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

Abstract 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.