Unconventional Preparation of Polymer/Amorphous Manganese Oxide-Based Biodegradable Nanohybrids for Low Premature Release and Acid/Glutathione-Activated Magnetic Resonance Imaging

Smart poly(methacrylic acid-co-N,N-bis(acryloyl)cystamine)/DOX/MnO2-2/polyethylene glycol theranostic nanohybrids (PMAABACy/DOX/MnO2-2/PEG TNs) were rationally fabricated using in situ generation of amorphous MnO2 by taking advantage of the spatial confinement effect of PMAABACy nanohydrogels, and its PEGylation was accomplished through Mn–N coordinate bonding. The amorphous MnO2 of PMAABACy/DOX/MnO2-2/PEG TNs was synthesized through the chelation between Mn2+ ions and carboxyl groups of PMAA chains, which served as a gatekeeper to prevent the premature leakage of DOX during blood circulation. In the presence of intracellular acidic glutathione (GSH), the release of Mn2+ ions from amorphous MnO2 as a dual T1/T2 contrast agent endowed the nanohybrids with enhanced acid/GSH-activated magnetic resonance imaging (MRI). In addition, the site-specific release of a chemotherapeutic drug (DOX) was also realized because of the disintegration of both amorphous MnO2 and PMAABACy in response to biological endogenous stimulus, such as increased GSH level and slightly acidic pH in tumor cells. The newly as-synthesized nanohybrids presented some excellent characteristics: they prevented premature release; enhanced the stability under physiological conditions; and exhibited excellent T1/T2 MRI performance, remarkable biodegradability, and efficient site-specific release of DOX. Our findings indicated that such polymer/amorphous manganese oxide-based biodegradable nanohybrids can facilitate the development of a drug delivery system with a capacity for low premature release for real-time MRI-guided cancer therapy.