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Bispecific GRPR-antagonistic anti-PSMA/GRPR heterodimer for PET and SPECT diagnostic imaging of prostate cancer
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.ORCID-id: 0000-0001-7921-3268
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Prostate specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are wellvalidated molecular targets that are overexpressed in most prostate cancers (PCa). Given thecomplexity and heterogeneity of PCa, targeting both receptors using bispecific radiotracers couldimprove the diagnostic accuracy and therapeutic outcome. The aim of this study was to develop aPSMA/GRPR-targeting bispecific heterodimer for SPECT and PET diagnostic imaging of PCa.Bispecific anti-GRPR/PSMA dimer NOTA-DUPA-RM26 was produced using a combination of solidphase and manual peptide synthesis. The heterodimer was successfully labeled with111In for SPECTand 68Ga for PET with radiochemical yields exceeding 99% for 111In and 98% for 68Ga. Theradiolabeled heterodimers demonstrated high label stability and retained binding specificity to PSMAand GRPR when tested using PC3-PIP cell line expressing both PSMA and GRPR. IC50 values fornatIn-NOTA-DUPA-RM26 were 4±1 nM towards GRPR and 350±240 nM towards PSMA. Cellularprocessing assay revealed a low degree of internalization for 111In-NOTA-DUPA-RM26. In vivobinding specificity tests in PC3-PIP xenografted mice 1 h pi of 111In-NOTA-DUPA-RM26demonstrated partially blockable tumor uptake when co-injected with excess of either PSMA- orGRPR-targeting agents. A pronounced blocking effect was observed for 111In and 68Ga-labeledheterodimer when co-injected simultaneously with excess of PSMA- and GRPR-targeting agents 1 hpi. Biodistribution was studied 1, 3 and 24 h pi for 111In-NOTA-DUPA-RM26, and 1 and 3 h pi for68Ga-NOTA-DUPA-RM26 and revealed a fast clearance of radioprobes from blood and normal organsvia renal excretion. Tumor uptake exceeded the uptake in all normal organs including excretory organsfor both 111In and 68Ga-labeled heterodimers 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantlylower tumor uptake (8±2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12±2%ID/g), but a two-foldhigher uptake in liver 1h pi. The faster clearance of radioactivity from normal tissues compared totumor lead to an overall increase in tumor-to-organ ratios for both 111In and 68Ga-labeled heterodimers3 h pi. At 24 h pi, tumor-to-organ ratios decreased for 111In-NOTA-DUPA-RM26. MicroPET/CT andmicroSPECT/CT scans confirmed the ex vivo data and suggested that anti-GRPR/PSMA heterodimerNOTA-DUPA-RM26 labeled with galium-68 (for PET) and indium-111 (for SPECT) is a suitablecandidate for imaging of GRPR and PSMA expression in PCa shortly after administration.

Nyckelord [en]
PSMA, GRPR, molecular imaging, prostate cancer
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:uu:diva-389562OAI: oai:DiVA.org:uu-389562DiVA, id: diva2:1337864
Tillgänglig från: 2019-07-17 Skapad: 2019-07-17 Senast uppdaterad: 2019-08-15Bibliografiskt granskad
Ingår i avhandling
1. Prostate cancer theranostics using GRPR antagonist RM26
Öppna denna publikation i ny flik eller fönster >>Prostate cancer theranostics using GRPR antagonist RM26
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The malignant transformation of cells is often associated with an alteration of their molecular phenotype, resulting in overexpression of several cell surface proteins. Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are examples of such pro-teins that are expressed at a high density in prostate cancer. GRPR is primarily expressed in earlier stages of prostate cancer and tends to decrease with disease progression. This expression pattern indicates that GRPR could be a promising target for imaging and treatment of oligometa-static prostate cancer, an early step in prostate cancer progression characterized by limited meta-static spread. In contrast, the expression of PSMA increases with cancer progression and is significantly upregulated as tumors dedifferentiate into higher grade, in androgen-insensitive and metastatic lesions.

This thesis is based on five original articles (papers I-V) and focuses on the preclinical de-velopment of radiotracers for imaging and treatment of prostate cancer. The work can be divided into three distinct parts: (1) the development and optimization of GRPR-antagonist RM26 for high contrast PET and SPECT imaging of oligometastatic prostate cancer (papers I-III), (2) the preclinical evaluation of 177Lu-labeled RM26 as a potential candidate for peptide receptor radionuclide therapy (PRRT) in GRPR-expressing tumors, alone or in combination with anti-HER2 antibody trastuzumab (paper IV), and (3) the development of a bispecific heterodimer targeting both PSMA and GRPR in prostate cancer (paper V).

We have demonstrated that the in vitro and in vivo properties of GRPR antagonist RM26 are strongly influenced by the choice of chelator-radionuclide complex and that long-lived radionuclides are desirable for high-contrast imaging. Furthermore, our data indicate that 55Co-NOTA-PEG2-RM26 has remarkable potential for next-day high-contrast PET imaging of GRPR-expressing tumors. Experimental PRRT using 177Lu-DOTAGA-PEG2-RM26 resulted in a pronounced inhibition of tumor growth and a significantly longer median survival. Interestingly, survival was further improved when trastuzumab was co-injected with 177Lu-DOTAGA-PEG2-RM26. These data indicate that blocking HER2 with trastuzumab decreased the repairing ability of irradiated cells. Finally, we developed a heterodimer (NOTA-DUPA-RM26) for imaging GRPR and PSMA expression in prostate cancer shortly after administration.

In conclusion, we have successfully developed and preclinically evaluated radioconjugates for GRPR-directed theranostics in oligometastatic prostate cancer using the bombesin antagonistic analog RM26.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 80
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 274
Nyckelord
Gastrin-releasing peptide receptor (GRPR), Bombesin, Prostate-specific membrane antigen (PSMA), Antagonist, Radionuclide molecular imaging, Theranostics, Peptide receptor radionuclide therapy (PRRT).
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-389563 (URN)978-91-513-0695-7 (ISBN)
Disputation
2019-09-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-08-23 Skapad: 2019-07-17 Senast uppdaterad: 2019-09-17

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Mitran, BogdanVarasteh, ZohrehRinne, Sara S.Larhed, MatsTolmachev, VladimirRosenström, UlrikaOrlova, Anna

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Mitran, BogdanVarasteh, ZohrehPuuvuori, EmmiAbousayed, AymanRinne, Sara S.Larhed, MatsTolmachev, VladimirRosenström, UlrikaOrlova, Anna
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