Collagenase Encapsulated pH-Responsive Nanoscale Coordination Polymers for Tumor Microenvironment Modulation and Enhanced Photodynamic Nanomedicine

摘要： The abundant tumor extracellular matrix (ECM) could result in the insufficient tumor retention and ineffective intra-tumor penetration of therapeutic agents, as well as acidic & hypoxic tumor microenvironment (TME), further leading to the unsatisfactory therapeutic outcomes for many types of therapies. Therefore, developing strategies to modulate the TME by selectively degrading the condensed ECM may be helpful to improve existing cancer therapies. Herein, collagenase (CLG) encapsulated nanoscale coordination polymers (NCPs) are synthesized based on Mn2+ and an acid-sensitive benzoic-imine organic linker (BI-linker), and then modified by polyethylene glycol (PEG). Upon intravenous (i.v.) injection, these CLG@NCP-PEG nanoparticles show efficient accumulation within the tumor, in which CLG would be released due to the collapse of NCP structures within the acidic TME. The released CLG enzyme could then specifically degrade collagens, the major component of ECM, leading to loosened ECM structure, enhanced tumor perfusion and relieved hypoxia. As the results, the second-wave of nanoparticles, chlorin e6 (Ce6)-loaded liposomes (Liposome@Ce6), would exhibit enhanced retention and penetration within the tumor. Such phenomena together with relieved tumor hypoxia could then lead to greatly enhanced photodynamic therapeutic effect of Liposome@Ce6 for mice pretreated with CLG@NCP-PEG. Our work thus presents a unique strategy for TME modulation using pH-responsive NCPs as smart enzyme carriers.