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Curcumin (Cur) is a highly pleiotropic anticancer agent that inhibits cell proliferation and induces apoptosis in cancer cells.A variety of nano-systems constituted by polymer-drug conjugates have been designed to overcome its shortages on water solubility, chemical instability, and poor bioavailability.However, most of them suffer from ineffective release of Cur in cancer cells in vivo.This work developed a novel flexible acid-responsive micelle formulation by covalently conjugating Cur on the hydrophilic terminals of pluronic F68 chains via cis-aconitic anhydride linkers.The synthesized F68-Cis-Cur conjugates can readily precipitate to form homogeneous micelles with average size about 100 nm in aqueous solution.In acid environments, F68-Cis-Cur could rapidly disassemble and release the Cur,resulted from the cleavage of cis-aconitic anhydride linkers.In vitro anticancer activity tests demonstrated that F68-Cis-Cur micelles induced higher cytotoxicity against both A2780 and SMMC 7721 cells than free Cur.It provided a larger decrease of mitochondrion membrane potential and induced cellular apoptosis.F68-Cis-Cur micelles remarkably increased cellular uptake of Cur than free Cur through caveolae-mediated endocytosis in an energy-dependent manner.This study demonstrates F68-Cis-Cur conjugation as a promising tool for improving intracellular drug delivery in cancer therapy.