Mesoporous Silica Nanoparticles with pH-Sensitive Nanovalves for Delivery of Moxifloxacin Provide Improved Treatment of Lethal Pneumonic Tularemia

Abstract

We have optimized mesoporous silica nanoparticles (MSNs) functionalized with pH-sensitive nanovalves for the delivery of the broad spectrum fluoroquinolone moxifloxacin (MXF) and demonstrated its efficacy in treating Francisella tularensis infections both in vitro and in vivo. We compared two different nanovalve systems, positive and negative charge modifications of the mesopores, and different loading conditions-varying pH, cargo concentration, and duration of loading-and identified conditions that maximize both the uptake and release capacity of MXF by MSNs. We have demonstrated in macrophage cell culture that the MSN-MXF delivery platform is highly effective in killing F. tularensis in infected macrophages, and in a mouse model of lethal pneumonic tularemia, we have shown that the drug-loaded MSNs are much more effective in killing F. tularensis than an equivalent amount of free MXF.

Redox‐Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap‐Tops Enhances Efficacy Against Pneumonic Tularemia in Mice

“…The higher release capacity in DMSO with 2‐mercaptoethanol indicates that not all MXF molecules were released from mesopores in PBS. In comparison, the highest release capacity obtained from using the pH‐sensitive nanovalve was around 8 wt% …”

“…Nanoparticles also have several other advantages over free drug, including shielding the drug from metabolism and excretion and providing more favorable pharmacokinetics. While several different nanoparticle delivery platforms have been studied for antibiotic delivery, including liposomes, solid lipid particles, poly‐L‐lactide (PLGA), and biological materials such as gelatin, chitosan, and alginates, mesoporous silica nanoparticles (MSNs) offer several important advantages, including structural and chemical stability, uniformity, inherent lack of toxicity, capacity to encapsulate exceptionally high concentrations of different types of cargo, and versatility in incorporating rational design features, including stimulus responsive drug release systems . In this work, we have developed a stimulus‐responsive MSN platform for treatment of tularemia that delivers the antibiotic moxifloxacin (MXF) intracellularly in response to the intracellular redox potential.…”

Stimuli-Responsive Mesoporous Silica NPs as Non-viral Dual siRNA/Chemotherapy Carriers for Triple Negative Breast Cancer

“…In another attempt, Li et al 107 . synthetized two pH-responsive nanovalves constructed from a stalk being covalently bound to the MSM-41 pore entrance, and cyclodextrin was applied as a capping molecule to the organic part of the stalk through hydrophobic-hydrophobic interactions after entrapment of cargo inside pores.…”

TPGS‐Functionalized Polydopamine‐Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

“…In fact, the favorable structural features of MSNs, such as intrinsic tunable pore size, high pore volume, and high surface area, could guarantee an extraordinary drug loading capacity and high encapsulation efficiency of a wide variety of cargo molecules . Additionally, their surfaces can be functionalized with “gate keepers,” some of which are highly sensitive to a variety of exogenous and endogenous stimuli, such as light, pH, temperature, and remote magnetic actuation, enabling controlled and on‐command release of the cargo …”