Targeted alpha therapy with 212Pb or 225Ac: Change in RBE from daughter migration

Ackerman, Nicole; Rosales, Liset de la Fuente; Falzone, Nadia; Vallis, Katherine A.; Bernal, Mario A.

doi:10.1016/j.ejmp.2018.05.020

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…Two decay paths can then be followed by 212 Bi that will lead to the emission of α‐particles of 6.1 and 8.8 MeV with respective probabilities of 36 and 64%. These particles have respective projected ranges of 50 and 91 µm in water and LET reaching 226 keV/µm along their path . The whole‐decay chain of 212 Pb also generates the emission of β‐particles, photons (γ‐ and x‐rays) and Auger electrons.…”

Section: Methodsmentioning

confidence: 99%

“…These particles have respective projected ranges of 50 and 91 µm in water and LET reaching 226 keV/µm along their path. 18 The whole-decay chain of 212 Pb also generates the emission of bparticles, photons (c-and x-rays) and Auger electrons. The electrons emitted during the decay chain (b-particles, Auger, or secondary electrons produced by photons) present LET values below 2.3 keV/µm in all cases.…”

Section: Bmentioning

confidence: 99%

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Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy

et al. 2020

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Purpose Targeted alpha therapy (TAT) takes advantage of the short‐range and high‐linear energy transfer of α‐particles and is increasingly used, especially for the treatment of metastatic lesions. Nevertheless, dosimetry of α‐emitters is challenging for the very same reasons, even for in vitro experiments. Assumptions, such as the uniformity of the distribution of radionuclides in the culture medium, are commonly made, which could have a profound impact on dose calculations. In this study we measured the spatial distribution of α‐emitting 212Pb coupled to an anti‐VCAM‐1 antibody (212Pb‐αVCAM‐1) and its evolution over time in the context of in vitro irradiations. Methods Two experimental setups were implemented without cells to measure α‐particle count rates and energy spectra in culture medium containing 15 kBq of 212Pb‐α‐VCAM‐1. Silicon detectors were placed above and below cell culture dishes for 20 h. One of the dishes had a 2.5‐µm‐thick mylar‐base allowing easy detection of the α‐particles. Monte Carlo simulations were performed to analyze experimental spectra. Experimental setups were modeled and α‐energy spectra were simulated in the silicon detectors for different decay positions in the culture medium. Simulated spectra were then used to deconvolute experimental spectra to determine the spatial distribution of 212Pb‐αVCAM‐1 in the medium. This distribution was finally used to calculate the dose deposition in cell culture experiments. Results Experimental count rates and energy spectra showed differences in measurements taken at the top and the bottom of dishes and temporal variations that did not follow 212Pb decay. The radionuclide spatial distribution was shown to be composed of a uniform distribution and concentration gradients at the top and the bottom, which were subjected to temporal variations that may be explained by gravity and electrostatic attraction. The absorbed dose in cells calculated from this distribution was compared with the dose expected for a uniform and static distribution and found to be 1.75 times higher, which is highly significant to interpret biological observations. Conclusions This study demonstrated that accurate dosimetry of α‐emitters requires the experimental determination of radionuclide spatial and temporal distribution and highlighted that in vitro assessment of dose for TAT cannot only rely on a uniform distribution of activity in the culture medium. The reliability and reproducibility of future experiments should benefit from specifically developed dosimetry tools and methods.

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Section: Methodsmentioning

confidence: 99%

Section: Bmentioning

confidence: 99%

Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy

et al. 2020

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“…An intriguing phenomenon for TRT with α-emitters is dissociation of the radionuclide from the chelating group upon decay, either due to the altered coordination chemistry of the daughter elements in the decay cascade or the high recoil energy generated upon the emission of α-particles. The recoiled daughter nuclei are often themselves α-emitters and this phenomenon may lead to toxicity or desired cytotoxic effect at the daughter decay sites as some daughter nuclei are long-lived and able to move away from the targeted cells before they decay ( Dekempeneer et al, 2016 ; Ackerman et al, 2018 ). Furthermore, these recoiled daughter nuclei have a LET that is at least 10 times greater than the ejected α-particles and may contribute significantly to ionization events in the immediate vicinity of the decay site ( Kozempel et al, 2018 ).…”

Section: Radiobiology Of Targeted Radionuclide Therapymentioning

confidence: 99%

Subcellular Targeting of Theranostic Radionuclides

et al. 2018

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The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit β particles have thus far dominated the field of targeted radionuclide therapy (TRT), mainly because the longer range (μm–mm track length) of these particles offsets the heterogeneous expression of the molecular target. Shorter range (nm–μm track length) α- and Auger electron (AE)-emitting radionuclides on the other hand provide high ionization densities at the site of decay which could overcome much of the toxicity associated with β-emitters. Given that there is a growing body of evidence that other sensitive sites besides the DNA, such as the cell membrane and mitochondria, could be critical targets in TRT, improved techniques in detecting the subcellular distribution of these radionuclides are necessary, especially since many β-emitting radionuclides also emit AE. The successful development of TRT agents capable of homing to targets with subcellular precision demands the parallel development of quantitative assays for evaluation of spatial distribution of radionuclides in the nm–μm range. In this review, the status of research directed at subcellular targeting of radionuclide theranostics and the methods for imaging and quantification of radionuclide localization at the nanoscale are described.

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“…The radiopharmaceuticals must be sufficiently stable compounds both in vitro and in vivo. The nuclear recoil energy of about 100-200 keV from α-decay is sufficient to break chemical bonds between the targeting moiety and the radionuclide, which can lead to circulating carrier-free daughter radionuclides in blood [114,[118][119][120][121]. The decay of the parent radionuclides 212 Pb/ 212 Bi, 225 Ac, 223 Ra, and 227 Th form multiple α-emitting daughter radionuclides ( Figure 2).…”

Section: Radionuclides Used For Psma-tatmentioning

confidence: 99%

“…The decay of the parent radionuclides 212 Pb/ 212 Bi, 225 Ac, 223 Ra, and 227 Th form multiple α-emitting daughter radionuclides ( Figure 2). The released daughter radionuclide can be retained inside the tumor and enhance the cytotoxic effect, but if the released daughter radionuclide has a long enough half-life, it can redistribute within the body and damage healthy tissues [118,120,122].…”

Section: Radionuclides Used For Psma-tatmentioning

confidence: 99%

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Juzeniene

Stenberg

Bruland

et al. 2021

Cancers

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Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β- therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.

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Targeted alpha therapy with 212Pb or 225Ac: Change in RBE from daughter migration

Cited by 16 publications

References 35 publications

Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy

Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy

Subcellular Targeting of Theranostic Radionuclides

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

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Targeted alpha therapy with 212Pb or 225Ac: Change in RBE from daughter migration

Cited by 16 publications

References 35 publications

Radionuclide spatial distribution and dose deposition for in vitro assessments of 212Pb‐αVCAM‐1 targeted alpha therapy

Radionuclide spatial distribution and dose deposition for in vitro assessments of 212Pb‐αVCAM‐1 targeted alpha therapy

Subcellular Targeting of Theranostic Radionuclides

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

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Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy

Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy