Reconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor-selective drugs. Here, as a proof-of-concept, the use of high-frequency sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self-aggregates in water to form ≈200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug-resistant cell lines. Only marginal cytotoxicity (80-100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25-40 µg mL-1 ). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor-mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell-collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono-active moieties.

BIOEMTECH 27 Neapoleos st Lefkippos Attica Technology Park N C S R Demokritos Athens 15341 Greece

Department of Chemical Engineering The University of Melbourne Parkville Victoria 3010 Australia

Dipartimento di Scienze e Tecnologie Chimiche Università degli Studi di Roma Tor Vergata via della ricerca scientifica 1 Rome 00133 Italy

International Clinical Research Center St Anne's University Hospital Brno 65691 Czechia

Molecular Pharmacology Unit Department of Applied Research and Technological Development Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Via Amadeo 42 Milan 20133 Italy

School of Chemistry The University of Melbourne Victoria 3010 Australia

School of Science RMIT University Melbourne Victoria 3000 Australia

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