SW43-DOX ± loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment - An in vitro evaluation.
Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma-2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma-2 receptor ligand SW43 and Doxorubicin (SW43-DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug-eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone. SW43-DOX binds specifically to the Sigma-2 receptor expressed on hepatocellular (Hep G2, Hep 3B), pancreatic (Panc-1) and colorectal (HT-29) carcinoma cell lines with high affinity and subsequent early specific internalization. Free SW43-DOX showed superior concentration and time depended cancer toxicity than treatment with Doxorubicin alone. Action mechanisms analysis revealed an apoptotic cell death with increased caspase 3/7 activation and reactive oxygen species (ROS) production. Only ROS scavenging with α-Tocopherol, but not the caspase inhibition (Z-VAD-FMK), partly reverted the effect. SW43-DOX could successfully be loaded onto DEB and showed prolonged eluting kinetics compared to Doxorubicin. SW43-DOX loaded DEB vs. Doxorubicin loaded DEB showed a significantly greater time dependent toxicity in all cell lines. In conclusion, the novel conjugate SW43-DOX ± loading onto DEB is a promising drug delivery platform for targeted systemic and locoregional cancer therapy.
Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT 06510, USA; Interventional Oncology Translational Laboratory, University of Pittsburgh School of Medicine, Presbyterian South Tower, 200 Lothrop Street, Pittsburgh, PA 15213-3553, USA.
Johannes M
JM
Ludwig
Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh School of Medicine, 100 Technology Drive, Pittsburgh, PA 15219, USA.
Yongkang
Y
Gai
Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh School of Medicine, 100 Technology Drive, Pittsburgh, PA 15219, USA.
Lingyi
L
Sun
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
Guangya
G
Xiang
Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh School of Medicine, 100 Technology Drive, Pittsburgh, PA 15219, USA. Electronic address: zengd@upmc.edu.
Dexing
D
Zeng
Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT 06510, USA; Interventional Oncology Translational Laboratory, University of Pittsburgh School of Medicine, Presbyterian South Tower, 200 Lothrop Street, Pittsburgh, PA 15213-3553, USA; Yale Cancer Center, Yale School of Medicine, New Haven, 330 Cedar Street, New Haven, CT 06510, USA. Electronic address: kevin.kim@yale.edu.
Hyun S
HS
Kim
D053961:Azabicyclo Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D008863:Microspheres; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism
D053961:Azabicyclo Compounds; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; C000624383:SW43-DOX compound; C106107:sigma-2 receptor; D004317:Doxorubicin; D020169:Caspases
Doxorubicin; Drug-eluting bead (DEB); Sigma-2 receptor; Targeted cancer therapy