Multifunctional Theranostic Liposomes Loaded with a Hypoxia-Activated Prodrug for Cascade-Activated Tumor Selective Combination Therapy

Photodynamic therapy (PDT) is becoming a promising therapeutic regimen but is limited by the hypoxic microenvironment in solid tumors and the undesirable posttreatment phototoxicity side effects on normal tissues. To overcome these restrictions and enhance the antitumor therapeutic effect, near-infrared (NIR) light-activated, cancer cell-specific, hypoxia prodrug-loaded chlorin e6 liposomes were developed for tumor selective combination therapy guided by multimodal imaging. The photothermal agent indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ) were coencapsulated into the liposomes, followed by modification with cRGD and conjugation with GdIII to form ICG/TPZ@Ce6-GdIII theranostic liposomes (ITC-GdIII TLs). In the ITC-GdIII TLs, both the fluorescence and photodynamic effect of Ce6 were quenched by ICG via fluorescence resonance energy transfer. The ITC-GdIII TLs can effectively reach the tumor site through the enhanced permeability and retention effect as well as the cRGD-mediated...