A collagenase-decorated Cu-based nanotheranostics: remodeling extracellular matrix for optimizing cuproptosis and MRI in pancreatic ductal adenocarcinoma

• Published in: Journal of nanobiotechnology 2024-11, Vol.22 (1), p.689-19, Article 689
• Main Authors: Wang, Yining, Zhou, Qiaomei, Luo, Wangping, Yang, Xiaoyan, Zhang, Jinguo, Lou, Yijie, Mao, Jin, Chen, Jiayi, Wu, Fan, Hou, Jue, Tang, Guping, Bai, Hongzhen, Yu, Risheng
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antimitotic agents; Antineoplastic agents; Cancer; Carcinoma, Pancreatic Ductal - diagnostic imaging; Carcinoma, Pancreatic Ductal - drug therapy; Care and treatment; Cell Line, Tumor; Chemotherapy; Collagenase; Collagenases - metabolism; Contrast media; Contrast Media - chemistry; Copper - chemistry; Cuproptosis; Diagnosis; Disulfiram - chemistry; Disulfiram - pharmacology; Dosage and administration; Extracellular matrix; Extracellular Matrix - metabolism; Health aspects; Humans; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Mice; Mice, Nude; Nanoparticles - chemistry; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - drug therapy; Patient outcomes; Risk factors; Theranostic Nanomedicine - methods
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-024-02968-6

Pancreatic ductal adenocarcinoma (PDAC), characterized by a dense extracellular matrix (ECM), presents significant therapeutic challenges due to its poor prognosis and high resistance to chemotherapy. Current chemodrugs and diagnostic agents largely fail to cross the barrier posed by the ECM, which severely limits the PDAC theranostics. This study introduces a novel theranostic strategy using thioether-hybridized hollow mesoporous organosilica nanoparticles (dsMNs) for the co-delivery of copper (Cu) and disulfiram (DSF), aiming to induce cuproptosis in PDAC cells. Our approach leverages the ECM-degrading enzyme collagenase, integrated with dsMNs, to enhance drug penetration by reducing matrix stiffness. Furthermore, the innovative use of a pancreatic cancer cell membrane coating on the nanoparticles enhances tumor targeting and stability (dsMCu-D@M-Co). The multifunctional platform not only facilitates deep drug penetration and triggers cuproptosis effectively but also utilizes the inherent properties of Cu to serve as a T1-weighted magnetic resonance imaging (MRI) contrast agent. In vitro and in vivo assessments demonstrate significant tumor size reduction in PDAC-bearing mice, highlighting the dual functionality of our platform in improving therapeutic efficacy and diagnostic precision. This integrated strategy represents a significant advancement in the management of PDAC, offering a promising new direction for overcoming one of the most lethal cancers.