uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and residualizing properties of the label
KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.ORCID-id: 0000-0003-3955-1320
Visa övriga samt affilieringar
2018 (Engelska)Ingår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, nr 1, s. 93-99Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Visualization of cancer-associated alterations of molecular phenotype using radionuclide imaging is a noninvasive approach to stratifying patients for targeted therapies. The engineered albumin-binding domain-derived affinity protein (ADAPT) is a promising tracer for radionuclide molecular imaging because of its small size (6.5 kDa), which satisfies the precondition for efficient tumor penetration and rapid clearance. Previous studies demonstrated that the human epidermal growth factor receptor type 2 (HER2)-targeting ADAPT6 labeled with radiometals at the N terminus is able to image HER2 expression in xenografts a few hours after injection. The aim of this study was to evaluate whether the use of a non-residualizing label or placement of the labels at the C terminus would further improve the targeting properties of ADAPT6. Methods: Two constructs, Cys(2)-ADAPT6 and Cys(59)-ADAPT6, having the (HE)(3)DANS sequence at the N terminus were produced and site-specifically labeled using In-111-DOTA or I-125-iodo-((4-hydroxyphenyl) ethyl) maleimide (HPEM). The conjugates were compared in vitro and in vivo. HER2-targeting properties and biodistribution were evaluated in BALB/C nu/nu mice bearing ovarian carcinoma cell (SKOV-3) xenografts. Results: Specific HER2 binding and high affinity were preserved after labeling. Both Cys(2)-ADAPT6 and Cys59-ADAPT6 were internalized slowly by HER2-expressing cancer cells. Depending on the label position, uptake at 4 h after injection varied from 10% to 22% of the injected dose per gram of tumor tissue. Regardless of terminus position, the I-125-HPEM label provided more than 140-fold lower renal uptake than the In-111-DOTA label at 4 after injection. The tumor-to-organ ratios were, in contrast, higher for both of the (111)InDOTA- labeled ADAPT variants in other organs. Tumor-to-blood ratios for In-111-labeled Cys(2)-ADAPT6 and Cys(59)-ADAPT6 did not differ significantly (250-280), but In-111-DOTA-Cys(59)-ADAPT6 provided significantly higher tumor-to-lung, tumor-to-liver, tumor-to-spleen, and tumor-to-muscle ratios. Radioiodinated variants had similar tumor-to-organ ratios, but I-125-HPEM-Cys(59)-ADAPT6 had significantly higher tumor uptake and a higher tumor-to-kidney ratio. Conclusion: Residualizing properties of the label strongly influence the targeting properties of ADAPT6. The position of the radiolabel influences targeting as well, although to a lesser extent. Placement of a label at the C terminus yields the best biodistribution features for both radiometal and radiohalogen labels. Low renal retention of the radioiodine label creates a precondition for radionuclide therapy using I-131-labeled HPEM-Cys(59)-ADAPT6.

Ort, förlag, år, upplaga, sidor
2018. Vol. 59, nr 1, s. 93-99
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-327415DOI: 10.2967/jnumed.117.197202ISI: 000419116200021PubMedID: 28864631OAI: oai:DiVA.org:uu-327415DiVA, id: diva2:1130735
Forskningsfinansiär
CancerfondenVetenskapsrådet
Anmärkning

De två första författarna delar förstaförfattarskapet.

Tillgänglig från: 2017-08-10 Skapad: 2017-08-10 Senast uppdaterad: 2018-02-07Bibliografiskt granskad
Ingår i avhandling
1. Development of ADAPT-based tracers for radionuclide molecular imaging of cancer
Öppna denna publikation i ny flik eller fönster >>Development of ADAPT-based tracers for radionuclide molecular imaging of cancer
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

ABD-Derived Affinity Proteins (ADAPTs) is a novel class of small engineered scaffold proteins based on albumin-binding domain (ABD) of streptococcal protein G. High affinity ADAPT  binders against various therapeutic targets can be selected.  In this thesis, we report a development of ADAPT-based radionuclide imaging agents providing high sensitivity and specificity of molecular imaging of HER2 expression in disseminated cancers.

We investigated the feasibility of the use of ADAPTs as imaging agents and influence of molecular design and radiolabeling chemistry on in vivo targeting and biodistribution properties of the tracers.

In Paper I we demonstrated the feasibility of the use of anti-HER2 ADAPT6 molecule as a high contrast imaging agent;

In Paper II we evaluated the influence of composition of histidine-containing tag on in vivo biodistribution of ADAPT-based tracers labeled with 99mTc using 99mTc(CO)3 binding to histidine-containing tags and 111In using DOTA chelator at N-terminus;

In Paper III we evaluated the influence of different aspects of N-terminus leading sequence on targeting including effect of sequence size on clearance rate and effect of the composition of the sequence on biodistribution profile;

In Paper IV, we evaluated the influence of residualizing properties and positioning of the label on biodistribution and targeting; and

In Paper V, we compared tumor-targeting properties of the ADAPT6 labeled at C-terminus with 99mTc using N3S chelator and 111In using DOTA chelator.

In conclusion, ADAPTs constitute a very promising class of targeting probes for molecular imaging providing high contrast. Molecular design of the ADAPT proteins and chelators/linkers for labeling has an appreciable effect on their imaging properties.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 99
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1354
Nyckelord
ADAPT, scaffold protein, albumin-binding domain (ABD), Affinity protein, HER2, radionuclide molecular imaging
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-327419 (URN)978-91-513-0030-6 (ISBN)
Disputation
2017-09-29, Fåhraeus Hall, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-09-06 Skapad: 2017-08-10 Senast uppdaterad: 2017-09-08

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltextPubMed

Personposter BETA

Garousi, JavadMitran, BogdanBuijs, JosAltai, MohamedOrlova, AnnaTolmachev, Vladimir

Sök vidare i DiVA

Av författaren/redaktören
Garousi, JavadMitran, BogdanBuijs, JosAltai, MohamedOrlova, AnnaTolmachev, Vladimir
Av organisationen
Medicinsk strålningsvetenskapAvdelningen för Molekylär Avbildning
I samma tidskrift
Journal of Nuclear Medicine
Medicin och hälsovetenskap

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 331 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf