Development of Improved Tumor-Residualizing, GRPR-Targeted Agents: Preclinical Comparison of an Endolysosomal Trapping Approach in Agonistic and Antagonistic Constructs

Zhang, Wenting; Fan, Wei; Ottemann, Brendan M.; Alshehri, Sameer; Garrison, Jered C.

doi:10.2967/jnumed.119.231282

Cited by 11 publications

(14 citation statements)

References 31 publications

(40 reference statements)

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“…Prolonged retention in the tumor is an attractive quality for a theranostic GRPR-seeking radiolabeled probe, agonist, or antagonist, especially during radionuclide therapy. This fact has been illustrated in a recent report, whereby cysteine cathepsin inhibitors are coupled to GRPR-peptides leading to improved tumor retention via endolysosomal trapping [46]. Another interesting finding of the current biodistribution study has been the lack of improvements in the tumor uptake in the mice treated with PA vs. the untreated controls at 4 h pi.…”

Section: Discussionmentioning

confidence: 78%

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Nock

Kaloudi

Kanellopoulos

et al. 2021

Cancers

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Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DGA-DPhe6,Sar11,LeuNHEt13]BBN(6-13); N4: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [99mTc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC50 = 0.37 ± 0.03 nM) and [99mTc]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 ± 2.78 %IA/g vs. 0.72 ± 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 ± 3.20 %IA/g vs. 3.82 ± 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [99mTc]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies.

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Section: Discussionmentioning

confidence: 78%

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Nock

Kaloudi

Kanellopoulos

et al. 2021

Cancers

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“…Despite the antagonistic nature of the pharmacophore (SR 142948A), these constructs demonstrated substantial amounts of internalization. This observation is not unique since the internalization of agents using antagonistic targeting vectors has been observed in other classes (e.g., gastrin-releasing peptide receptor) of receptor-targeted agents . For the most part, the rate of internalization roughly followed NTSR1-affinity.…”

Section: Discussionmentioning

confidence: 86%

“…In prior work, our laboratory has successfully applied this approach using an NTSR1-targeted agonistic peptide . Additionally, we have applied this same approach in other receptor-targeted constructs using an antagonistic targeting vector . In both agonistic and antagonistic constructs, the endolysosomal trapping (ET) approach yielded substantial (i.e., two–three-fold) enhancements in the in vivo tumor retention of the receptor-targeted agents.…”

Section: Introductionmentioning

confidence: 99%

Examination of Charge Modifications of an Endolysosomal Trapping Inhibitor in an Antagonistic NTSR1-Targeted Construct for Colon Cancer

et al. 2022

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Many low-molecular weight targeted radiotherapeutics (TRTs) are capable of rapidly achieving exceptional tumor to non-target ratios shortly after administration. However, the low tumor residence time of many TRTs limits therapeutic dose delivery and has become the Achilles heel to their clinical translation. To combat the tumor efflux of these otherwise promising agents, we have previously presented a strategy of equipping low-molecular weight TRTs with irreversible cysteine cathepsin inhibitors (e.g., E-64 analogues). These inhibitors are capable of forming irreversible adducts with cysteine proteases within the endolysosomal compartments of cells. Using these endolysosomal trapping agents (ETs), the receptor-targeted constructs are able to increase tumor retention and, thus, deliverable therapeutic doses. In this study, we examine this approach in the development of agents targeting the neurotensin receptor subtype 1 (NTSR1), a receptor overexpressed in numerous cancers. Using an antagonistic NTSR1-targeting vector, we explore the impact of charge modification of the ETs on the in vitro and in vivo biological performance of the constructs using HT-29 colon cancer models. Four ETs (based on the epoxysuccinyl peptide E-64) with various charge states were synthesized and incorporated into the structures of the NTSR1-targeted antagonist. These four 177 Lu-labeled, ET-enhanced, NTSR1-targeted agents ( 177 Lu-NA-ET1-4), along with the structurally analogous 177 Lu-3BP-227, currently in clinical trials, underwent a battery of in vitro assays using HT-29 xenograft colon cancer cells to examine their NTSR1 binding, internalization and efflux, inhibition, and adduct formation properties. The biodistribution profile of these constructs was studied in an HT-29 mouse model. Charge modification of the terminal carboxylic acid and arginine of the ETs had deleterious effects on inhibition kinetics and in vitro adduct formation. Contrastingly, deletion of the arginine resulted in a modest increase in inhibition kinetics. Incorporation of ETs into the NTSR1-targeted agents was well-tolerated with minimal impact on the in vivo NTSR1 targeting but resulted in increased renal uptake. This study demonstrates that the ETs can be successfully incorporated into antagonistic NTSR1-targeted constructs without compromising their adduct formation capabilities. Based on these results, further exploration of the endolysosomal trapping approach is warranted in NTSR1-and other receptor-targeted antagonistic constructs.

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“…Immunotherapy may also enhance therapeutic efficacy of PRRT, as recently shown for the [ 177 Lu]Lu-RM26 and trastuzumab combination in prostate cancer mice models [ 110 ]. In a recent innovative approach, prolonged tumor retention could be achieved in mice models when using GRPR peptide radioligands, either agonists or antagonists, modified with cysteine cathepsin inhibitors, via an endolysosomal trapping mechanism [ 117 ].…”

Section: Newer Trends In the Application Of Anti-grpr Theranostic Radiopeptidesmentioning

confidence: 99%

Radiolabeled Bombesin Analogs

Mansi

Nock

Dalm³

et al. 2021

Cancers

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The gastrin-releasing peptide receptor (GRPR) is expressed in high numbers in a variety of human tumors, including the frequently occurring prostate and breast cancers, and therefore provides the rationale for directing diagnostic or therapeutic radionuclides on cancer lesions after administration of anti-GRPR peptide analogs. This concept has been initially explored with analogs of the frog 14-peptide bombesin, suitably modified at the N-terminus with a number of radiometal chelates. Radiotracers that were selected for clinical testing revealed inherent problems associated with these GRPR agonists, related to low metabolic stability, unfavorable abdominal accumulation, and adverse effects. A shift toward GRPR antagonists soon followed, with safer analogs becoming available, whereby, metabolic stability and background clearance issues were gradually improved. Clinical testing of three main major antagonist types led to promising outcomes, but at the same time brought to light several limitations of this concept, partly related to the variation of GRPR expression levels across cancer types, stages, previous treatments, and other factors. Currently, these parameters are being rigorously addressed by cell biologists, chemists, nuclear medicine physicians, and other discipline practitioners in a common effort to make available more effective and safe state-of-the-art molecular tools to combat GRPR-positive tumors. In the present review, we present the background, current status, and future perspectives of this endeavor.

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Development of Improved Tumor-Residualizing, GRPR-Targeted Agents: Preclinical Comparison of an Endolysosomal Trapping Approach in Agonistic and Antagonistic Constructs

Cited by 11 publications

References 31 publications

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Examination of Charge Modifications of an Endolysosomal Trapping Inhibitor in an Antagonistic NTSR1-Targeted Construct for Colon Cancer

Radiolabeled Bombesin Analogs

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