TME-responsive switch-on nano-contrast for targeted BBB-traversing MRI of glioma

MRI for intracranial lesions has unsatisfactory signal-to-noise ratios due to BBB (Blood Brain Barrier) obstruction and the rapid metabolism of contrast agent molecules. A pH-sensitive nanosystem can cloak Gd3+ from protons in normal tissues and activate Gd3+ signals in acidic TME (tumor microenvironment). In addition, based on the theory of homologous binding between tumor cells and the membranous inheritance of the initial BBB-traversing ability of brain metastatic breast tumor cells, nanoparticles camouflaged by the U87-4T1-hybridized-membrane obtained the potential in traversing the BBB and targeting to glioma. This study aimed to construct a biocompatible TME-responsive MRI nano-contrast agent with potent BBB-traversing and tumor-targeting ability for glioma diagnosis with significantly enhanced T1WI signal intensity. PGdCa@hCCM was synthesized with an average particle size and zeta potential of 199.1 ± 24.5 nm and 23.4 ± 6 mV, respectively, which remained stable within 7 days. Camouflage by U87 cell membrane endowed nanoparticles with homologous affinity and led to stronger accumulation in U87 cells. The MFI of PGdCa@hCCM that traversed the artificial BBB model and targeted to U87 cells was significantly higher than that of PGdCa@CCM (U87 only) or PGdCa (without membrane camouflage) (p < 0.001), indicating the hybridized membranes facilitated nanoparticles crossing BBB and targeting to U87 cells. The MRI signals of PGdCa@hCCM under neutral PBS (a.u.=196.3 ± 6.9) and pH7.4 PBS (a.u.=239.8 ± 13.2) were significantly weaker than that under pH6.5 (a.u.=711.1 ± 27.8), indicating that the MRI capacity could be activated under acidic environment. The MRI signal in PGdCa@CCM (U87 only) group exhibited a signal-to-noise ratio of 14.9 ± 1.3 after 6 h, while the tumor-to-noise ratio in mice injected with PGdCa@hCCM was enhanced to 30.2 ± 5.5 after 6 h. PGdCa@hCCM was also proved to possess good biosafety and prolonged circulation time and metabolizability. In this study, an in situ activable MRI nano-contrast PGdCa@hCCM was engineered. With the substantial improvements in tumor-targeting and BBB-traversing efficiency, as well as the pH-sensitive switch on/off function, PGdCa@hCCM successfully promoted the sensitivity and accuracy in MR imaging of glioma.