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Targeted drug delivery coupled with rapid drug release in cytoplasm is a powerful strategy to enhance efficacy and reduce off-target effects of anti-cancer drugs. Herein, we describe a dual-functional mixed micellar system consisting of a pH-responsive copolymer D-α-tocopheryl polyethylene glycol 1000-blockpoly-(β-amino ester) (TPGS-b-PBAE, TP) and AS1411 aptamer (Apt) decorated TPGS polymer (Apt-TPGS), which recognizes the over-expressed nucleolin on the plasma membrane of cancer cells. The anti-cancer drug paclitaxel (PTX) was encapsulated in the Apt-mixed micelles, and these drug-loaded micelles had a suitable particle size and zeta potential of 116.3 nm ± 12.4 nm and -26.2 mV ±4.2 mV, respectively. PTX/Apt-mixed micelles were stable at pH 7.4, but they dissociated and quickly released the encapsulated PTX in a weakly acidic environment (pH 5.5). Compared with non-Apt modified mixed micelles, more Apt-modified mixed micelles were internalized in SKOV3 ovarian cancer cells, whereas no significant difference in cellular uptake was observed in normal cells (LO2 cells). The enhanced transmembrane ability of Apt-modified mixed micelles was achieved through Apt-nucleolin interaction. With a synergistic effect of cancer cell recognition and pH-sensitive drug release, we observed significantly increased cytotoxicity and G2/M phase arrest against SKOV3 cells by PTX/Apt-mixed micelles. Intravenous administration of PTX/Apt-mixed micelles for 16 days significantly increased tumor accumulation of PTX, inhibited tumor growth, and reduced myelosuppression on tumor-bearing mice compared with free PTX injection. Therefore, this dual-functional Apt-mixed micellar system is a promising drug delivery system for targeted cancer therapy.
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