1 research outputs found
<sup>177</sup>Lu Labeled Cyclic Minigastrin Analogues with Therapeutic Activity in CCK2R Expressing Tumors: Preclinical Evaluation of a Kit Formulation
Minigastrin
(MG) analogues specifically target cholecystokinin-2
receptors (CCK2R) expressed in different tumors and enable targeted
radiotherapy of advanced and disseminated disease when radiolabeled
with a beta emitter such as <sup>177</sup>Lu. Especially truncated
MG analogues missing the penta-Glu sequence are associated with low
kidney retention and seem therefore most promising for therapeutic
use. Based on [d-Glu<sup>1</sup>,desGlu<sup>2–6</sup>]MG (MG11) we have designed the two cyclic MG analogues cyclo<sup>1,9</sup>[γ-d-Glu<sup>1</sup>,desGlu<sup>2–6</sup>,d-Lys<sup>9</sup>]MG (cyclo-MG1) and cyclo<sup>1,9</sup>[γ-d-Glu<sup>1</sup>,desGlu<sup>2–6</sup>,d-Lys<sup>9</sup>,Nle<sup>11</sup>]MG (cyclo-MG2). In the present
work we have developed and preclinically evaluated a pharmaceutical
kit formulation for the labeling with <sup>177</sup>Lu of the two
DOTA-conjugated cyclic MG analogues. The stability of the kits during
storage as well as the stability of the radiolabeled peptides was
investigated. A cell line stably transfected with human CCK2R and
a control cell line without receptor expression were used for <i>in vitro</i> and <i>in vivo</i> studies with the radioligands
prepared from kit formulations. In terms of stability <sup>177</sup>Lu-DOTA-cyclo-MG2 showed advantages over <sup>177</sup>Lu-DOTA-cyclo-MG1.
Still, for both radioligands a high receptor-mediated cell uptake
and favorable pharmacokinetic profile combining receptor-specific
tumor uptake with low unspecific tissue uptake and low kidney retention
were confirmed. Investigating the therapy efficacy and treatment toxicity
in xenografted BALB/c nude mice a receptor-specific and comparable
therapeutic effect could be demonstrated for both radioligands. A
1.7- to 2.6-fold increase in tumor volume doubling time was observed
for receptor-positive tumors in treated versus untreated animals,
which was 39–73% higher when compared to receptor-negative
tumors. The treatment was connected with transient bone marrow toxicity
and minor signs of kidney toxicity. All together the obtained results
support further studies for the clinical translation of this new therapeutic
approach