Abstract
Radiolabeled peptides which target tumor-specific membrane structures of cancer cells represent a promising class of targeted radiopharmaceuticals for the diagnosis and therapy of cancer. A potential drawback of a number of reported radiopeptides is the rapid washout of a substantial fraction of the initially delivered radioactivity from cancer cells and tumors. This renders the initial targeting effort in part futile and results in a lower imaging quality and efficacy of the radiotracer than achievable. We are investigating the combination of internalizing radiopeptides with molecular entities specific for an intracellular target. By enabling intracellular interactions of the radioconjugate, we aim at reducing/decelerating the externalization of radioactivity from cancer cells. Using the “click-to-chelate” approach, the 99mTc-tricarbonyl core as a reporter probe for single-photon emission computed tomography (SPECT) was combined with the binding sequence of bombesin for extracellular targeting of the gastrin-releasing peptide receptor (GRP-r) and peptidic inhibitors of the cytosolic heat shock 90 protein (Hsp90) for intracellular targeting. Receptor-specific uptake of the multifunctional radioconjugate could be confirmed, however, the cellular washout of radioactivity was not improved. We assume that either endosomal trapping or lysosomal degradation of the radioconjugate is accountable for these observations.
Highlights
IntroductionRegulatory peptides are known to display high specificity and affinity towards different G-protein coupled receptors (GPCRs) which are overexpressed on the cell membrane of various cancer cells [1]
Regulatory peptides are known to display high specificity and affinity towards different G-protein coupled receptors (GPCRs) which are overexpressed on the cell membrane of various cancer cells [1].On this account, a number of radiopharmaceuticals based on these peptides as tumor-targeting vectors are currently under preclinical and clinical evaluation or have already found application in nuclear medicine for the management of cancer [2,3,4]
We have recently reported a 99mTc-tricarbonyl-labeled, dual-targeting radiopeptide conjugate made of a modified amino acid sequence of BBS, [Nle14]BBS(7-14) (QWAVGHLNle), for extracellular targeting of the gastrin-releasing peptide receptor (GRP-r) and a triphenylphosphonium (TPP) entity specific for mitochondria by its ability to accumulate electrophoretically driven in the energized membrane of the organelle [10]
Summary
Regulatory peptides are known to display high specificity and affinity towards different G-protein coupled receptors (GPCRs) which are overexpressed on the cell membrane of various cancer cells [1]. After receptor-mediated uptake of radiolabeled regulatory peptides into tumors, a rapid washout of a significant fraction of radioactivity is often observed [5,6,7,8,9] This renders the initial targeting efforts in part futile but may impair imaging quality and the efficacy of radiopharmaceuticals where therapeutic radionuclides are employed. A possible approach to achieve this goal is represented by the application of radiolabeled conjugates which combine extra- and intracellular targeting Such multifunctional radioconjugates have the promise to be recognized first by an extracellular target (e.g., a GPCR) that triggers cell internalization by endocytosis. We wish to report the synthesis of BBS-shepherdin radioconjugates prepared by the previously reported modular “click-to-chelate” approach [25,26] (Figure 1) and their evaluation in vitro
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