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Transforming the Chemical Structure and Bio-Nano Activity of Doxorubicin by Ultrasound for Selective Killing of Cancer Cells

SK. Bhangu, S. Fernandes, GL. Beretta, S. Tinelli, M. Cassani, A. Radziwon, M. Wojnilowicz, S. Sarpaki, I. Pilatis, N. Zaffaroni, G. Forte, F. Caruso, M. Ashokkumar, F. Cavalieri

. 2022 ; 34 (13) : e2107964. [pub] 20220218

Jazyk angličtina Země Německo

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc22018890

Grantová podpora
FT140100873 Australian Research Council
GNT1135806 National Health and Medical Research Council Senior Principal Research Fellowship
European Union's Horizon 2020
690901 Marie Skłodowska-Curie
CZ.02.1.01/0.0/0.0/15_003/0000492 European Social Fund and European Regional Development Fund-Project MAGNET
European Union's horizon
800924 Marie Skłodowska-Curie

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.

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