Pharmacodynamic studies of fluorescent diamond carriers of doxorubicin in liver cancer cells and colorectal cancer organoids

Ron Firestein, Cezary Marcinkiewicz, Linyan Nie, Hui Kheng Chua, Ines Velazquez Quesada, Marco Torelli, Mark Sternberg, Bojana Gligorijevic, Olga Shenderova, Romana Schirhagl, Giora Z. Feuerstein*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

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Samenvatting

Background: We recently reported on preferential deposition of bare fluorescent diamond particles FDP-NV-700/800nm (FDP-NV) in the liver following intravenous administration to rats. The pharmacokinetics of FDP-NV in that species indicated short residency in the circulation by rapid clearance by the liver. Retention of FDP-NV in the liver was not associated with any pathology. These observations suggested that cancer therapeutics, such as doxorubicin, linked to FDP-NV, could potentially serve for anti-cancer treatment while sparing toxicities of peripheral organs.

Purpose: To generate proof-of-concept (POC) and detail mechanisms of action of doxor-ubicin-coated FDP-NV-700/800nm (FDP-DOX) as a prospective chemotherapeutic for meta-static liver cancer.

Methods: FDP-DOX was generated by adsorption chemistry. Experimental design included concentration and time-dependent efficacy studies as compared with naïve (baren) FDP-NV in in vitro liver cancer cells models. Uptake of FDP-NV and FDP-DOX by HepG-2, Hep-3B and hCRC organoids were demonstrated by flow-cytometry and fluorescent microscopy. FDP-DOX pharmacodynamic effects included metabolic as well as cell death biomarkers Annexin V, TUNEL and LDH leakage. DOX desorpted from FDP-DOX was assessed by confocal microscopy and chemical assay of cells fractions.

Results: FDP-DOX efficacy was dose-and time-dependent and manifested in both liver cancer cell lines and human CRC organoids. FDP-DOX was rapidly internalized into cancer cells/organoids leading to cancer growth inhibition and apoptosis. FDP-DOX disrupted cell membrane integrity as evident by LDH release and suppressing mitochondrial metabolic pathways (AlamarBlue assay). Access of free DOX to the nuclei was confirmed by direct UV-Visible fluorescent assay and confocal microscopy of DOX fluorescence.

Conclusion: The rapid uptake and profound cancer inhibition observed using FDP-DOX in clinically relevant cancer models, highlight FDP-DOX promise for cancer chemotherapeu-tics. We also conclude that the in vitro data justify further investment in in vivo POC studies.

Originele taal-2English
Pagina's (van-tot)139-159
Aantal pagina's21
TijdschriftNanotechnology, Science and Applications
Volume14
DOI's
StatusPublished - sep.-2021

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