Overcoming hypoxia-induced drug resistance via promotion of drug uptake and reoxygenation through acousto-mechanical oxygen delivery

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Pharmacy. 2022 Apr 20;14(5):902. doi: 10.3390/pharmaceutics14050902.

ABSTRACT

Hypoxia-induced drug resistance (HDR) is a critical issue in cancer therapy. The presence of hypoxic tumor cells impairs drug absorption and reduces the cytotoxicity of chemotherapeutic drugs, resulting in HDR and increasing the likelihood of tumor recurrence and metastasis. Microbubbles, which are used as ultrasound contrast agent and drug/gas carrier, can locally deliver drugs/gas and produce acousto-mechanical effect to improve cell permeability under ultrasound sonication. The present study applied oxygen-charged microbubbles (OMBs) to assess mechanisms for overcoming HDR via promotion of drug uptake and reoxygenation. A hypoxic mouse prostate tumor cell model was established by hypoxic incubation for 4 h. After OMB treatment, HDR cell permeability was improved by 23 ± 5% and doxorubicin uptake was increased by 11 ± 7%. Reoxygenation of 61 ± 14% of HDR cells increased doxorubicin cytotoxicity from 18 ± 4% to 58 ± 6%. In the combined treatment with OMB and doxorubicin, the relative contributions of uptake and reoxygenation promotion to overcoming HDR were 11 ± 7% and 28 ± 10%, respectively. Our study demonstrated that reoxygenation from hypoxic conditions is a critical mechanism in inhibiting HDR and improving OMB treatment outcomes.

PMID:35631488 | DOI:10.3390/pharmaceutical14050902

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