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Feasibility of Affi...
Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors
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- Honarvar, Hadis (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Vladimir Tolmachev
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- Westerlund, Kristina (författare)
- KTH,Proteinteknologi
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- Altai, Mohamed (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Vladimir Tolmachev
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- Sandström, Mattias (författare)
- Uppsala universitet,Radiologi
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- Orlova, Anna (författare)
- Uppsala universitet,Plattformen för preklinisk PET,Anna Orlova
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Vladimir Tolmachev
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- Eriksson Karlström, Amelie (författare)
- KTH,Proteinteknologi
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(creator_code:org_t)
- Ivyspring International Publisher, 2016
- 2016
- Engelska.
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 6:1, s. 93-103
- Relaterad länk:
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https://doi.org/10.7...
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https://doi.org/10.7...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.7...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Nyckelord
- Affibody
- peptide nucleic acid
- radionuclide pretargeting
- scaffold protein
- HER2
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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