Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead - A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model

Johannes M. Ludwig, Minzhi Xing, Yongkang Gai, Lingyi Sun, Dexing Zeng, Hyun S. Kim

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The purpose of this article is to evaluate feasibility and safety of the cancer targeting (radio)-chemoembolization drug-eluting bead (TRCE-DEB) concept drug SW43-DOX-L-NETA(89Y) DEB for the intra-arterial treatment of VX2 rabbit liver tumors. The treatment compound comprises of the sigma-2 receptor ligand SW43 for cancer targeting, doxorubicin (DOX), and 89yttrium (89Y) as nonradioactive surrogate for therapeutic (yttrium-90, lutetium-177) and imaging (yttrium-86) radioisotopes via the chelator L-NETA. Ten New Zealand white rabbits with VX2 tumor allografts were used. SW43-DOX-89Y was synthesized, loaded onto DEB (100 μL; 100-300 μm), and administered intra-arterially in six rabbits at increasing doses (0.2-1.0 mg/kg). As controls, two rabbits each received either doxorubicin IV (0.3 mg/kg) or no treatment. Consecutive serum analysis for safety and histopathological evaluation after sacrifice were performed. One-Way ANOVA incl. Bonferroni Post-Hoc test was performed to compare groups. Targeted compound synthesis, loading onto DEB, and intra-arterial administration were feasible and successful in all cases. Serum liver enzyme levels increased in a dose dependent manner within 24 h and normalized within 3 days for 0.2/0.6 mg/kg SW43-DOX-89Y loaded onto DEB. The two rabbits treated with 1 mg/kg SW43-DOX-89Y had to be euthanized after 3/24 h due to worsening general condition. Histopathological necrosis increased over time in a dose depended manner with 95-100% tumor necrosis 3-7 days post treatment (0.6 mg/kg). SW43-DOX-89Y loaded onto DEB can be formulated and safely administered at a concentration of 0.6 mg/kg. Loading with radioactive isotopes (e.g., 86yttrium/90yttrium/177lutetium) to synthesize the targeted radio-chemoembolization drug-eluting bead (TRCE-DEB) concept drug is feasible.

Original languageEnglish (US)
Pages (from-to)2824-2830
Number of pages7
JournalMolecular Pharmaceutics
Volume14
Issue number8
DOIs
StatePublished - Aug 7 2017
Externally publishedYes

Keywords

  • interventional radiology
  • New Zealand white rabbit
  • radiochemoembolization
  • sigma-2 receptor
  • SW43
  • VX2

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Fingerprint Dive into the research topics of 'Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead - A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model'. Together they form a unique fingerprint.

  • Cite this