Design and evaluation of collagenase-loaded nanoparticles for mechanical intervention of orthotopic hepatocellular carcinoma in rat model

Abstract

Altered tissue mechanics is vital for cancer development and malignancy, whether targeting the mechanical microenvironment could retard the initiation and progression of tumor is less explored. In this study, an orthotopic hepatocellular carcinoma (HCC) rat model was constructed to reproduce the mechanical and pathophysiological microenvironment of HCC development. LpMSN@CLG, a liver-targeted (L) and pH-sensitive (p) mesoporous silica nanoparticle (MSN) encapsulated with collagenase type-I (CLG), and DOX-LpMSN@CLG, on the basis of LpMSN@CLG, encapsulated with CLG and doxorubicin (DOX), were prepared to reduce matrix stiffness by degrading collagen in liver and HCC tumor. LpMSN@CLG, and DOX-LpMSN@CLG were respectively injected (i.v.) into rats at the stage of fibrosis and HCC, resulting in decreased collagen content in liver and HCC tissue, as well as reduced matrix stiffness. In addition, LpMSN@CLG treatment at the fibrosis stage retarded HCC initiation, and DOX-LpMSN@CLG treatment inhibited the growth of HCC tumor when compared with that of the rats treated by DOX alone, suggesting that reducing matrix stiffness in HCC tumor can improve the therapeutic efficacy of DOX. Taken together, our study demonstrated that mechanical intervention of tissue stiffness by CLG-loaded nanoparticles could retard the initiation and progression of HCC, suggesting the promising of mechanical intervention of hepatocellular carcinoma.