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Rinne, Sara S.
Publications (10 of 24) Show all publications
Mitran, B., Varasteh, Z., Puuvuori, E., Abousayed, A., Rinne, S. S., Larhed, M., . . . Orlova, A. (2019). Bispecific GRPR-antagonistic anti-PSMA/GRPR heterodimer for PET and SPECT diagnostic imaging of prostate cancer. Cancers, 11(9), Article ID 1371.
Open this publication in new window or tab >>Bispecific GRPR-antagonistic anti-PSMA/GRPR heterodimer for PET and SPECT diagnostic imaging of prostate cancer
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 9, article id 1371Article in journal (Refereed) Published
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.

Keywords
PSMA, GRPR, molecular imaging, prostate cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-389562 (URN)10.3390/cancers11091371 (DOI)000489719000156 ()31540122 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/425Swedish Research Council, 2015-02509
Available from: 2019-07-17 Created: 2019-11-08 Last updated: 2019-08-15Bibliographically approved
Vorobyeva, A., Schulga, A., Konovalova, E., Güler, R., Mitran, B., Garousi, J., . . . Tolmachev, V. (2019). Comparison of tumor-targeting properties of directly and indirectly radioiodinated designed ankyrin repeat protein (DARPin) G3 variants for molecular imaging of HER2. International Journal of Oncology, 54(4), 1209-1220
Open this publication in new window or tab >>Comparison of tumor-targeting properties of directly and indirectly radioiodinated designed ankyrin repeat protein (DARPin) G3 variants for molecular imaging of HER2
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2019 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 54, no 4, p. 1209-1220Article in journal (Refereed) Published
Abstract [en]

Evaluation of human epidermal growth factor receptor 2 (HER2) expression levels in breast and gastroesophageal cancer is used for the stratification of patients for HER2-targeting therapies. The use of radionuclide molecular imaging may facilitate such evaluation in a non-invasive way. Designed ankyrin repeat proteins (DARPins) are engineered scaffold proteins with high potential as probes for radionuclide molecular imaging. DARPin G3 binds with high affinity to HER2 and may be used to visualize this important therapeutic target. Studies on other engineered scaffold proteins have demonstrated that selection of the optimal labeling approach improves the sensitivity and specificity of radionuclide imaging. The present study compared two methods of labeling G3, direct and indirect radioiodination, to select an approach providing the best imaging contrast. G3-H-6 was labeled with iodine-124, iodine-125 and iodine-131 using a direct method. A novel construct bearing a C-terminal cysteine, G3-GGGC, was site-specifically labeled using [I-125]I-iodo-[(4-hydroxyphenyl)ethyl]maleimide (HPEM). The two radiolabeled G3 variants preserved binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was demonstrated. Biodistribution comparison of [I-131]I-G3-H-6 and [I-125]I-HPEM-G3-GGGC in mice, bearing HER2-expressing SKOV3 xenografts, demonstrated an appreciable contribution of hepatobiliary excretion to the clearance of [I-125]I-HPEM-G3-GGGC and a decreased tumor uptake compared to [I-131]I-G3-H-6. The direct label provided higher tumor-to-blood and tumor-to-organ ratios compared with the indirect label at 4 h post-injection. The feasibility of high contrast PET/CT imaging of HER2 expression in SKOV3 xenografts in mice using [I-124]I-G3-H-6 was demonstrated. In conclusion, direct radioiodination is the preferable approach for labeling DARPin G3 with iodine-123 and iodine-124 for clinical single photon emission computed tomography and positron emission tomography imaging.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD, 2019
Keywords
DARPin, HER2, imaging, radionuclide, iodine, radioiodination
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-380422 (URN)10.3892/ijo.2019.4712 (DOI)000461097600006 ()
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509Vinnova, 2016-04060Swedish Cancer Society, 2015/350Swedish Cancer Society, 2017/425
Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-02Bibliographically approved
Rosestedt, M., Andersson, K. G., Rinne, S. S., Leitao, C. D., Mitran, B., Vorobyeva, A., . . . Orlova, A. (2019). Improved contrast of affibody-mediated imaging of HER3 expression in mouse xenograft model through co-injection of a trivalent affibody for in vivo blocking of hepatic uptake. Scientific Reports, 9, Article ID 6779.
Open this publication in new window or tab >>Improved contrast of affibody-mediated imaging of HER3 expression in mouse xenograft model through co-injection of a trivalent affibody for in vivo blocking of hepatic uptake
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6779Article in journal (Refereed) Published
Abstract [en]

