Gutenberg Open Science: DOTA conjugate of bisphosphonate and PSMA-inhibitor : a promising combination for therapy of prostate cancer related bone metastases

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8203

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DC Field	Value	Language
dc.contributor.author	Grus, Tilmann	-
dc.contributor.author	Lahnif, Hanane	-
dc.contributor.author	Bausbacher, Nicole	-
dc.contributor.author	Miederer, Matthias	-
dc.contributor.author	Rösch, Frank	-
dc.date.accessioned	2022-11-02T10:35:36Z	-
dc.date.available	2022-11-02T10:35:36Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8218	-
dc.description.abstract	Prostate cancer (PCa) is one of the most common cancer types worldwide. 90% of men with late stage PCa will develop bone metastases. Since the expression level of PSMA (prostate-specific membrane antigen) in bone metastases can vary significantly, a compound is being searched for which accumulates in bone metastases independently of PSMA level. With DOTA-L-Lys(SA.Pam)-PSMA-617, we present a compound that, in addition to a PSMA inhibitor as a target vector, also contains a bisphosphonate that is established as a bone tracer and thus combines the advantages of PSMA targeting and bone targeting. This is a class of small molecules combining targeting of two different targets with the potential advantages for treatment of biologically heterogeneous bone metastasis from prostate cancer. The molecule can be labeled with lutetium-177 and used for the therapy of PCa-related bone metastases. DOTA-L-Lys(SA.Pam)-PSMA-617 was synthesized and radiolabelled in 1 M ammonium acetate buffer pH 5.5 at 95◦C. Different amounts of precursor were evaluated. Complex stability was evaluated in three different media. LogD7.4 value was evaluated via the determination of the equilibrium distribution in a PBS/n-octanol mixture. A hydroxyapatite binding assay was used to evaluate the potential binding to bone metastases. In vitro affinity was determined and Ki value was evaluated. To evaluate the binding potential in mice, ex vivo biodistribution studies were carried out in LNCaP tumor-bearing Balb/c mice. [177Lu]Lu-labeling of DOTA-L-Lys(SA.Pam)-PSMA-617 showed quantitative RCY within 10 min and high complex stability over 14 days. The lipophilicity of the labeled compound was similar to the lipophilicity of the reference compound [177Lu]Lu-PSMA-617 and showed an excellent and selective HAP binding of 98.2 ± 0.11%. With a Ki of 42.3 ± 7.7 nM PSMA binding affinity is lower in comparison to [177Lu]Lu-PSMA-617. First ex vivo biodistribution studies with LNCaP tumor-bearing Balb/c mice showed a PSMA dependent tumor accumulation of 4.2 ± 0.7%ID/g and a femur accumulation of 3.4 ± 0.4%ID/g. [177Lu]Lu-DOTA-L-Lys(SA.Pam)-PSMA-617 is a promising compound for therapy of PCa related bone and tissue metastases. Accumulation on the bone metastases via two mechanisms also enables the treatment of bone metastases that show little or no PSMA expression.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	540 Chemie	de_DE
dc.subject.ddc	540 Chemistry and allied sciences	en_GB
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	DOTA conjugate of bisphosphonate and PSMA-inhibitor : a promising combination for therapy of prostate cancer related bone metastases	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8203	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.department	FB 09 Chemie, Pharmazie u. Geowissensch.	de
jgu.organisation.number	2700	-
jgu.organisation.number	7950	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Frontiers in nuclear medicine	de
jgu.journal.volume	2	de
jgu.pages.alternative	892147	de
jgu.publisher.year	2022	-
jgu.publisher.name	Frontiers Media	de
jgu.publisher.place	Lausanne	de
jgu.publisher.issn	2673-8880	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	540	de
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.3389/fnume.2022.892147	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Lebenswissenschaften	de
Appears in collections:	DFG-491381577-G

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