Small molecule targeted NIR dye conjugate for imaging LHRH receptor positive cancers

Abstract

Overexpression of Luteinizing Hormone Releasing Hormone Receptor (LHRH-R) in various cancers and restricted expression of the receptor in healthy cells qualifies it as a valuable cancer biomarker. Previously, LHRH-R targeted peptides have been utilized to deliver attached payloads to LHRH-R expressing cancers. We report here for the first time the utilization of a small molecule non-peptidic ligand (BOEPL) of LHRH-R to deliver attached payloads to LHRH-R positive tumors. For this purpose, we linked the BOEPL ligand to a near infrared dye via various linkers. In vitro, these conjugates demonstrated low nanomolar binding affinity and in vivo they exhibited receptor-mediated uptake specifically in tumor tissue. Moreover, tumor uptake could be blocked by administration of excess unlabeled conjugate, and time course experiments showed retention of the dye conjugate in the tumor up to 12 h post injection. Because uptake of BOEPL-targeted NIR dye conjugates by nonmalignant organs/tissues was negligible and since the transient presence of targeted NIR dye in the kidneys was a result of clearance mechanism, we suggest that a BOEPL-targeted NIR dye might constitute a useful agent for fluorescence-guided surgery of LHRH-R positive cancers. Moreover, our results also provide proof of concept that BOEPL can be successfully used to deliver attached payloads to LHRH-R positive tumors in vivo.

Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas

“…[42][43][44][45] Likewise, other groups are attempting to develop novel conjugated NIR agents that target various extracellular receptors in a tumor-specific manner. [46][47][48][49] These novel dyes are showing varying levels of promise in preclinical and clinical trials and may one day be an integral part of the oncologic surgeons' armamentarium.…”

Doubly Strapped Zwitterionic NIR‐I and NIR‐II Heptamethine Cyanine Dyes for Bioconjugation and Fluorescence Imaging

“…It is worth noting that there is a growing family of fluorescent probes that utilize NIR-I heptamethine cyanine dyes with structures that are closely related to ZW800-1 and each is likely to have stability limitations due to the presence of a reactive 4'-phenoxy group. [35,36,[76][77][78][79][80] In each case, it should be straightforward to prepare doubly strapped versions of these NIR-I dyes with an expectation of improved stability and imaging performance. An attractive feature of the modular synthetic method is the straightforward manner that the terminal heterocycles can be varied, as highlighted by the preparation of the doubly strapped heptamethine cyanine dye, dsZW1015, with terminal benzo[c,d]indole heterocycles that extend the absorption/emission wavelengths into the NIR-II region.…”

Cyanine Conjugate‐Based Biomedical Imaging Probes

“…For example, the methoxy group on one aromatic ring of antagonist NBI42902 was substituted with propanoic acid for facile conjugation, which was performed under the guidance of structure–activity relationship. [ 41 ] The modified version, named BOEPL, was linked to S0456 ( 29 ) for imaging of luteinizing hormone releasing hormone receptor‐positive cancer. More straightforwardly, marketed drugs or its derivatives with validated targets can be functionalized with cyanine fluorophores as well.…”