PVIS-Ir

PVIS-Ir is a **novel anticancer conjugate drug** designed to target hepatocellular carcinoma (HCC) and related cancers characterized by high tryptophan 2,3-dioxygenase (TDO) expression. It is a **conjugate of irinotecan (a topoisomerase I inhibitor) and a TDO inhibitor** linked by a cleavable succinate linker. In weakly acidic tumor environments, PVIS-Ir hydrolyzes to release both irinotecan and a TDO inhibitor derivative (PVIS-OH), providing a dual mechanism of direct cytotoxic action through topoisomerase I inhibition and an immunomodulatory effect via TDO inhibition. PVIS-Ir shows markedly greater cytotoxicity against HepG2 (liver cancer) cells compared to either irinotecan or the TDO inhibitor alone, while sparing normal hepatocyte (LO2) cells. In vitro and in vivo studies demonstrate that PVIS-Ir induces G2 phase cell cycle arrest, triggers mitochondria-dependent apoptosis (upregulating Bax, cleaved caspase-3, and PARP while downregulating Bcl-2), and stimulates significant proliferation of CD4+ and CD8+ T cells, indicating enhanced antitumor immune response. The drug is not yet approved and is in preclinical research as an immunochemotherapeutic agent, particularly for HCC.[1]