Radiolabeling of a polypeptide polymer for intratumoral delivery of alpha-particle emitter, 225 Ac, and beta-particle emitter, 177 Lu

• Published in: Nuclear medicine and biology Vol. 104-105; p. 11
• Main Authors: Shalgunov, Vladimir, Engudar, Gokce, Bohrmann, Lennart, Wharton, Luke, Maskell, Keiran, Johann, Kerstin, Barz, Matthias, Schaffer, Paul, Herth, Matthias M, Radchenko, Valery
• Format: Journal Article
• Language: English
• Published: United States 01-01-2022
• Subjects: Animals; Cell Line, Tumor; Humans; Lutetium - chemistry; Lutetium - therapeutic use; Mice; Mice, Nude; Peptides; Polymers; Radiochemistry; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - therapeutic use; Ac; Tetrazine ligation; Polypeptides; Lu; Targeted radionuclide therapy; Polyglutamic acid
• ISSN: 1872-9614

Radiotherapy of cancer requires both alpha- and beta-particle emitting radionuclides, as these radionuclide types are efficient at destroying different types of tumors. Both classes of radionuclides require a vehicle, such as an antibody or a polymer, to be delivered and retained within the tumor. Polyglutamic acid (pGlu) is a polymer that has proven itself effective as a basis of drug-polymer conjugates in the clinic, while its derivatives have been used for pretargeted tumor imaging in a research setup. trans-Cyclooctene (TCO) modified pGlu is suitable for pretargeted imaging or therapy, as well as for intratumoral radionuclide therapy. In all cases, it becomes indirectly radiolabeled via the bioorthogonal click reaction with the tetrazine (Tz) molecule carrying the radionuclide. In this study, we report the radiolabeling of TCO-modified pGlu with either lutetium-177 (
Lu), a beta-particle emitter, or actinium-225 (
Ac), an alpha-particle emitter, using the click reaction between TCO and Tz.
A panel of Tz derivatives containing a metal ion binding chelator (DOTA or macropa) connected to the Tz moiety directly or through a polyethylene glycol (PEG) linker was synthesized and tested for their ability to chelate
Lu and
Ac, and click to pGlu-TCO. Radiolabeled
Lu-pGlu and
Ac-pGlu were isolated by size exclusion chromatography. The retention of
Lu or
Ac by the obtained conjugates was investigated in vitro in human serum.
All DOTA-modified Tzs efficiently chelated
Lu resulting in average radiochemical conversions (RCC) of >75%. Isolated radiochemical yields (RCY) for
Lu-pGlu prepared from
Lu-Tzs ranged from 31% to 55%. TLC analyses detected <5% unchelated
Lu for all
Lu-pGlu preparations over six days in human serum. For
Ac chelation, optimized RCCs ranged from 61 ± 34% to quantitative for DOTA-Tzs and were quantitative for the macropa-modified Tz (>98%). Isolated radiochemical yields (RCY) for
Ac-pGlu prepared from
Ac-Tzs ranged from 28% to 51%. For 3 out of 5
Ac-pGlu conjugates prepared from DOTA-Tzs, the amount of unchelated
Ac stayed below 10% over six days in human serum, while
Ac-pGlu prepared from macropa-Tz showed a steady release of up to 37%
Ac.
We labeled TCO-modified pGlu polymers with alpha- and beta-emitting radionuclides in acceptable RCYs. All
Lu-pGlu preparations and some
Ac-pGlu preparations showed excellent stability in human plasma. Our work shows the potential of pGlu as a vehicle for alpha- and beta-radiotherapy of tumors and demonstrated the usefulness of Tz ligation for indirect radiolabeling.