Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer

Published on Oct 16, 2020in Pharmaceutics4.421
· DOI :10.3390/PHARMACEUTICS12100977
Ayman Abouzayed4
Estimated H-index: 4
Hanna Tano1
Estimated H-index: 1
+ 7 AuthorsAnna Orlova53
Estimated H-index: 53
The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [111In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.
#1Javad Garousi (Uppsala University)H-Index: 13
#2Emma von Witting (KTH: Royal Institute of Technology)H-Index: 4
Last. Sophia Hober (KTH: Royal Institute of Technology)H-Index: 41
view all 11 authors...
Abstract Molecular recognition in targeted therapeutics is typically based on immunoglobulins. Development of engineered scaffold proteins (ESPs) has provided additional opportunities for the development of targeted therapies. ESPs offer inexpensive production in prokaryotic hosts, high stability and convenient approaches to modify their biodistribution. In this study, we demonstrated successful modification of the biodistribution of an ESP known as ADAPT (Albumin-binding domain Derived Affinity...
1 CitationsSource
#1Badar ul Islam (AMU: Aligarh Muslim University)H-Index: 8
#2Mohd Shahnawaz Khan (KSU: King Saud University)H-Index: 21
Last. Shams Tabrez (KAU: King Abdulaziz University)H-Index: 28
view all 9 authors...
Over the past several decades, plant-derived products (phytochemicals) have been suggested to possess immense therapeutic potential. Among these phytochemicals, different flavonoids have been reported for their potent anticancer activity. To exhibit their anticancer potential, these flavonoids modulate different signaling pathways. Among these pathways, the mammalian target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade has been...
2 CitationsSource
#1Jie Zang (Peking Union Medical College Hospital)H-Index: 5
#2Qingxing Liu (Peking Union Medical College Hospital)H-Index: 5
Last. Xiaoyuan Chen (NIH: National Institutes of Health)H-Index: 162
view all 11 authors...
In this study, we applied a new strategy to identify sentinel lymph node (SLN) metastasis by combining 68Ga-NOTA-Evans Blue (68Ga-NEB) for SLN mapping and 68Ga-NOTA-RM26 for LN metastasis detection in breast cancer patients. A total of 24 female patients with breast cancer diagnosed by core biopsy or suspected by mammography or ultrasonography were recruited and provided informed consent. All patients underwent 68Ga-NEB and 68Ga-NOTA-RM26 PET/CT imaging. Visual analysis of 68Ga-NEB PET/CT images...
5 CitationsSource
#1Bogdan Mitran (Uppsala University)H-Index: 16
#2Vladimir Tolmachev (Uppsala University)H-Index: 61
Last. Anna Orlova (Uppsala University)H-Index: 53
view all 3 authors...
BACKGROUND: Radionuclide molecular imaging of gastrin-releasing peptide receptor (GRPR) expression promises unparalleled opportunities for visualizing subtle prostate tumors, which due to small size, adjacent benign tissue, or a challenging location would otherwise remain undetected by conventional imaging. Achieving high imaging contrast is essential for this purpose and the molecular design of any probe for molecular imaging of prostate cancer should be aimed at obtaining as high tumor-to-orga...
4 CitationsSource
#1Jens Kurth (University of Rostock)H-Index: 7
#2Bernd J. Krause (University of Rostock)H-Index: 57
Last. Martin Heuschkel (University of Rostock)H-Index: 6
view all 6 authors...
Purpose Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insuffi...
23 CitationsSource
#1Bogdan Mitran (Uppsala University)H-Index: 16
#2Sara S. Rinne (Uppsala University)H-Index: 8
Last. Anna Orlova (Uppsala University)H-Index: 53
view all 12 authors...
Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclidetherapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2-RM26 ...
10 CitationsSource
#1James M. Kelly (Cornell University)H-Index: 10
#2Alejandro Amor-Coarasa (Cornell University)H-Index: 10
Last. John W. Babich (Cornell University)H-Index: 63
view all 7 authors...
: Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting prostate-specific membrane antigen (PSMA), 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor because of suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors but also in kidneys. We aimed to use structural modifications to inc...
16 CitationsSource
#1Freddie Bray (IARC: International Agency for Research on Cancer)H-Index: 119
#1Freddie Bray (IARC: International Agency for Research on Cancer)H-Index: 18
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 139
view all 6 authors...
This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer...
31.7k CitationsSource
#1Mohamed Altai (Uppsala University)H-Index: 19
#2Hao Liu (KTH: Royal Institute of Technology)H-Index: 22
Last. Torbjörn Gräslund (KTH: Royal Institute of Technology)H-Index: 21
view all 8 authors...
Abstract Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, ZHER2:2891, conjugated with the cytotoxic mayt...
22 CitationsSource
#1Mohamed Altai (Uppsala University)H-Index: 19
#2Charles Dahlsson Leitao (KTH: Royal Institute of Technology)H-Index: 6
Last. Anna Orlova (Uppsala University)H-Index: 53
view all 9 authors...
Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (AB...
11 CitationsSource
Cited By1