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

3 Citations (Scopus)

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

Fingerprint

Yttrium
Feasibility Studies
Liver Neoplasms
Doxorubicin
Rabbits
Safety
Pharmaceutical Preparations
Neoplasms
Yttrium Radioisotopes
Radio
Necrosis
Lutetium
Liver
Chelating Agents
Serum
Radioisotopes
Allografts
Analysis of Variance
Ligands
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead - A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model. / Ludwig, Johannes M.; Xing, Minzhi; Gai, Yongkang; Sun, Lingyi; Zeng, Dexing; Kim, Hyun S.

In: Molecular Pharmaceutics, Vol. 14, No. 8, 07.08.2017, p. 2824-2830.

Research output: Contribution to journalArticle

Ludwig, Johannes M. ; Xing, Minzhi ; Gai, Yongkang ; Sun, Lingyi ; Zeng, Dexing ; Kim, Hyun S. / Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead - A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model. In: Molecular Pharmaceutics. 2017 ; Vol. 14, No. 8. pp. 2824-2830.
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