Figure 3.

Stimuli-responsive strategies invoking a gatekeeping mechanism. (A) A cartoon illustration of the gatekeeping strategy in which the pores (green cylinders) of mesoporous silica nanoparticles (MSNPs, depicted as blue spheres) are blocked by a gate (yellow crosses). Stimulus activation results in opening of the gate and release of encapsulated imaging agents or therapeutics (red spheres). Note that other nanomaterials such as core–shell particles also employ similar approaches to release cargo. (B) A literature example of a pH-activated MSNP. In this example, a β-cyclodextrin (β-CD) is used to cap the pores of drug- or fluorophore-carrying MSNPs. At physiological pH, the β-CD encapsulates aromatic amines that are appended to the periphery of the MSNP, blocking the nanopore and entrapping cargo. Protonation of the amines following a decrease in pH results in the release of the cyclodextrin gate, enabling free diffusion of the pore contents. (C) Fluorescent images illustrating doxorubicin release from the β-CD-gated MSNPs described in panel B after internalization of the materials into acidified endosomal compartments of KB-13 cells. Release of doxorubicin was also correlated with a decrease in cell viability. Neutralization of lysosomal pH by the addition of NH₄Cl results in inhibition of doxorubicin release and toxcity, providing support for the proposed mechanism of activation. Panels B and C are adapted from Meng et al.⁵¹ with permission from the American Chemical Society.