Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy

Haller, Stephanie; Reber, Josefine; Brandt, Simone; Bernhardt, Peter; Groehn, Viola; Schibli, Roger; Müller, Cristina

doi:10.1016/j.nucmedbio.2015.06.006

Cited by 40 publications

(53 citation statements)

References 30 publications

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“…Although kidney uptake is prominent for both compounds, the tumor-to-kidney ratios for CTT1403 are 2-4 fold higher than CTT1401 at all time points. This is consistent with literature data showing that addition of albumin-binding entity comes with the benefit of enhanced tumor:kidney ratio 33, 39, 64. The biodistribution of CTT1403 showed a tumor:kidney ratio of ~1 at time points longer than 4 h. For comparison, for the 211 At-labeled urea-based agent, the kidney uptake was 3-4 fold greater than that of the tumor, and long-term toxicity studies confirmed that the high kidney uptake was dose-limiting 63.…”

Section: Discussionsupporting

confidence: 93%

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¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

Choy¹,

Ling²,

Geruntho³

et al. 2017

Theranostics

104

171

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Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. While both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.

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Section: Discussionsupporting

confidence: 93%

“…This would likely then decrease the amount of 177 Lu-labeled PSMA agent required for efficacy and decrease toxicity to normal tissues. There is precedence for this with the 177 Lu-cm09, which showed decreased folate receptor-mediated kidney uptake and lower kidney dose compared to the same compound minus an albumin binding domain 39.…”

Section: Discussionmentioning

confidence: 99%

¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

Choy¹,

Ling²,

Geruntho³

et al. 2017

Theranostics

104

171

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“…In a previous study, in which the long-term damage of kidneys was investigated, a significant reduction in renal size was reported at five to eight months after treatment with 177 Lu-folate [22]. A kidney dose of 23 Gy resulted in an absolute kidney weight reduction of 23% as compared to control mice after eight months.…”

Section: Resultsmentioning

confidence: 99%

“…Groups of six mice received either only saline or 177 Lu-folate at different activities (10 MBq, 20 MBq and 30 MBq), corresponding to mean absorbed kidney doses of 23 Gy, 46 Gy and 69 Gy, respectively (Table 2) [22]. The body weight and general health status of mice were monitored over the whole study period.…”

Section: Resultsmentioning

confidence: 99%

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

et al. 2017

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Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage.

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“…Trüssel et al (22) and Dumelin et al (23) worked extensively to identify albumin-binding molecules by screening chemical libraries; one such molecule was 4-(p-iodophenyl)butanoic acid, which was evaluated by Müller et al for use as a means to improve a folate receptor-binding tracer or radiotherapy agent (24). Subsequent labeling with 177 Lu for radiotherapy of tumor-bearing mice produced promising results (24,25). Although Müller et al did not explicitly mention that their modifications could be used to label other biomolecules, this use seemed to be chemically feasible.…”

Section: Discussionmentioning

confidence: 99%

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

et al. 2016

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One of the major design considerations for a drug is its pharmacokinetics in the blood. A drug with a short half-life in the blood is less available at a target organ. Such a limitation dictates treatment with either high doses or more frequent doses, both of which may increase the likelihood of undesirable side effects. To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we developed an "add-on" molecule that contains 3 groups: a truncated Evans blue dye molecule that binds to albumin with a low micromolar affinity and provides a prolonged half-life in the blood; a metal chelate that allows radiolabeling for imaging and radiotherapy; and maleimide for easy conjugation to drug molecules. Methods: The truncated Evans blue molecule was conjugated with the chelator NOTA or DOTA, and the resulting conjugate was denoted as NMEB or DMEB, respectively. As a proof of concept, we coupled NMEB and DMEB to c(RGDfK), which is a small cyclic arginine-glycine-aspartic acid (RGD) peptide, for targeting integrin a v b 3 . NMEB and DMEB were radiolabeled with 64 Cu and 90 Y, respectively, and tested in xenograft models. Results: The resulting radiolabeled conjugates showed a prolonged circulation half-life and enhanced tumor accumulation in integrin a v b 3 -expressing tumors. Tumor uptake was markedly improved over that with NOTA-or DOTA-conjugated c(RGDfK). Tumor radiotherapy experiments in mice with 90 Y-DMEB-RGD showed promising results; existing tumors were eliminated. Conclusion: Conjugation of our novel add-on molecule, NMEB or DMEB, to potential tracers or therapeutic agents improved blood half-life and tumor uptake and could transform such agents into theranostic entities. Thegoalofdr ug development is to achieve high activity and specificity for a desired biologic target. However, many potential pharmaceuticals that meet these criteria fail as therapeutics because of unfavorable pharmacokinetics, in particular, rapid blood clearance, which prevents the achievement of therapeutic concentrations. For some drugs, the administration of large or frequently repeated doses is required to achieve and maintain therapeutic levels (1) but can, in turn, increase the probability of undesired side effects. One chemical modification that delays the rate of drug clearance and has been effective for some drugs is the addition of polyethylene glycol (PEG) (2). However, recent studies showed that PEGylation of drugs has disadvantages, including immunogenicity caused by the development of anti-PEG antibodies, heterogeneity of the PEGylated drugs, and decreased biologic activity and bioavailability of the drugs (1,3).To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we made use of molecules with a high affinity for albumin. We previously developed a radiolabeled truncated derivative of Evans blue (EB) that allowed imaging of the blood volume because of the affinity of EB for albumin (4). This result encouraged us to e...

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Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy

Cited by 40 publications

References 30 publications

¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

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Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy

Cited by 40 publications

References 30 publications

177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

Contact Info

Product

Resources

About

¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice