Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors
2016 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 6, no 1, 93-103 p.Article in journal (Refereed) PublishedText
Affibody molecules are small (7 kDa), non-immunoglobulin scaffold proteins with a potential as targeting agents for radionuclide imaging of cancer. However, high renal re-absorption of Affibody molecules prevents their use for radionuclide therapy with residualizing radiometals. We hypothesized that the use of Affibody-based peptide nucleic acid (PNA)-mediated pretargeting would enable higher accumulation of radiometals in tumors than in kidneys. To test this hypothesis, we designed an Affibody-PNA chimera Z(HER2:342)-SR-HP1 containing a 15-mer HP1 PNA recognition tag and a complementary HP2 hybridization probe permitting labeling with both I-125 and In-111. In-111-Z(HER2:342)-SR-HP1 bound specifically to HER2-expressing BT474 and SKOV-3 cancer cells in vitro, with a K-D of 6+/-2 pM for binding to SKOV-3 cells. Specific high affinity binding of the radiolabeled complementary PNA probe In-111-/I-125-HP2 to Z(HER2:342)-SR-HP1 pre-treated cells was demonstrated. In-111-Z(HER2:342)-SR-HP1 demonstrated specific accumulation in SKOV-3 xenografts in BALB/C nu/nu mice and rapid clearance from blood. Pre-saturation of SKOV-3 with non-labeled anti-HER2 Affibody or the use of HER2-negative Ramos xenografts resulted in significantly lower tumor uptake of In-111-Z(HER2:342)-SR-HP1. The complementary PNA probe In-111/I-125-HP2 accumulated in SKOV-3 xenografts when Z(HER2:342)-SR-HP1 was injected 4 h earlier. The tumor accumulation of In-111/I-125-HP2 was negligible without Z(HER2:342)-SR-HP1 pre-injection. The uptake of In-111-HP2 in SKOV-3 xenografts was 19+/-2 % ID/g at 1 h after injection. The uptake in blood and kidneys was approximately 50- and 2-fold lower, respectively. In conclusion, we have shown that the use of Affibody-based PNA-mediated pretargeting enables specific delivery of radiometals to tumors and provides higher radiometal concentration in tumors than in kidneys.
Place, publisher, year, edition, pages
Ivyspring International Publisher , 2016. Vol. 6, no 1, 93-103 p.
Affibody, peptide nucleic acid, radionuclide pretargeting, scaffold protein, HER2
Immunology in the medical area
IdentifiersURN: urn:nbn:se:kth:diva-184565DOI: 10.7150/thno.12766ISI: 000371806600001PubMedID: 26722376ScopusID: 2-s2.0-84954489812OAI: oai:DiVA.org:kth-184565DiVA: diva2:916889
FunderSwedish Cancer Society, 2012/354Swedish Research Council, 521-2012-2228, 621-2013-5135
QC 201604052016-04-052016-04-012016-04-05Bibliographically approved