Ultrasound-DrivenCoassembly of Anticancer Drugs intoCarrier-Free Particles

The evolution of drug resistance in tumor malignancies has necessitated advancements in anticancer drug therapy. Drug combination therapy, which can burden cancer progression at multiple target sites, has been used to address drug resistance and includes the coencapsulation of synergistic drugs within nanoparticle carriers. However, the use of organic and inorganic carriers can lead to additional material-induced safety concerns, including inflammation and antibody formation. Herein, we report an ultrasound-driven approach to combine synergistic anticancer drugs into carrier-free particles. Venetoclax (Vtx) (as a model anticancer drug) is combined with an anticancer anthracycline drug, doxorubicin (Dox), or a myeloid cell leukemia-1 inhibitor drug (S63845) to form spherical, submicrometer-sized (∼200–1000 nm in diameter) particles, consisting predominantly of the drug molecules stabilized by hydrophobic interactions. The coassembled particles, i.e., nanodrugs (NDs), display comparable and 2-fold higher anticancer activity than the free drugs and the monocomponent NDs, respectively, in Vtx-resistant SKOV-3 cells. The coassembled NDs containing Vtx and Dox increased the survival of SKOV-3 xenograft-bearing mice by at least 6 days in comparison with free Vtx or Vtx NDs and at least 10 days in comparison with saline-treated mice. Microscopy analysis of tumor tissues confirmed greater tissue damage and apoptosis induced by the NDs than those induced by the free drugs. The present findings highlight the potential of sono-driven assembled carrier-free systems in anticancer combination therapy, combining the advantages of a high surface area and slow-release particulate system with the synergistic action of multiple drugs to combat drug resistance.