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

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(Y) 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 yttrium (Y) 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-Y 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-Y loaded onto DEB. The two rabbits treated with 1 mg/kg SW43-DOX-Y 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-Y loaded onto DEB can be formulated and safely administered at a concentration of 0.6 mg/kg. Loading with radioactive isotopes (e.g., yttrium/yttrium/lutetium) to synthesize the targeted radio-chemoembolization drug-eluting bead (TRCE-DEB) concept drug is feasible.

Lipidic Cubic-Phase Nanoparticles (Cubosomes) Loaded with Doxorubicin and Labeled with 177Lu as a Potential Tool for Combined Chemo and Internal Radiotherapy for Cancers

“…it exhibited a high tumor/background ratio. Analogous radiolabeled liposomes have been investigated on other cancer models [ 9 , 10 , 11 , 12 ]. Targeted therapy, based on the folate-functionalized lipid nanoparticle containing doxorubicin and 90 Y radionuclide, was studied on a carcinoma cell line CNE1 and showed significant tumor growth suppression compared with the control groups.…”

Future Interventional Oncology Catheter-Based Therapies

“…The same authors later published an in vivo study using a rabbit VX2 tumor model. 21 In that study, SW43-DOX was loaded onto DEBs and conjugated to the chelator L-NETA. L-NETA can be loaded with radioactive isotopes 90 Y and 177 Lu for imaging or therapy.…”

“…DEB, drug-eluting bead; SW43-DOX, doxorubicin onto SW43. (Reproduced with permission from Ludwig et al21 ) Copyright 2017 American Chemical Society.…”

A thiopyrylium salt for PET/NIR‐II tumor imaging and image‐guided surgery

“…Inspired by that, our strategy is to modify XB1034‐cetuximab with TCO to afford XB1034‐cetuximab‐TCO and get the NIR‐II tumor imaging (Adumeau et al , 2016; Zeglis et al , 2015). The subsequent injection of radiolabeled Tz‐(2,2′‐((6‐amino‐1‐(4,7‐bis(carboxymethyl)‐1,4,7‐triazonan‐1‐yl)hexan‐2‐yl)azanediyl)diacetic acid (L‐NETA, a metal chelating agent, Ludwig et al , 2017) enables click conjugation of TCO and Tz, accompanied by rapid renal clearance of unbound 68 Ga‐NETA‐Tz. After ten half‐lives of radioisotope (half‐life of 68 Ga: 68 min), NIR‐II imaging‐guided surgery would be performed (Scheme 1).…”