Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Tschan, Viviane J.; Borgna, Francesca; Busslinger, Sarah D.; Stirn, Martina; Rodríguez, Josep M. Monné; Bernhardt, Peter; Schibli, Roger; Müller, Cristina

doi:10.1007/s00259-022-05837-2

Cited by 21 publications

(23 citation statements)

References 35 publications

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“…Cell uptake and internalization of [ 225 Ac]Ac-SibuDAB (59 ± 1% and 25 ± 5%, respectively) into PC-3 PIP tumor cells was in the same range as for [ 225 Ac]Ac-PSMA-617 (63 ± 5% and 19 ± 3%, respectively) and their respective 177 Lu-labeled counterparts [ 17 , 24 ] after a 4 h-incubation period ( p > 0.05) ( Figure 2 A, Figure S1 ). PSMA-mediated uptake was confirmed by the fact that the uptake of both radioligands into PSMA-negative PC-3 flu cells was <1%.…”

Section: Resultsmentioning

confidence: 83%

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617

Busslinger

Tschan

Richard³

et al. 2022

Cancers

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In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.

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Section: Resultsmentioning

confidence: 83%

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617

Busslinger

Tschan

Richard³

et al. 2022

Cancers

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“…Earlier, 177 Lu-dotatate has been approved by the FDA for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). It has been shown to inhibit SSTR2-positive tumors and has emerged as a powerful alternative to octreotide in the treatment of neuroendocrine tumors. , 177 Lu has a short range of β-rays and little effect on normal tissues while targeting tumors. − We speculate, however, that α-rays have a shorter range and theoretically cause less radiation damage to normal tissues around tumors under the premise of precise targeting. Since β-particle-labeled somatostatin analogues have achieved better therapeutic results, α-particle ones should be more effective.…”

Section: Discussionmentioning

confidence: 99%

Effective Treatment of SSTR2-Positive Small Cell Lung Cancer Using ²¹¹At-Containing Targeted α-Particle Therapy Agent Which Promotes Endogenous Antitumor Immune Response

Qin,

Yang,

Zhang

et al. 2023

Mol. Pharmaceutics

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Small cell lung cancer (SCLC) is a neuroendocrine tumor with a high degree of malignancy. Due to limited treatment options, patients with SCLC have a poor prognosis. We have found, however, that intravenously administered octreotide (Oct) armed with astatine-211 ([ 211 At]SAB-Oct) is effective against a somatostatin receptor 2 (SSTR2)-positive SCLC tumor in SCLC tumor-bearing BALB/c nude mice. In biodistribution analysis, [ 211 At]SAB-Oct achieved the highest concentration in the SCLC tumors up to 3 h after injection as time proceeded. A single intravenous injection of [ 211 At]SAB-Oct (370 kBq) was sufficient to suppress SSTR2-positive SCLC tumor growth in treated mice by inducing DNA double-strand breaks. Additionally, a multitreatment course (370 kBq followed by twice doses of 370 kBq for a total of 1110 kBq) inhibited the growth of the tumor compared to the untreated control group without significant off-target toxicity. Surprisingly, we found that [ 211 At]SAB-Oct could up-regulate the expressions of calreticulin and major histocompatibility complex I (MHC-I) on the tumor cell membrane surface, suggesting that αparticle internal irradiation may activate an endogenous antitumor immune response through the regulation of immune cells in the tumor microenvironment, which could synergically enhance the efficacy of immunotherapy. We conclude that [ 211 At]SAB-Oct is a potential new therapeutic option for SSTR2-positive SCLC.

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“…Determining efficacy and safety is critical during the initial phases of drugs discovery and development, and ultimately for approval and commercialization. Some of the drugs approved by the FDA or EMA, and listed above, were tested in rodent models (92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102).…”

Section: Current Therapies For Prostate Cancermentioning

confidence: 99%

Evolution of Models of Prostate Cancer: Their Contribution to Current Therapies

et al. 2022

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Prostate cancer (PCa) is among the most frequent cancers worldwide. Nowadays, several therapeutic strategies are available for PCa treatment, namely chemotherapy, immunotherapy, radiotherapy, and hormonal therapy. Despite existing therapeutic approaches, in vitro and in vivo models are essential to better understand cancer development and search for more effective therapies, with a positive impact in cancer patient survival and quality of life. Among several models available, the rat model is the one most frequently used, since it shares anatomical, physiological, pathological, and behavioral features with humans. Animal models can be classified as: spontaneous, chemically-induced; hormonally-induced; implantation of cancer cell lines obtained from humans or from the same species, in the place of disease development or in a different place; and genetically-modified models. The chemically-induced models are among the most frequently used for PCa research. This manuscript provides a comprehensive overview of PCa models, presenting their application, advantages, and disadvantages, and their importance for the development of current therapies for prostate cancer.Prostate cancer (PCa) is among the most common cancers in men. In 2020, PCa was the third most diagnosed neoplasia, with 1,414,259 new cases (7.3% of all cancer cases) and 375,304 deaths (1).During the last decades, PCa therapy has seen a remarkable evolution in many sectors, namely chemotherapy, immunotherapy, radiotherapy, and hormonal therapy. New precision medicine strategies and treatments are also suffering massive developments nowadays, also for PCa management, namely new proteomic and genomic technologies, non-coding RNA therapeutics or gene editing technologies (2).Over the decades, different animal and non-animal models have been used to describe PCa morphologically, evaluate its development, set up prognostics, and develop more successful and globally used treatments.This work aimed to review the different models used in PCa research among the decades and highlight their significant contribution to the discovery of various therapies regularly used nowadays to treat men with PCa and significantly improve their lives. Prostate Cancer: An OverviewPCa is a neoplasia that results from the uncontrolled growth of the prostatic gland cells. Almost all PCas are adenocarcinomas. However, histologically, two types can be considered: acinar adenocarcinoma and non-acinar carcinoma. PCa acinar 323

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Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Cited by 21 publications

References 35 publications

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617

Effective Treatment of SSTR2-Positive Small Cell Lung Cancer Using ²¹¹At-Containing Targeted α-Particle Therapy Agent Which Promotes Endogenous Antitumor Immune Response

Evolution of Models of Prostate Cancer: Their Contribution to Current Therapies

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Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Cited by 21 publications

References 35 publications

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617

Effective Treatment of SSTR2-Positive Small Cell Lung Cancer Using 211At-Containing Targeted α-Particle Therapy Agent Which Promotes Endogenous Antitumor Immune Response

Evolution of Models of Prostate Cancer: Their Contribution to Current Therapies

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Effective Treatment of SSTR2-Positive Small Cell Lung Cancer Using ²¹¹At-Containing Targeted α-Particle Therapy Agent Which Promotes Endogenous Antitumor Immune Response