Abstract
Iron is an essential element for various cellular metabolism. Cancer cells also have high requirement of iron in their proliferation, invasion, and metastasis processes. Alendronate (ALN), a kind of FDA-approved bisphosphonates with metal-chelating capability, is initially certified to selectively bind to intracellular Fe(3+) theoretically and experimentally in this study. Hence, CaALN iron nanochelator is rationally designed to kill cancer cells by synergism of Fe-depletion and calcium accumulation. In vitro experiments and RNA sequencing analysis indicate that CaALN nanomedicine inhibits the proliferation of cancer cells by depleting Fe, interfering with DNA replication, and triggering intracellular reactive oxygen species (ROS). Meanwhile, released Ca(2+) and ROS mutually promote and induce damage of cellular macromolecules, which leads to mitochondrial apoptosis of cancer cells. In an intraperitoneal disseminated mouse model with the human ovarian cancer cells SKOV3, CaALN nanoparticles selectively accumulate in tumor tissues and result in significant retardation of tumor growth and ascites formation. The mean survival time of SKOV3-bearing mice in treatment group is prolonged from 33 to 90 d. These results indicate that the alendronate-originated iron chelator can serve as an efficient strategy for the treatment of peritoneal carcinomatosis.