TY - JOUR
T1 - Pharmacodynamic studies of fluorescent diamond carriers of doxorubicin in liver cancer cells and colorectal cancer organoids
AU - Firestein, Ron
AU - Marcinkiewicz, Cezary
AU - Nie, Linyan
AU - Chua, Hui Kheng
AU - Quesada, Ines Velazquez
AU - Torelli, Marco
AU - Sternberg, Mark
AU - Gligorijevic, Bojana
AU - Shenderova, Olga
AU - Schirhagl, Romana
AU - Feuerstein, Giora Z.
N1 - Publisher Copyright:
© 2021 Firestein et al.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Doxorubicin
KW - Fluorescent diamond particles-NV-700/800nm
KW - Human colorectal cancer organoids
KW - Liver cancer cell-lines
UR - https://www.scopus.com/pages/publications/85114919980
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000696669400001&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.2147/NSA.S321725
DO - 10.2147/NSA.S321725
M3 - Article
C2 - 34522092
SN - 1177-8903
VL - 14
SP - 139
EP - 159
JO - Nanotechnology, Science and Applications
JF - Nanotechnology, Science and Applications
ER -
