A versatile two-light mode triggered system for highly localized sequential release of reactive oxygen species and conjugated drugs from mesoporous organosilica particles

Abstract

The increasing prevalence of antimicrobial resistance and adverse effects of systemic treatments calls for urgent reevaluation of current methods that rely on excessive, uncontrolled drug administration. In recent years triggerable systems have emerged as promising alternatives, enabling time-controlled and localized drug release, which are only activated if necessary. Light is an obvious candidate as an external trigger, since it allows for localized activation, is non-invasive and its wavelength and intensity can be tailored to fit the demands of the drug release system. Such localized and triggered systems minimize off-target effects and undesired exposure, making it a promising tool for combating health threats such as antimicrobial resistance. However, the limited tissue penetration of visible light significantly limits the applicability of this concept in vivo. Here, we introduce an innovative triggerable drug release system, based on mono-, bi-, and tri-functionalized mesoporous organosilica particles (MOPs). The limited tissue penetration is addressed by an advanced trigger system featuring two-photon absorption. Two-photon absorption enables utilization of near-infrared (NIR) light as a trigger, which is known to exhibit an enhanced penetration depth. The particles are designed to release reactive oxygen species (ROS) upon NIR irradiation and undergo Förster resonance energy transfer (FRET) to a ROS producing dye. Moreover, by oxidative cleavage, an additional therapeutic agent is released in a cascade reaction, enhancing the system's effectiveness. The ROS release is microscopically demonstrated in situ and, for the first time, release of a fluorescent compound (therapeutic agent) in a cascade reaction is observed in real-time, providing valuable insights into the behavior and performance of our particles. This novel sequential dual-release platform for light-triggered therapeutic delivery has great potential for advanced therapeutic applications in both superficial and deep tissue treatments.