Therapeutic Radionuclides: Biophysical and Radiobiologic Principles

Kassis, Amin I.

doi:10.1053/j.semnuclmed.2008.05.002

Cited by 243 publications

(237 citation statements)

References 37 publications

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“…The b emitters such as 90 Y, 131 I, and 177 Lu are appropriate candidates for current systemic radionuclide therapy. Both 131 I and 177 Lu emit g radiation in addition to its b -particle, whereas 90 Y is a pure b -emitter (12). Recently, the promising therapeutic lowmolecular-weight compound 131 I-MIP-1095 was clinically investigated.…”

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confidence: 99%

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Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

et al. 2015

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Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversedphase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent 67/68 Ga and 177 Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K i ] 5 2.34 ± 2.94 nM on LNCaP; K i 5 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-tobackground contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.

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confidence: 99%

“…Endoradiotherapy with the aforementioned radiometals, however, bear a high potential to improve the clinical situation. For example, 177 Lu presents a lower proportion of g radiation, which would result in a reduced stay in the hospital and lower hemotoxicity in comparison to 131 I (12).…”

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Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

et al. 2015

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“…With several of these folate-based drug conjugates, respectable anticancer effects were achieved in preclinical (13)(14)(15)(16) and clinical studies (17). If b 2 -particle-emitting radioisotopes are used for targeted therapy, cancer cells are irradiated not only by decays taking place at or within the targeted cells but also by decays in neighboring or distant cells by the so-called cross-fire effect (18). In targeted radionuclide therapy, it is not necessary therefore to reach every cell within the tumor as is the case for targeted chemotherapy (19,20).…”

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DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted ¹⁷⁷Lu-Radionuclide Tumor Therapy in Mice

et al. 2012

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The folate receptor (FR) has proven a valuable target for nuclear imaging using folic acid radioconjugates. However, using folatebased radiopharmaceuticals for therapy has long been regarded as an unattainable goal because of their considerable renal accumulation. Herein, we present a novel strategy in which a DOTA-folate conjugate with an albumin-binding entity (cm09) was designed with the aim of prolonging circulation in the blood and therewith potentially improving tumor-to-kidney ratios. Methods: The folate conjugate cm09 was radiolabeled with 177 LuCl 3 , and stability experiments were performed in plasma. Cell uptake studies were performed on FR-positive KB tumor cells, and an ultrafiltration assay was used to determine the plasma protein-binding properties of 177 Lu-cm09. In vivo, 177 Lu-cm09 was tested in KB tumor-bearing mice using SPECT/CT. The therapeutic anticancer effect of 177 Lu-cm09 (20 MBq) applied as a single injection or as fractionated injections was investigated in different groups of mice (n 5 5) by monitoring tumor size and the survival time of treated mice, compared with untreated controls. Results: Compound cm09 was radiolabeled at a specific activity of 40 MBq/nmol, a radiochemical yield of more than 98%, and a stability of more than 99% over 5 d in plasma. Ultrafiltration revealed significant binding of 177 Lu-cm09 to serum proteins (;91%) in plasma, compared with folate radioconjugate without an albumin-binding entity. Cell uptake and internalization of 177 Lu-cm09 was FR-specific and comparable to other folate radioconjugates. In vivo studies resulted in high tumor uptake (17.56 percentage injected dose per gram [%ID/g] at 4 h after injection), which was almost completely retained for at least 72 h. Renal accumulation was significantly reduced (28 % ID/g at 4 h after injection), compared with folate conjugates that lack an albumin-binding entity (;70 %ID/g at 4 h after injection). These circumstances enabled SPECT imaging of excellent quality. Radionuclide therapy (1 · 20 MBq) revealed complete remission of tumors in 4 of 5 cases and a significantly prolonged survival time, compared with untreated controls. Conclusion: The modification of a folate radioconjugate with an albuminbinding entity resulted in a significant increase of the tumor-tokidney ratio of radioactivity, enabling for the first time, to our knowledge, the preclinical application of folic acid-targeted radionuclide therapy in mice.

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“…However, radiolabeled molecules able to selectively target tumor cells mostly lead to nonuniform activity distributions (5)(6)(7)(8)(9). A way to counterbalance the effects of tumor cell heterogeneity and poor penetration capabilities of radionuclide carriers was found in the use of penetrating beta emitters (10,11). Nonetheless, energy deposition of long-range beta electrons affects healthy cells located in the proximity of the target.…”

Section: The Original Mird Formalism Of Cellular S-valuesmentioning

confidence: 99%

The COOLER Code: A Novel Analytical Approach to Calculate Subcellular Energy Deposition by Internal Electron Emitters

et al. 2017

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Therapeutic Radionuclides: Biophysical and Radiobiologic Principles

Cited by 243 publications

References 37 publications

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted ¹⁷⁷Lu-Radionuclide Tumor Therapy in Mice

The COOLER Code: A Novel Analytical Approach to Calculate Subcellular Energy Deposition by Internal Electron Emitters

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Therapeutic Radionuclides: Biophysical and Radiobiologic Principles

Cited by 243 publications

References 37 publications

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted 177Lu-Radionuclide Tumor Therapy in Mice

The COOLER Code: A Novel Analytical Approach to Calculate Subcellular Energy Deposition by Internal Electron Emitters

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DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted ¹⁷⁷Lu-Radionuclide Tumor Therapy in Mice