Specific targeting of cancer cell mitochondria with a malaria drug improves pancreatic cancer outcome.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. In this paper, we present DZ-ART1, a first-in-class, dual-function therapeutic. This innovative agent is composed of a tumor-targeting heptamethine carbocyanine dye conjugated to artemisinin (ART). Near-infrared imaging demonstrated precise tumor localization of DZ-ART1 in mice. DZ-ART1 accumulated 5- to 10-fold more in cancer cells compared to normal cells. DZ-ART1 significantly decreased the survival of eight PDAC cell lines with little effect on normal cells. It increased the lethal effect of chemotherapies in vitro and in vivo. Functional assays confirmed DZ-ART1's ability to disrupt mitochondrial bioenergetics, deplete ATP, and induce reactive oxygen species production. Mitochondrial depletion of cancer cells decreased DZ-ART1 uptake and cytotoxicity, highlighting its mechanistically unique, mitochondria-dependent action. Transcriptomic profiling revealed DZ-ART1's broad reprogramming of PDAC pathways related to cell survival, cancer stemness, and metastasis. In three rigorously validated preclinical models - Krasþ/LSLG12D;Trp53þ/LSLR172H;Pdx-1-Cre (KPC) transgenic, syngeneic, and patient-derived xenografts (PDX) - DZ-ART1 markedly suppressed tumor growth and metastasis and prolonged survival, all without toxicity to normal tissues. DZ-ART1 represents a new class of anti-cancer therapeutics that uniquely combines diagnostic imaging and cancer cell organelle-specific targeting.