Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates—new perspectives for folate receptor–targeted radionuclide therapy

Guzik, Patrycja; Benešová, Martina; Ratz, Magdalena; Rodríguez, Josep M. Monné; Deberle, Luisa M.; Schibli, Roger; Müller, Cristina

doi:10.1007/s00259-020-04980-y

Cited by 13 publications

(51 citation statements)

References 26 publications

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“…At day 0 and day 7 of the study, the mice were intravenously injected with vehicle only (Group A: PBS with 0.05% BSA; sham-treatment), [ 161 Tb]Tb-DOTATOC (Group B: 10 MBq, 0.2 nmol), [ 177 Lu]Lu-DOTATOC (Group C: 10 MBq, 0.2 nmol), [ 161 Tb]Tb-DOTA-LM3 (Group D: 10 MBq, 0.2 nmol), and [ 177 Lu]Lu-DOTA-LM3 (Group E: 10 MBq, 0.2 nmol) (Table 1 ). The relative body weight (RBW) and the relative tumor volume (RTV) were defined based on the values at therapy start as previously described ( Supplementary Material ) [ 47 ]. The endpoint criteria were defined according to a scoring system which required euthanasia of mice with a score ≥ 3 ( Supplementary Material ).…”

Section: Methodsmentioning

confidence: 99%

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Borgna

Haller

Rodríguez

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.

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Section: Methodsmentioning

confidence: 99%

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Borgna

Haller

Rodríguez

et al. 2021

Eur J Nucl Med Mol Imaging

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“…Uptake and internalization of [ 177 Lu]Lu-6 R -RedFol-14, [ 177 Lu]Lu-6 S -RedFol-14, and [ 177 Lu]Lu-OxFol-14 into FR-positive KB tumor cells were in the same range (23–36% and 4.3–7.3%, respectively) as for the folate radioconjugates with an albumin-binding entity (Figure ). FR specificity was confirmed by preincubation of KB cells with an excess of folic acid, which reduced the radioconjugate uptake to <0.2%. The FR-binding affinities of [ 177 Lu]Lu-6 R -RedFol-14, [ 177 Lu]Lu-6 S -RedFol-14, and [ 177 Lu]Lu-OxFol-14 were all in the same range ( K D values 2.0–4.9 nM) (Supporting Information, Table S4).…”

Section: Resultsmentioning

confidence: 93%

“…Addition of ascorbic acid guaranteed radiolytic stability of all radioconjugates over 24 h when incubated at a high activity concentration (250 MBq/500 μL) resulting in ≥95% intact radiolabeled product relative to the amount immediately after labeling (set as 100%) (Supporting Information, Table S2). Due to the lack of the lipophilic p -iodophenyl entity, [ 177 Lu]Lu-6 R -RedFol-14, [ 177 Lu]Lu-6 S -RedFol-14, and [ 177 Lu]Lu-OxFol-14 were more hydrophilic (logD values below −5) than the folate conjugates containing an albumin binder (log D values approximately −3.9) (Supporting Information, Table S3) …”

Section: Resultsmentioning

confidence: 99%

“…The modification of the folates with an albumin-binding entity did not have an impact on the affinity of the radioconjugates to the FR as shown by similar K D values of [ 177 Lu]Lu-6 R -RedFol-1, [ 177 Lu]Lu-6 S -RedFol-1, and [ 177 Lu]Lu-OxFol-1 (1.0–3.6 nM) (Supporting Information, Table S4). In contrast to [ 177 Lu]Lu-6 R -RedFol-14, [ 177 Lu]Lu-6 S -RedFol-14, and [ 177 Lu]Lu-OxFol-14 that showed virtually no binding to mouse and human plasma, pronounced albumin-binding properties were observed for [ 177 Lu]Lu-6 R -RedFol-1, [ 177 Lu]Lu-6 S -RedFol-1, and [ 177 Lu]Lu-OxFol-1 due to the integrated p -iodophenyl moiety (Supporting Information, Table S5) …”

Section: Resultsmentioning

confidence: 99%

“…Chemical structures of (A) albumin-binding OxFol-1, 6 R -RedFol-1, and 6 S -RedFol-1 and (B) OxFol-14, as well as newly designed 6 R -RedFol-14 and 6 S -RedFol-14 without a dedicated albumin-binding functional unit.…”

