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Survival of tumor and normal cells upon targeting with electron-emitting radionuclides.

ABSTRACT: Previous studies have shown that the mean absorbed dose to a tissue element may not be a suitable quantity for correlating with the biological response of cells in that tissue element. Cell survival can depend strongly on the distribution of radioactivity at the cellular and multicellular levels. Furthermore, when cellular absorbed doses are examined, the cross-dose from neighbor cells can be less radiotoxic than the self-dose component. To better understand how the nonuniformity of activity among cells can affect the dose response, a computer model of a 3D tissue culture was previously constructed and showed that activity distribution among cells is significantly more relevant than the mean absorbed dose for low-energy-electron emitters. The present work greatly expands upon those findings.In the present study, we used this same computer model but restricted the number of labeled cells to a fraction of the whole cell population (50%, 10%, and 1%, respectively). The labeled cells were randomly distributed among the whole cell population.While the activity distribution is an important factor in determining the tissue response for low-energy-electron emitters, the fraction of labeled cells has an even more pronounced effect on survival response. For all electron energies studied, reducing the percentage of cells labeled significantly increases the surviving fraction of the whole population.This study provides abundant information on killing tumor and normal cells under some conditions relevant to targeted radionuclide therapy of isolated tumor cells and micrometastases. The percentage of cells labeled, activity distribution among the labeled cells, and electron energy play key roles in determining their response. Most importantly, and not previously demonstrated, lognormal activity distributions can have a profound impact on the response of the tumor cells even when the radionuclide emits high-energy electrons.

SUBMITTER: Rajon D

PROVIDER: S-EPMC3543371 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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Project description:Pretargeted radioimmunotherapy (PRIT) with the ?-emitting radionuclide 177Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using ?-emitting radionuclides such as 213Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of 213Bi and 177Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213Bi-IMP288 were compared with those of 177Lu-IMP288. Tumor targeting of 213Bi-IMP288 and 177Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of 213Bi-IMP288 (6, 12, or 17 MBq) and 177Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of 177Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of 213Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g). 213Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of 213Bi-IMP288 was comparable to that of 177Lu-IMP288. Mice treated with a single dose of 213Bi-IMP288 or 177Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq 213Bi-IMP288, 12 MBq 213Bi-IMP288, and 60 MBq 177Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq 213Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: To our knowledge, this study shows for the first time that PRIT with TF2 and 213Bi-IMP288 is feasible and at least as effective as 177Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity.

Project description:Magnetic nanoparticles are well known to possess chemically active surfaces and large surface areas that can be employed to extract a range of ions from aqueous solutions. Additionally, their superparamagnetic properties provide a convenient means for bulk collection of the material from solution after the targeted ions have been adsorbed. Herein, two nanoscale amphoteric metal oxides, each possessing useful magnetic attributes, were evaluated for their ability to collect trace levels of a chemically diverse range of alpha emitting radioactive isotopes (polonium (Po), radium (Ra), uranium (U), and americium (Am)) from a wide range of aqueous solutions. The nanomaterials include commercially available magnetite (Fe3O4) and magnetite modified to incorporate manganese (Mn) into the crystal structure. The chemical stability of these nanomaterials was evaluated in Hanford Site, WA ground water between the natural pH (~8) and pH 1. Whereas the magnetite was observed to have good stability over the pH range, the Mn-doped material was observed to leach Mn at low pH. The materials were evaluated in parallel to characterize their uptake performance of the alpha-emitting radionuclide spikes from ground water across a range of pH (from ~8 down to 2). In addition, radiotracer uptake experiments were performed on Columbia River water, seawater, and human urine at their natural pH and at pH 2. Despite the observed leaching of Mn from the Mn-doped nanomaterial in the lower pH range, it exhibited generally superior analyte extraction performance compared to the magnetite, and analyte uptake was observed across a broader pH range. We show that the uptake behavior of the various radiotracers on these two materials at different pH levels can generally be explained by the amphoteric nature of the nanoparticle surfaces. Finally, the rate of sorption of the radiotracers on the two materials in unacidified ground water was evaluated. The uptake curves generally indicate that equilibrium is obtained within a few minutes, which is attributed to the high surface areas of the nanomaterials and the high level of dispersion in the liquids. Overall, the results indicate that these nanomaterials may have the potential to be employed for a range of applications to extract radionuclides from aqueous solutions.

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Survival of tumor and normal cells upon targeting with electron-emitting radionuclides.

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