Mathematical Modeling of <i>In Vivo</i> Alpha Particle Generators and Chelator Stability

Zaid, Nouran; Kletting, Peter; Beer, Ambros; Stallons, Tania A. Rozgaja; Torgue, Julien; Glatting, Gerhard

doi:10.1089/cbr.2020.4112

Cited by 5 publications

(5 citation statements)

References 26 publications

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“…In addition, optimal values for global pharmacokinetic parameters, such as ligand affinities, internalization and sorting rates, can be simulated using the 212 Pb-SSTA-PBPK model for newly developed in vivo alpha particle generators in α-PRRT. The model can be used to study the effect of using different chelators with different dissociation fractions of 212 Bi-chelator complexes after beta decay of conjugated 212 Pb [23].…”

Section: Discussionmentioning

confidence: 99%

“…The parameters of the 212 Pb-SSTA-PBPK model are classified into mice-specific and 212 Pb-SSTA-specific parameters with values taken from literature (Supplementary Material Table S1) [4,16,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Briefly, the main mice-specific parameters considered in the model are blood flow, tissue volumes, relevant volumes of tissue compartments (vascular, interstitial, early endosomes and sorting (late endosomes) compartments) and SSTR2 expression on cell membranes.…”

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

“…Relevant biological mechanisms of 212 Pb-SSTA (diffusion, SSTR2-specific and non-specific binding, internalization, recycling, sorting and excretion) are included in the model. In addition, the model takes into account the physicochemical properties of 212 Pb-SSTA, such as physical decay rates and the chemical stability of the 212 Bi-chelator complexes after beta decay of conjugated 212 Pb [23]. The distribution of 212 Pb-SSTA and unlabeled SSTA is described using two similar systems sharing the same physiological parameter values [16].…”

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

“…The two systems are linked by the competition of 212 Pb-SSTA and unlabeled SSTA for free binding sites and the physical decay rates as shown in Figure 2. Each compartment in the 212 Pb-SSTA-PBPK model represents the in vivo alpha particle generator model described before [23]. The biodistribution of free 212 Bi is described by integrating a PBPK model for free 212 Bi into the 212 Pb-SSTA-PBPK model [29].…”

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

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A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

et al. 2021

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In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the efficacy and safety of α-PRRT. A murine whole-body physiologically based pharmacokinetic (PBPK) model was developed for 212Pb-labeled somatostatin analogs (212Pb-SSTA). The model describes pharmacokinetics of 212Pb-SSTA and its decay products, including specific and non-specific glomerular and tubular uptake. Absorbed dose coefficients (ADC) were calculated for bound and unbound radiolabeled SSTA and its decay products. Kidneys received the highest ADC (134 Gy/MBq) among non-target tissues. The alpha-emitting 212Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on 212Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on 212Bi-SSTA for a given kidneys absorbed dose. In both approaches, the energies released in the glomeruli and proximal tubules account for 54% and 46%, respectively, of the total energy absorbed in kidneys. The 212Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

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A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

et al. 2021

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“…DOTA and TCMC are derived from the aza-crown ether cyclen, with four carboxymethyl groups on DOTA and four acetamide groups that decorate the tetraaza core. It has been reported that the electron conversion occurring with the β decay of 212 Pb results in a hyperoxidized state of 212 Bi that potentially breaks the 212 Bi-chelator bonds, causing release of free 212 Bi 3+ from these chelators [ 22 , 31 ]. For example, previous studies reported that approximately 36% of 212 Bi 3+ was released from a DOTA chelator [ 23 ] and 16% of 212 Bi 3+ was ejected from the TCMC chelator in an anti-CD37 radioimmunoconjugate [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of a Lead Specific Chelator (PSC) Conjugated to Radiopeptides for 203Pb and 212Pb-Based Theranostics

Baumhover

Liu

et al. 2023

Pharmaceutics

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203Pb and 212Pb have emerged as promising theranostic isotopes for image-guided α-particle radionuclide therapy for cancers. Here, we report a cyclen-based Pb specific chelator (PSC) that is conjugated to tyr3-octreotide via a PEG2 linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified 212Pb at 25 °C and also to 212Bi at 80 °C. Efficient radiolabeling of mixed 212Pb and 212Bi in PSC-PEG-T was also observed at 80 °C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [203Pb]Pb-PSC-PEG-T for 72 h and [212Bi]Bi-PSC-PEG-T for 5 h. Stable [212Pb]Pb-PSC-PEG-T and progeny [212Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [203Pb]Pb-PSC-PEG-T for 55 h and [212Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [212Pb]Pb-PSC-PEG-T in tumor-free CD-1 Elite mice and athymic mice bearing AR42J xenografts revealed rapid tumor accumulation, excellent tumor retention and fast renal clearance of both 212Pb and 212Bi, with no in vivo redistribution of progeny 212Bi. Single-photon emission computed tomography (SPECT) imaging of [203Pb]Pb-PSC-PEG-T and [212Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical 203Pb/212Pb radionuclide pair.

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A Whole-Body Physiologically Based Pharmacokinetic Model for Alpha Particle Emitting Bismuth in Rats

Zaid

Kletting

Winter

et al. 2022

Cancer Biotherapy and Radiopharmaceuticals

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Mathematical Modeling of In Vivo Alpha Particle Generators and Chelator Stability

Cited by 5 publications

References 26 publications

A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

Preclinical Evaluation of a Lead Specific Chelator (PSC) Conjugated to Radiopeptides for 203Pb and 212Pb-Based Theranostics

A Whole-Body Physiologically Based Pharmacokinetic Model for Alpha Particle Emitting Bismuth in Rats

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