Section: Introductionmentioning

confidence: 99%

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Novel Synthetic Strategies Enable the Efficient Development of Folate Conjugates for Cancer Radiotheranostics

et al. 2021

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The folate receptor (FR) is an interesting target for radiotheranostics due to its overexpression in several tumor types. The progress in developing novel folate radioconjugates is, however, slow due to the synthetic challenges that folate chemistry presents. The goal of this study was, thus, to establish versatile solid-phase synthetic strategies for a convenient preparation of novel folate conjugates. Two approaches were established based on an orthogonal fluorenylmethyloxycarbonyl (Fmoc)-protection strategy to enable a modular buildup of an albumin-binding DOTA conjugate (known as OxFol-1) using folic acid (oxidized folate version) as a targeting agent. The main difference between the two approaches was the sequence of conjugating the single structural units. The approach that introduced the folate entity as the last unit appeared particularly useful for the preparation of conjugates based on 6R- or 6S-5-methyltetrahydrofolic acid (5-MTHF; a reduced folate version) as targeting entity. Three types of folate conjugates were synthesized either with a p-iodophenyl-based albumin binder (OxFol-1, 6R-RedFol-1, and 6S-RedFol-1) or without an albumin-binding entity (OxFol-14, 6R-RedFol-14, and 6S-RedFol-14). All six conjugates were obtained with high chemical purity (>98%) after 9–13 synthesis steps and a single final HPLC purification. Radiolabeling with lutetium-177 was feasible at high molar activity, and the resulting radioconjugates were stable over at least 24 h. Biodistribution and SPECT/CT imaging studies confirmed the favorable effect of an albumin-binding entity to increase the tumor uptake and reduce kidney retention of folate radioconjugates. The increased tumor-to-kidney ratios obtained with [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 as compared to [177Lu]Lu-OxFol-1 indicated that 5-MTHF is the preferred FR-targeting agent for albumin-binding radioconjugates. This was, however, not the case for folate radioconjugates without an albumin binder. Thanks to the established synthesis strategy, the preparation of further folate radioconjugates will be facilitated, potentially enabling the optimization of the tissue distribution characteristics even more.

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Preclinical comparison of (radio)lanthanides using mass spectrometry and nuclear imaging techniques: biodistribution of lanthanide-based tumor-targeting agents and lanthanides in ionic form

Wallimann,

Mehta,

Mapanao

et al. 2024

Eur J Nucl Med Mol Imaging

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Purpose With the growing interest in exploring radiolanthanides for nuclear medicine applications, the question arises as to whether they are generally interchangeable without affecting a biomolecule’s pharmacokinetic properties. The goal of this study was to investigate similarities and differences of four (radio)lanthanides simultaneously applied as complexes of biomolecules or in ionic form. Methods Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the simultaneous detection of four lanthanides (Ln = lutetium, terbium, gadolinium and europium) in biological samples. In vitro tumor cell uptake and in vivo biodistribution studies were performed with Ln-DOTATATE, Ln-DOTA-LM3, Ln-PSMA-617 and Ln-OxFol-1. AR42J cells, PC-3 PIP cells and KB cells expressing the somatostatin receptor, the prostate-specific membrane antigen and the folate receptor, respectively, were used in vitro as well as to obtain the respective tumor mouse models for in vivo studies. The distribution of lanthanides in ionic form was investigated in immunocompetent mice. Dual-isotope SPECT/CT imaging studies were performed with mice administered with the radiolabeled biomolecules or chloride salts of lutetium-177 and terbium-161. Results Similar in vitro cell uptake was observed for all four lanthanide complexes of each biomolecule into the respective tumor cell lines. AR42J tumor uptake of Ln-DOTATATE and Ln-DOTA-LM3 in mice showed similar values for all lanthanide complexes (3.8‒5.1% ID/g and 4.5‒5.0% ID/g; 1 h p.i., respectively). Accumulation of Ln-PSMA-617 in PC-3 PIP tumors (24–25% ID/g; 1 h p.i.) and of Ln-OxFol-1 in KB tumors (28–31% ID/g; 24 h p.i.) were also equal for the four lanthanide complexes of each biomolecule. After injection of lanthanide chloride salts (LnCl3; Ln = natLu, natTb, natGd, natEu), the liver uptake was different for each metal (~ 12% ID/g, ~ 22% ID/g, ~ 31% ID/g and ~ 37% ID/g; 24 h p.i., respectively) which could be ascribed to the radii of the respective lanthanide ions. In the bones, accumulation was considerably higher for lutetium than for other lanthanides (25 ± 5% ID/g vs. 14‒15% ID/g; 24 h p.i.). These data were confirmed visually by 177Lu/161Tb-based dual-isotope SPECT/CT images. Conclusions The presented study confirmed similar properties of Ln-complexes, suggesting that lutetium-177 can be replaced by other radiolanthanides, most probably without affecting the tissue distribution profile of the resultant radiopharmaceuticals. On the other hand, the different radii of the lanthanide ions affected their uptake and resorption mechanisms in liver and bones when injected in uncomplexed form.

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Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates—new perspectives for folate receptor–targeted radionuclide therapy

Cited by 13 publications

References 26 publications

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Novel Synthetic Strategies Enable the Efficient Development of Folate Conjugates for Cancer Radiotheranostics

Preclinical comparison of (radio)lanthanides using mass spectrometry and nuclear imaging techniques: biodistribution of lanthanide-based tumor-targeting agents and lanthanides in ionic form

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