Self-delivery of metal-coordinated mitochondria protonophore uncoupler for O₂-exhausting enhanced bioreductive therapy.

Abstract

Mitochondrial uncouplers are capable of maximizing cell respiration to induce local hypoxia, which provides a promising target for bioreductive therapy. In this work, we develop a metal-coordinated mitochondria protonophore uncoupler (designated as Cu-BAQ) for O₂-exhausting enhanced bioreductive therapy. In brief, carrier free Cu-BAQ is self-assembled by copper ion (Cu²⁺), mitochondria protonophore uncoupler (BAM15) and bioreductive drug (AQ4N), which possesses a favorable stability and an improved bioavailability. After intravenous administration, nanosized Cu-BAQ prefers to accumulate at tumor site for effective cellular uptake. Moreover, the Cu²⁺-coordinated nanomedicine of Cu-BAQ exhibits a glutathione (GSH) responsive drug release behavior and the released BAM15 could promote the mitochondria uncoupling to maximize the cell respiration. As a result, the excessive O₂ consumption would induce local hypoxia to activate AQ4N for enhanced bioreductive therapy. In vivo investigations demonstrate that Cu-BAQ is able to regulate tumor hypoxia microenvironment and significantly inhibit tumor growth with a minimized side effect. This GSH-responsive self-delivery nanoplatform provides a new insight for the development of individualized biomedicine for hypoxic tumor precision therapy.