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Dolastatin derivatives, represented by monomethylauristatin E (MMAE), have been translated in clinic with a form of antibody-drug conjugate; however, their potential in nanoparticle systems has not been well established due to the potential risk of immature release of extremely high cytotoxic dolastatin drugs during blood circulation. Herein, we rationally propose monomethylauristatin F (MMAF), a dolastatin-derived, loaded nanoparticle system composed of bombesin (BBN)-tethered ROS-responsive micelle system (BBN-PEG-PPADT) to achieve efficient anticancer therapy with targeted and efficient delivery of MMAF. The developed MMAF-loaded BBN-PEG-PPADT micelles (MMAF@BBN-PEG-PPADT) exhibited improved cellular uptake via interactions between BBN and gastrin-releasing peptide receptors on the cancer cells and the intracellular burst release of MMAF, owing to the ROS-responsive disruption, which allowed the efficient anticancer effects of MMAF in vitro. This study suggests the potential of nanoparticle systems in the delivery of dolastatin drugs.

Bombesin-Tethered Reactive Oxygen Species (ROS)-Responsive Nanoparticles for Monomethyl Auristatin F (MMAF) Delivery