Calculated and TLD-based absorbed dose estimates for I-131-labeled 3F8 monoclonal antibody in a human neuroblastoma xenograft nude mouse model.
ABSTRACT Preclinical evaluation of the therapeutic potential of radiolabeled antibodies is commonly performed in a xenografted nude mouse model. To assess therapeutic efficacy it is important to estimate the absorbed dose to the tumor and normal tissues of the nude mouse. The current study was designed to accurately measure radiation does to human neuroblastoma xenografts and normal organs in nude mice treated with I-131-labeled 3F8 monoclonal antibody (MoAb) against disialoganglioside GD2 antigen. Absorbed dose estimates were obtained using two different approaches: (1) measurement with teflon-imbedded CaSO4:Dy mini-thermoluminescent dosimeters (TLDs) and (2) calculations using mouse S-factors. The calculated total dose to tumor one week after i.v. injection of the 50 microCi I-131-3F8 MoAb was 604 cGy. The corresponding decay corrected and not corrected TLD measurements were 109 +/- 9 and 48.7 +/- 3.4 cGy respectively. The calculated to TLD-derived dose ratios for tumor ranged from 6.1 at 24 h to 5.5 at 1 week. The light output fading rate was found to depend upon the tissue type within which the TLDs were implanted. The decay rate in tumor, muscle, subcutaneous tissue and in vitro, were 9.5, 5.0, 3.7 and 0.67% per day, respectively. We have demonstrated that the type of tissue in which the TLD was implanted strongly influenced the in vivo decay of light output. Even with decay correction, a significant discrepancy was observed between MIRD-based calculated and CaSO4:Dy mini-TLD measured absorbed doses. Batch dependence, pH of the tumor or other variables associated with TLDs which are not as yet well known may account for this discrepancy.
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ABSTRACT: To optimize the efficacy of radioimmunotherapy (RIT), the ideal antibody-radioisotope combinations should be used to deliver the highest tumor and the lowest normal tissue doses. In a mouse model, tumor and critical organ-absorbed doses delivered by different radioimmunoconjugates were calculated and compared. We used a Medical Internal Radiation Dosimetry (MIRD)-style mouse dosimetry model that incorporates cross-organ beta doses to make refined estimates of the radiation absorbed dose to tissues. Biodistribution data from neuroblastoma xenografted nude mice were used to estimate tumor, organ and bone marrow absorbed dose values for 90Y-3F8, 131I-3F8 and 131I-F(ab')2 fragments. Immunoreactive fractions of the radiolabeled antibodies were comparable. Although tumor uptake of the radioiodinated and radiometal labeled 3F8 was much higher than that of the radioiodinated F(ab')2 fragments (maximum percent injected dose per gram values were 39.4, 33.2 and 20.1 for 131I-3F8, 90Y-3F8 and 131I-F(ab')2, respectively), tumor to nontumor ratios were higher for radioiodinated fragments (with the exception of tumor to kidney ratio). For the minimum tumor dose necessary for complete ablation, the bone marrow received 195, 278 and 401 cGy for 131I-F(ab')2, 131I-3F8 and 90Y-3F8, respectively. Tumor doses were 50.1, 232 and 992 cGy/MBq for 131I-F(ab')2, 131I-3F8 and 90Y-3F8, respectively. Tumor to bone marrow dose, which is defined as the therapeutic index, was 21.5, 14.7 and 10.4 for 131I-F(ab')2, 131I-3F8 and 90Y-3F8. 131I-F(ab')2 fragments produced the highest therapeutic index but also the lowest tumor dose for radioimmunotherapy. Radiometal conjugated IgG produced the highest tumor dose but also the lowest therapeutic index.Nuclear Medicine and Biology 02/1996; 23(1):1-8. DOI:10.1016/0969-8051(95)02001-2 · 2.41 Impact Factor
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ABSTRACT: A method of producing CaSO4:Dy thermoluminescent mini-dosimeters was reported in 1986 by B W Wessels for determination of the in vivo absorbed dose in radioimmunotherapy, a field in which absorbed dose gradients are important. These dosimeters, which undergo dissolution when used in a liquid environment, showed a sensitivity loss of up to 30% after 4 days of immersion in our tests. Moreover, several studies have shown that biocompatibility problems can occur during in vivo studies in animals. This paper describes the production and testing of a new type of thermoluminescent mini-dosimeter obtained by microextrusion of a mixture of LiF:Mg,Cu,P polypropylene and plastic adjuvants. These dosimeters, in the form of long 400 microm diameter filaments, can be cut to the desired length. The production process allows an LiF:Mg,Cu,P load of up to 50%. Results obtained in external irradiation indicate that these new miniature LiF:Mg,Cu,P dosimeters have good sensitivity (about 1.6 times that of CaSO4:Dy mini-TLDs), homogeneous response within a production batch (mean +/-4%), response stability in water (0.7% of variation in sensitivity after 2 weeks of immersion) and stability in aqueous solutions at different pH. LiF:Mg,Cu,P mini-dosimeters appear to be highly promising for internal dosimetry, and evaluation is in progress in animals.Physics in Medicine and Biology 03/2000; 45(2):479-94. DOI:10.1088/0031-9155/45/2/315 · 2.92 Impact Factor
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ABSTRACT: Preclinical evaluation of new radiopharmaceuticals is performed in animal systems before testing is started in humans. These studies, often performed in murine or other rodent models, are important in understanding the relationship between absorbed dose and response, which can be translated to preclinical results for humans. In performing such calculations, either electrons are assumed to deposit all of their energy locally or idealized models of mouse anatomy are used to determine absorbed fractions. Photon contributions are generally considered negligible. To improve the accuracy of such absorbed dose calculations, mouse-specific S factors for (131)I, (153)Sm, (32)P, (188)Re, and (90)Y have been generated, and the photon and electron portions have been tabulated separately. Absorbed fractions for 5 monoenergetic electrons, ranging in energy from 0.5 to 2 MeV, are also provided. Female athymic mouse MR images were obtained on a 4.7-T MRI device. Fifteen T1-weighted, 1.5-mm-thick slices (0.5-mm gap) were collected. Using a previously developed software package, 3-dimensional Internal Dosimetry (3D-ID), organ contours were drawn to obtain a 3-dimensional representation of liver, kidneys, and spleen. Using a point-kernel convolution, the mean absorbed dose to each organ from the individual contributions of each source organ were calculated. S factor equivalent values were obtained by assuming a uniform distribution of radioactivity in each organ. Results were validated by comparing 3D-ID generated electron S factors for different-sized spheres with published data. Depending on matrix size, sphere size, and radionuclide, 1% (256(2) matrix) to 18% (64(2) matrix) agreement was obtained. S factor values were calculated for liver, spleen, and right and left kidneys. Cross-organ electron-absorbed fractions of up to 0.33 were obtained (e.g., (90)Y right kidney to liver). Comparisons between S factor values and values obtained assuming complete absorption of electron energy yielded differences of more than 190% ((90)Y spleen self-dose). The effect of cross-organ and self-absorbed dose is dependent on emission energy and organ geometry and should be considered in murine dose estimates. The approach used to generate these S factors is applicable to other animal systems and also to nonuniform activity distributions that may be obtained by small-animal SPECT or PET imaging or by quantitative autoradiography.Journal of Nuclear Medicine 06/2003; 44(5):784-91. · 5.56 Impact Factor