Evaluation of fluorophore-tethered platinum complexes to monitor the fate of cisplatin analogs.
The platinum drugs cisplatin, carboplatin, and oxaliplatin are highly utilized in the clinic and as a consequence have been extensively studied in the laboratory setting, sometimes by generating fluorophore-tagged analogs. Here, we synthesized two Pt(II) complexes containing ethane-1,2-diamine ligands linked to a BODIPY fluorophore, and compared their biological activity with previously reported Pt(II) complexes conjugated to carboxyfluorescein and carboxyfluorescein diacetate. The cytotoxicity and DNA damage capacity of Pt-fluorophore complexes was compared to cisplatin, and the Pt-BODIPY complexes were found to be more cytotoxic with reduced cytotoxicity in cisplatin-resistant cells. Microscopy revealed a predominately cytosolic localization, with nuclear distribution at higher concentrations. Spheroids grown from parent and resistant cells revealed penetration of Pt-BODIPY into spheroids, and retention of the cisplatin-resistant spheroid phenotype. While most activity profiles were retained for the Pt-BODIPY complexes, accumulation in resistant cells was only slightly affected, suggesting that some aspects of Pt-fluorophore cellular pharmacology deviate from cisplatin.
Laboratory of Cell Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Rm. 2108, Bethesda, MD, 20892, USA.
Justin C
JC
Jagodinsky
Imaging Probe Development Center, National Institutes of Health, Rockville, MD, USA.
Agnieszka
A
Sulima
Laboratory of Cell Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Rm. 2108, Bethesda, MD, 20892, USA.
Yiqi
Y
Cao
Laboratory of Cell Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Rm. 2108, Bethesda, MD, 20892, USA.
Joanna E
JE
Poprawski
Imaging Probe Development Center, National Institutes of Health, Rockville, MD, USA.
Burchelle N
BN
Blackman
Advanced Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
John R
JR
Lloyd
Imaging Probe Development Center, National Institutes of Health, Rockville, MD, USA.
Rolf E
RE
Swenson
Laboratory of Cell Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Rm. 2108, Bethesda, MD, 20892, USA. mgottesman@nih.gov.
Michael M
MM
Gottesman
Laboratory of Cell Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Rm. 2108, Bethesda, MD, 20892, USA.
Matthew D
MD
Hall
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D018613:Microscopy, Confocal; D010984:Platinum / Q000737:chemistry* / Q000633:toxicity*
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000970:Antineoplastic Agents; D001896:Boron Compounds; D056831:Coordination Complexes; D005456:Fluorescent Dyes; D010984:Platinum; D002945:Cisplatin
Accumulation; Platinum; Resistance; Trafficking