Human epidermal growth factor receptor type 3 (HER3) plays a crucial role in the progression of many cancer types. In vivo radionuclide imaging could be a reliable method for repetitive detection of HER3-expression in tumors. The main challenge of HER3-imaging is the low expression in tumors together with endogenous receptor expression in normal tissues, particularly the liver. A HER3-targeting affibody molecule labeled with radiocobalt via a NOTA chelator [Co-57]Co-NOTA-Z(08699) has demonstrated the most favorable biodistribution profile with the lowest unspecific hepatic uptake and high activity uptake in tumors. We hypothesized that specific uptake of labeled affibody monomer might be selectively blocked in the liver but not in tumors by a co-injection of non-labeled corresponding trivalent affibody (Z(08699))(3). Biodistribution of [Co-57]Co-NOTA-Z(08699) and [In-111]ln-DOTA-(Z(08699))(3) was studied in BxPC-3 xenografted mice. [Co-57]Co-NOTA-Z(08699) was co-injected with unlabeled trivalent affibody DOTA-(Z(08699))(3) at different monomer:trimer molar ratios. HER3-expression in xenografts was imaged using [Co-57]Co-NOTA-Z(08699) and [Co-57]Co-NOTA-Z(08699): DOTA-(Z(08699))(3). Hepatic activity uptake of [Co-57] Co-NOTA-Z(08699): DOTA-(Z(08699))(3) decreased with increasing monomer:trimer molar ratio. The tumor activity uptake and tumor-to-liver ratios were the highest for the 1:3 ratio. SPECT/CT images confirmed the biodistribution data. Imaging of HER3 expression can be improved by co-injection of a radiolabeled monomeric affi body-based imaging probe together with a trivalent affibody.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-386176 (URN)10.1038/s41598-019-43145-2 (DOI)000466358700048 ()31043683 (PubMedID)
Funder
Swedish Research Council, 621-2012-5236Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Vinnova, 2016-04060Knut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Cancer Society, CAN2016-463Swedish Cancer Society, CAN2014-474Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2018/436
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Ding, H., Altai, M., Rinne, S. S., Vorobyeva, A., Tolmachev, V., Gräslund, T. & Orlova, A. (2019). Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates. Cancers, 11(8), Article ID 1168.
Open this publication in new window or tab >>Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 8, article id 1168Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderateto high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (Z(HER2:2891))(2) -ABD-MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-3-MC-DM1, or a hexaglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-6-MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (Z(HER2:2891))(2)-ABD-MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
affibody, drug conjugates, hepatic uptake, DM1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-394647 (URN)10.3390/cancers11081168 (DOI)000484438000128 ()31416167 (PubMedID)
Funder
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Cancer Society, CAN 2018/824Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Vinnova, 2016-04060Vinnova, 2019-00104Swedish Society for Medical Research (SSMF)
Available from: 2019-10-17 Created: 2019-10-17 Last updated: 2019-10-17Bibliographically approved
Vorobyeva, A., Schulga, A., Rinne, S. S., Günther, T., Orlova, A., Deyev, S. & Tolmachev, V. (2019). Indirect Radioiodination of DARPin G3 Using N-succinimidyl-Para-Iodobenzoate Improves the Contrast of HER2 Molecular Imaging. International Journal of Molecular Sciences, 20(12), Article ID 3047.
Open this publication in new window or tab >>Indirect Radioiodination of DARPin G3 Using N-succinimidyl-Para-Iodobenzoate Improves the Contrast of HER2 Molecular Imaging
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2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 12, article id 3047Article in journal (Refereed) Published
Abstract [en]

