pH-Responsive chitosan-modified gadolinium oxide nanoparticles delivering 5-aminolevulinic acid: A dual cellular and metabolic T1-T2* contrast agent for glioblastoma brain tumors detection.

• A dual cellular and metabolic T 1 and T 2 * contrast agent was formulated. • CS-modified Gd 2 O 3 NPs were applied for 5-ALA delivery. • CS-coated Gd 2 O 3 NPs improved significantly transverse and longitudinal relaxivities. • 5-ALA combined with FAC improved remarkably the transverse relaxation rate of C 6 cells treated with the NPs. Diagnosis of glioblastoma multiforme (GBM) with high sensitivity and specificity requires cellular and metabolic imaging. In this study, we aimed to endow gadolinium oxide nanoparticles (Gd 2 O 3 NPs) as an interesting T 1 contrast agent with T 2 * contrast ability through intracellular iron assistance induced by 5-aminolevulinic acid (5-ALA) with ferric ammonium citrate (FAC). Chitosan (CS)-loaded Gd 2 O 3 NPs were loaded with 5-aminolevulinic acid (Gd 2 O 3 /CS-TPP@5-ALA NPs), and then evaluated as a pH-responsive dual cellular and metabolic T 1 and T 2 * contrast agent for GBM diagnosis. The target NPs with an average size of 138 nm revealed concentration-dependent toxicity against glioblastoma C 6 cells. The relaxation rate (R 1) of the C 6 cells treated with Gd 2 O 3 /CS-TPP@5-ALA NPs plus FAC was remarkably higher than the controls including Gd 2 O 3 /CS-TPP NPs, Gd 2 O 3 /CS-TPP@5-ALA NPs, and FAC (17.2 ± 2.4 vs. 8 ± 1.5, 8.4 ± 1.2, and 2.3 ± 0.5, respectively). Interestingly, the transverse relaxation rate (R 2 *) of the C 6 cells treated with Gd 2 O 3 /CS-TPP@5-ALA NPs + FAC was significantly higher than the controls including Gd 2 O 3 /CS-TPP NPs, Gd 2 O 3 /CS-TPP@5-ALA NPs, and FAC (96 ± 8 vs. 25 ± 4, 27 ± 5, and 19 ± 2.6, respectively). We believe that Gd 2 O 3 /CS-TPP@5-ALA NPs + FAC could be introduced as promising dual cellular and metabolic T 1 -T 2 * contrast agents for GBM diagnosis in MRI. [ABSTRACT FROM AUTHOR]