Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance

Abstract

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of “unchelated” 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate.

[68Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity

“…Our motivation was not only to explore the broad calcium mineral affinity of BPs but also to combine the superior performance of PET imaging with the simplicity of radionuclide generator kit-based synthesis and availability, that has been largely responsible for the long-term success of 99m Tc radiochemistry and the nuclear imaging field. Here, we describe the development of [ 68 Ga]­Ga-THP-Pam, a 68 Ga complex of the efficient gallium chelator ( tris )­hydroxypyridinone (THP), ,− conjugated with the clinically used BP pamidronate (Pam) (Figure A) and its comparison with [ 18 F]­NaF and two other 68 Ga-labeled BPsBPAMD (Figure B) and NO2AP BP (Figure C)which have undergone extensive evaluation including first in human studies. ,− ,− , …”

Biotin-streptavidin-guided two-step pretargeting approach using PLGA for molecular ultrasound imaging and chemotherapy for ovarian cancer

“…The two-step biotin-avidin pre-targeting technology has the characteristics of strong binding in vivo and multi-level amplification and has been applied in other imaging fields ( Qiu et al, 2015 ). The T/NT value using a pre-targeting technique is significantly higher than that of direct targeting methods ( Hapuarachchige & Artemov, 2020 ; Hapuarachchige et al, 2020 ; Imberti et al, 2020 ). However, this method is rarely used in ultrasound molecular targeting research.…”

Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy

“…On the other hand, the serum stability demonstrated by the Pt-succ-DFO- 68 Ga suggests that the complex should be stable in blood circulation in the absence of photoirradiation. Notably, the 68 Ga biodistribution observed by dynamic PET imaging is typical of a small hydrophilic molecule such as Pt-succ-DFO- 68 Ga , rather than of unchelated Ga which displays slower clearance and a more diffuse distribution …”

“…Notably, the 68 Ga biodistribution observed by dynamic PET imaging is typical of a small hydrophilic molecule such as Pt-succ-DFO-68 Ga, rather than of unchelated Ga which displays slower clearance and a more diffuse distribution. 46 Beyond cancer phototherapy, another potential application of Pt-succ-DFO-68 Ga is in the field of photoactivated antibiotics, exploiting the ability of several bacteria (e.g. Pseudomonas aeruginosa, Staphylococcus aureus) to take up iron and gallium complexes of the siderophore DFO.…”