Radionuclide molecular imaging of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal cancer might be used to stratify patients for HER2-targeted therapy as well as monitor treatment response and disease progression. Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins with favorable properties for molecular imaging. Herein we compared two methods for labeling the anti-HER2 DARPin (HE)(3)-G3, direct and indirect radioiodination. We hypothesized that the use of N-succinimidyl-para-iodobenzoate (SPIB) for radioiodination would facilitate the clearance of radiometabolites and improve the contrast of imaging. Both radiolabeled (HE)(3)-G3 variants preserved their binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was also demonstrated. A biodistribution comparison of [I-125]I-(HE)(3)-G3 and [I-125]I-PIB-(HE)(3)-G3, in mice bearing HER2 expressing SKOV3 xenografts, showed rapid clearance of [I-125]I-PIB-(HE)(3)-G3 from normal organs and tissues and low accumulation of activity in organs with NaI-symporter expression. Both radiolabeled (HE)(3)-G3 variants had equal tumor uptake. Consequently, the indirect label provided higher tumor-to-blood and tumor-to-organ ratios compared with the direct label. Comparative Single Photon Emission Computed Tomography (SPECT)/CT imaging of HER2 expression in SKOV3 xenografts, using both radiolabeled DARPins, demonstrated the superior imaging contrast of the indirect label. Indirect radioiodination of (HE)(3)-G3 using SPIB could be further applied for SPECT and PET imaging with iodine-123 and iodine-124.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
DARPin, HER2, imaging, radionuclide, iodine, radioiodination
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-390692 (URN)10.3390/ijms20123047 (DOI)000473756000197 ()31234471 (PubMedID)
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509Swedish Cancer Society, CAN 2015/350Swedish Cancer Society, 2017/425
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Dahlsson Leitao, C., Rinne, S. S., Mitran, B., Vorobyeva, A., Andersson, K. G., Tolmachev, V., . . . Orlova, A. (2019). Molecular Design of HER3-Targeting Affibody Molecules: Influence of Chelator and Presence of HEHEHE-Tag on Biodistribution of 68Ga-Labeled Tracers. International Journal of Molecular Sciences, 20(5), Article ID 1080.
Open this publication in new window or tab >>Molecular Design of HER3-Targeting Affibody Molecules: Influence of Chelator and Presence of HEHEHE-Tag on Biodistribution of 68Ga-Labeled Tracers
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2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 5, article id 1080Article in journal (Refereed) Published
Abstract [en]

Affibody-based imaging of HER3 is a promising approach for patient stratification. We investigated the influence of a hydrophilic HEHEHE-tag ((HE)3-tag) and two different gallium-68/chelator-complexes on the biodistribution of Z08698 with the aim to improve the tracer for PET imaging. Affibody molecules (HE)3-Z08698-X and Z08698-X (X = NOTA, NODAGA) were produced and labeled with gallium-68. Binding specificity and cellular processing were studied in HER3-expressing human cancer cell lines BxPC-3 and DU145. Biodistribution was studied 3 h p.i. in Balb/c nu/nu mice bearing BxPC-3 xenografts. Mice were imaged 3 h p.i. using microPET/CT. Conjugates were stably labeled with gallium-68 and bound specifically to HER3 in vitro and in vivo. Association to cells was rapid but internalization was slow. Uptake in tissues, including tumors, was lower for (HE)3-Z08698-X than for non-tagged variants. The neutral [68Ga]Ga-NODAGA complex reduced the hepatic uptake of Z08698 compared to positively charged [68Ga]Ga-NOTA-conjugated variants. The influence of the chelator was more pronounced in variants without (HE)3-tag. In conclusion, hydrophilic (HE)3-tag and neutral charge of the [68Ga]Ga-NODAGA complex promoted blood clearance and lowered hepatic uptake of Z08698. [68Ga]Ga-(HE)3-Z08698-NODAGA was considered most promising, providing the lowest blood and hepatic uptake and the best imaging contrast among the tested variants.

Keywords
HER3, affibody, NOTA, NODAGA, molecular imaging, gallium-68, PET
National Category
Biochemistry and Molecular Biology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-381825 (URN)10.3390/ijms20051080 (DOI)000462542300079 ()30832342 (PubMedID)
Funder
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Research Council, 2012-05236Vinnova, 2016/04060Swedish Cancer Society, CAN2014/474Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2018/436Swedish Cancer Society, CAN2017/649Swedish Cancer Society, CAN2016/463
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-18Bibliographically approved
Rinne, S. S., Leitao, C. D., Mitran, B., Bass, T. Z., Andersson, K. G., Tolmachev, V., . . . Orlova, A. (2019). Optimization of HER3 expression imaging using affibody molecules: Influence of chelator for labeling with indium-111. Scientific Reports, 9, Article ID 655.
Open this publication in new window or tab >>Optimization of HER3 expression imaging using affibody molecules: Influence of chelator for labeling with indium-111
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 655Article in journal (Refereed) Published
Abstract [en]

