Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

Abstract

BackgroundIn this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.ResultsShort linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.ConclusionsThis study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0372-x) contains supplementary material, which is available to authorized users.

Production and Use of the First-Row Transition Metal PET Radionuclides43,44Sc,52Mn, and45Ti

“…43 Sc can be produced via proton irradiation of 43 Ca or 46 Ti, as well as a-irradiation of 40 Ca or deuteron irradiation of 44 Ca (5-7). 44g,m Sc can be produced via proton irradiation of 44 Ca, 47 Ti, or 45 Sc or deuteron irradiation of 44 Ca (2,(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Enriched targets are preferred to avoid production of contaminants such as 46,48 Sc (18).…”

“…In this case, the pair would be 43,44g Sc as the diagnostic agent and 47 Sc as the therapeutic agent. Studies have compared the labeling efficiencies of 68 Ga, 177 Lu, and 44g Sc for DOTA-HPMA (N-(2-hydroxypropyl) methacrylamide) conjugates and showed that the 44g Sclabeled polymer was highly stable for up to 24 h, showing promising characteristics for in vivo imaging (12). A similar study determined that reaction rates were increased when buffers including EtOH were used, allowing for lower temperatures and a reduced time to achieve labeling yields above 90% for DOTA complexes with these 3 radioisotopes (26).…”

Production of scandium radionuclides for theranostic applications: towards standardization of quality requirements

“…The scandium radionuclides labeled bombesin analogs (Koumarianou et al 2012), RGD peptides (Domnanich et al 2017c), folate derivatives (Muller et al 2018;Muller et al 2014;Siwowska et al 2019) and PSMA ligands (Umbricht et al 2017) have been evaluated pre-clinically. Few studies have also reported on scandium radiolabeled antibodies, antibody fragments or affibodies (Chakravarty et al 2014;Honarvar et al 2017;Moghaddam-Banaem 2012) and nanoparticles (Eppard et al 2018). A summary is given in Table 6.…”

Nanoparticulate formulations of radiopharmaceuticals: Strategy to improve targeting and biodistribution properties

“…In certain cases, a reactive polymer like those containing ester groups can be functionalized with multiple ligands. For example, perfluorinated ester synthesized by controlled radical polymerization followed by postsynthesis modification can yield well‐defined, low‐dispersity, multifunctional copolymers of HPMA 144 . To reduce radiation‐induced nephrotoxicity in somatostatin receptor (SSR)‐positive tumours, a poly(lactide‐ co ‐glycolide) nanoparticle with anti‐β‐hCG antibodies and 177 Lu labelling has been successfully employed in vivo with a very high (approx.…”