from biocompatible precursors that are neither toxic by themselves nor in the form of nanoparticles. With these features, MPCs may be applied as drug delivery systems and have the potential to reduce the side effects of current chemotherapies.

Mesoporous Silica Nanoparticles as pH-Responsive Carrier for the Immune-Activating Drug Resiquimod Enhance the Local Immune Response in Mice.

Nanoparticle-based delivery systems for cancer immunotherapies aim to improve the safety and efficacy of these treatments through local delivery to specialized antigen-presenting cells (APCs). Multifunctional mesoporous silica nanoparticles (MSNs), with their large surface areas, their tunable particle and pore sizes, and their spatially controlled functionalization, represent a safe and versatile carrier system. In this study, we demonstrate the potential of MSNs as a pH-responsive drug carrier system for the anticancer immune-stimulant R848 (resiquimod), a synthetic Toll-like receptor 7 and 8 agonist. Equipped with a biotin-avidin cap, the tailor-made nanoparticles showed efficient stimuli-responsive release of their R848 cargo in an environmental pH of 5.5 or below. We showed that the MSNs loaded with R848 were rapidly taken up by APCs into the acidic environment of the lysosome and that they potently activated the immune cells. Upon subcutaneous injection into mice, the particles accumulated in migratory dendritic cells (DCs) in the draining lymph nodes, where they strongly enhanced the activation of the DCs. Furthermore, simultaneous delivery of the model antigen OVA and the adjuvant R848 by MSNs resulted in an augmented antigen-specific T-cell response. The MSNs significantly improved the pharmacokinetic profile of R848 in mice, as the half-life of the drug was increased 6-fold, and at the same time, the systemic exposure was reduced. In summary, we demonstrate that MSNs represent a promising tool for targeted delivery of the immune modulator R848 to APCs and hold considerable potential as a carrier for cancer vaccines.