Pharmacokinetics modulation in solid tumors through thrombin-embedded nanomedicine

The development of anti-tumor nanomedicines grapples with the critical challenge of achieving sustained retention and massive intratumoral distributions of chemotherapeutics. Herein, we attempted multifaceted prodrug nanomedicine with precise spatiotemporal responsiveness, integrating dual prodrugs-redox-responsive SN38 and pH-responsive thrombin and ensuring drug release coinciding with the striking tumor acidity and reductive stress, while its spatial selectivity is directed by the overexpression of integrins on cancerous cells. Most importantly, the thrombin component induces vascular occlusion within tumors, leading to normalization of the elevated interstitial fluid pressure and promoting accumulation of chemotherapeutic agents. This approach not only facilitates the massive intratumoral distribution of the nanomedicine but also ensures sustained retention of SN38 within the tumor microenvironment, thereby augmenting the cytotoxic potencies. Of note, the advanced mass spectrum mapping technology unprecedentedly validated the successful activation of the SN38 prodrug and massive distribution throughout the solid tumors for thrombin-containing nanomedicine, in stark to apparent entrapment in tumor vasculature and stroma for the conventional thrombin-free nanomedicine. Hence, the multifunctionalities of our proposed dual prodrug nanomedicine is underscored by its ability to actively target cancerous cells, induce vasculature occlusion, and orchestrate a controlled release of chemotherapeutic agents.