Development of Heterobivalent Theranostic Probes Having High Affinity/Selectivity for the GRPR/PSMA

Prostate cancer is the second leading cause of cancer death in men in the United States. The consequences of the metastatic form of this disease, including severe pain, and poor prognosis have prompted the need for more effective diagnosis and therapy. Currently, the existing therapies are not specific and this results in dose-limiting side effects and collateral damage to healthy tissues. Therefore, alternative treatments, such as targeted radiotherapy with radiolabeled peptides, antibodies or small molecules may result in better response in patients with metastatic prostate cancer. A number of targeted radiolabeled peptides and small molecules have been developed for imaging and therapy of prostate cancer but the current agents have some limitations. Gastrin releasing peptide receptor (GRPR) is reported to be highly expressed in early prostate cancer lesions unlike in advanced diseases. In contrast, high expression of Prostate specific membrane antigen (PSMA) expression is characteristic of late-stage prostate cancer. Therefore, a monovalent peptide specific for GRPR or PSMA is likely to target either early or advanced prostate cancer, but not both. However, a bivalent GRPR/PSMA-targeting peptide will most likely target tumors throughout the progression of the disease.

To address this, University of Missouri researchers: Rajendra Bandari, Terry Carmack, Anil Malhotra, Lisa Watkinson, Emily Fergason Cantrell, Professor Michael Lewis, and Professor Charles Smith developed new and novel PSMA/GRPR heterobivalent peptides for targeted radiotherapy and Single-photon emission computed tomography imaging (SPECT). The original research work is now published in the Journal of Medicinal Chemistry.

The research team developed heterobivalent [DUPA-6-Ahx-([111In]In-DO3A)-8-Aoc-BBN ANT] and [DUPA-6-Ahx-([177Lu]Lu-DO3A)-8-Aoc-BBN ANT] radiotracers with a very high selectivity/specificity for GRPR/PSMA-expressing cells. This was confirmed via metallation, purification and characterization studies, as well as in vitro and in vivo evaluation of the new small-molecule-/peptide-based radiopharmaceuticals, which demonstrated their utility for imaging and potentially therapy.

Using PC-3 cells and LNCaP cell membranes, the competitive displacement binding assays conducted revealed that the tracers had a high binding affinity for GRPR or PSMA. In addition, in animal studies, biodistribution experiments showed that the new tracers displayed a favorable excretion pharmacokinetics with high tumor uptake seen in mice with PC-3 or PC-3 prostatic inhibin peptide tumor. Furthermore, at 4 hours post intravenous injection, microSPECT molecular imaging investigations conducted revealed a very high uptake of the tracers in tumors, with negligible accumulation in the surrounding collateral tissues in xenografted mice.

In conclusion, through this study the authors reported the development of novel and promising heterobivalent tracers with a high selectivity/specificity for either GRPR- or PSMA-expressing cells and high uptake and retention in tumors with pharmacokinetic and excretion profiles. As multivalent cell-targeting agents, these tracers could be better alternative to currently existing monovalent tracers because they allow for capture a larger family of biomarker-expressing tumors. In addition, this researchers demonstrated that the new tracers overcome the various disadvantages that might hinder the usefulness of producing a new theranostic probe. The University of Missouri scientists are advancing further the new tracers and currently, single-dose acute toxicity studies are underway to evaluate the toxicological profile of one of the tracers in a mouse model. These new studies along will pave the way for the translation of these novel tracers into future human clinical investigations.