Iron oxide nanoclusters formed by acid-induced in situ calcium ion cross-linking for targeted magnetic resonance imaging of glioblastoma

•Developed a novel GBM-targeted acid-responsive MRI probe (DANG-SPIO@CaP).•DANG-SPIO@CaP exhibits specifically T2 signal enhancement in acidic GBM tumor sites.•The locations and features of GBM can be precisely identified by DANG-SPIO@CaP. Contrast agents (CAs) enhanced magnetic resonance imaging (MRI) are potential candidates for the effective diagnosis of glioblastoma (GBM). However, the invasiveness and high heterogeneity of GBM interfere the effectiveness of most CAs. Compared with the conventional CAs with “always on” contrast signals, stimulus-responsive CAs that alter the MR signal in response to a specific change in their surrounding environment acquire the capability to achieve accurate diagnosis of GBM. In this study, inspired by that 1) nanocomposites can be formed by simple and controllable cross-linking anion-rich materials via multivalent cations; 2) and calcium phosphate (CaP) with good biocompatibility can be degraded triggered by acid and release divalent Ca2+, an unprecedented acid-responsive nano-CA was designed for targeted MRI of GBM. The acid-responsive targeted nano-CA (DANG-SPIO@CaP) was prepared by coating CaP on the surface of polyacrylic acid (PAA)-coated ultra-small superparamagnetic iron oxide (PAA/SPIO) nanoparticles, and then modified with the GBM-targeting DANG peptide. DANG-SPIO@CaP has good stability and relatively low T2 relaxivity at the physiological condition. However, under the weakly acidic condition in tumor microenvironment, the CaP shell of DANG-SPIO@CaP degrades, and the released Ca2+ will cross-link the exposed PAA/SPIO to form large nanoclusters with high T2 relaxivity. Consequently, DANG-SPIO@CaP can specifically navigate to GBMs, undergo the in situ acid-responsive degradation and reaggregation processes and form large nanoclusters with stronger T2 enhancing effect, allowing the locations of GBMs to be clearly recognized and even the features of different GBMs to be revealed.