Radionuclide molecular imaging of human epidermal growth factor receptor 3 (HER3) expression using affibody molecules could be used for patient stratification for HER3-targeted cancer therapeutics. We hypothesized that the properties of HER3-targeting affibody molecules might be improved through modification of the radiometal-chelator complex. Macrocyclic chelators NOTA (1,4,7-triazacyclononane-N,N',N ''-triacetic acid), NODAGA (1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid), and DOTAGA (1,4,7,10-tetraazacyclododececane, 1-(glutaric acid)-4,7,10-triacetic acid) were conjugated to the C-terminus of anti-HER3 affibody molecule Z(08698) and conjugates were labeled with indium-111. All conjugates bound specifically and with picomolar affinity to HER3 in vitro. In mice bearing HER3-expressing xenografts, no significant difference in tumor uptake between the conjugates was observed. Presence of the negatively charged In-111-DOTAGA-complex resulted in the lowest hepatic uptake and the highest tumor-to-liver ratio. In conclusion, the choice of chelator influences the biodistribution of indium-111 labeled anti-HER3 affibody molecules. Hepatic uptake of anti-HER3 affibody molecules could be reduced by the increase of negative charge of the radiometal-chelator complex on the C-terminus without significantly influencing the tumor uptake.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-376820 (URN)10.1038/s41598-018-36827-w (DOI)000456554600094 ()30679757 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Research Council, 2012-05236VINNOVA, 2016/04060Swedish Cancer Society, CAN2014/474Swedish Cancer Society, CAN2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN2016/463
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-18Bibliographically approved
Mitran, B., Thisgaard, H., Rinne, S. S., Dam, J. H., Azami, F., Tolmachev, V., . . . Rosenström, U. (2019). Selection of an optimal macrocyclic chelator improves the imaging of prostate cancer using cobalt-labeled GRPR antagonist RM26. Scientific Reports, 9, Article ID 17086.
Open this publication in new window or tab >>Selection of an optimal macrocyclic chelator improves the imaging of prostate cancer using cobalt-labeled GRPR antagonist RM26
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 17086Article in journal (Refereed) Published
Abstract [en]

Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used Co-55 (T(1/2=)17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of Co-55-labeled PEG(2)-RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG(2)-RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG(2)-RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using Co-55).

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-398422 (URN)10.1038/s41598-019-52914-y (DOI)000497701800043 ()31745219 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN 2018/436Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Abouzayed, A., Yim, C.-B., Mitran, B., Rinne, S. S., Tolmachev, V., Larhed, M., . . . Orlova, A. (2019). Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer. Pharmaceutics, 11(7), Article ID 358.
Open this publication in new window or tab >>Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer
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2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 7, article id 358Article in journal (Refereed) Published
Abstract [en]

Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)(8) (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [I-125]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [I-125]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [I-125]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%-35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [I-125]I-BO530 is a promising agent for theranostics application in prostate cancer.

Keywords
prostate cancer, GRPR, PSMA, bispecific heterodimers, theranostics, radio-iodine
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-393138 (URN)10.3390/pharmaceutics11070358 (DOI)000478995100060 ()31340483 (PubMedID)
Funder
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2018/436
Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2019-09-23Bibliographically approved
Mitran, B., Rinne, S. S., Konijnenberg, M. W., Maina, T., Nock, B. A., Altai, M., . . . Orlova, A. (2019). Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26. International Journal of Cancer, 145(12), 3347-3358
Open this publication in new window or tab >>Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 12, p. 3347-3358Article in journal (Refereed) Published
Abstract [en]

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 for labeling with 177Lu and further determinedthe effect of treatment with 177Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in amurine model. The PEG2-RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelatorconjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC-3xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2-RM26, (C) 177LuDOTAGA-PEG2-RM26, (D) trastuzumab or (E) 177Lu-DOTAGA-PEG2-RM26 in combination with trastuzumab. 177Lu-DOTAGA-PEG2-RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% ofradioligand remained when coinjected with phosphoramidon), high affinity to GRPR (KD = 0.4 0.2 nM), and favorablebiodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu-DOTAGAPEG2-RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorterthan for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantlyimproved survival. No treatment-related toxicity was observed. In conclusion, based on in vitro and in vivo characterization ofthe four 177Lu-labeled PEG2-RM26 analogs, we concluded that 177Lu-DOTAGA-PEG2-RM26 was the most promising analog forTRT. Radiotherapy using 177Lu-DOTAGA-PEG2-RM26 effectively inhibited tumor growth in vivo in a murine prostate cancermodel. Anti-HER2 therapy additionally improved survival.

Keywords
radionuclide therapy, GRPR, HER2, prostate cancer, lutetium-177
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-389561 (URN)10.1002/ijc.32401 (DOI)000491231500016 ()31077356 (PubMedID)
Funder
Swedish Cancer Society, CAN2014-474Swedish Cancer Society, CAN 2018/436Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2017/425Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353
Available from: 2019-07-17 Created: 2019-07-17 Last updated: 2019-11-08Bibliographically approved
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