Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells

Nano-biotechnology has been introduced into cancer theranostics by engineering a new generation of highly versatile hybrid mesoporous composite nanocapsules (HMCNs) for manganese-based pH-responsive dynamic T₁-weighted magnetic resonance imaging (MRI) to efficiently respond and detect the tumor acidic microenvironment, which was further integrated with ultrasonographic function based on the intrinsic unique hollow nanostructures of HMCNs for potentially in vitro and in vivo dual-modality cancer imaging. The manganese oxide-based multifunctionalization of hollow mesoporous silica nanoparticles was achieved by an in situ redox reaction using mesopores as the nanoreactors. Due to the dissolution nature of manganese oxide nanoparticles under weak acidic conditions, the relaxation rate r₁ of manganese-based mesoporous MRI-T₁ contrast agents (CAs) could reach 8.81 mM^-1s^-1, which is a 11-fold magnitude increase compared to the neutral condition, and is almost two times higher than commercial Gd^III-based complex agents. This is also the highest r₁ value ever reported for manganese oxide nanoparticles-based MRI-T₁ CAs. In addition, the hollow interiors and thin mesoporous silica shells endow HMCNs with the functions of CAs for efficient in vitro and in vivo ultrasonography under both harmonic- and B-modes. Importantly, the well-defined mesopores and large hollow interiors of HMCNs could encapsulate and deliver anticancer agents (doxorubicin) intracellularly to circumvent the multidrug resistance (MDR) of cancer cells and restore the anti-proliferative effect of drugs by nanoparticle-mediated endocytosis process, intracellular drug release and P-gp inhibition/ATP depletion in cancer cells.