Pancreatic cancer is a more aggressive and refractory
malignancy. Resistance and toxicity limit drug efficacy. Herein, we report a lower toxic and higher effective
miriplatin (MPt)-loaded
liposome, LMPt, exhibiting totally different anti-
cancer mechanism from previously reported
platinum agents. Both in
gemcitabine (GEM)-resistant/sensitive (GEM-R/S)
pancreatic cancer cells, LMPt exhibits prominent anti-
cancer activity, led by faster cellular entry-induced larger accumulation of MPt. The level of
caveolin-1 (Cav-1) determines entry rate and switch of entry pathways of LMPt, indicating a novel role of Cav-1 in nanoparticle entry. After endosome-lysosome processing, in unchanged metabolite, MPt is released and targets mitochondria to enhance binding of mitochondria
protease LONP1 with POLG and TFAM, to degrade POLG and TFAM. Then, via PINK1-Parkin axis, mitophagy is induced by POLG and TFAM degradation-initiated
mitochondrial DNA (
mtDNA) replication blocking. Additionally, POLG and TFAM are identified as novel prognostic markers of
pancreatic cancer, and
mtDNA replication-induced mitophagy blocking mediates their pro-
cancer activity. Our findings reveal that the target of this liposomal
platinum agent is mitochondria but not
DNA (target of most
platinum agents), and totally distinct mechanism of MPt and other formulations of MPt. Self-assembly offers LMPt special efficacy and mechanisms. Prominent action and characteristic mechanism make LMPt a promising
cancer candidate.