Intracellular Construction of Cathepsin B‐Guided Gadolinium Nanoparticles for Enhanced T2‐Weighted MR Tumor Imaging

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T₂ -weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a "smart" Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T₂ -weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T₂ -weighted MRI studies using MDA-MB-231 murine xenografts show that the T₂ -weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T₂ -weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T₂ contrast agent for the clinical diagnosis of cancers at an early stage.