Evaluation of the in vivo biodistribution of indium-111 and yttrium-88 labeled dendrimer-1B4M-DTPA and its conjugation with anti-tac monoclonal antibody

Hisataka Kobayashi, Chuanchu Wu, Meyoung-Kon Kim, Chang H. Paik, Jorge A. Carrasquillo, Martin W. Brechbiel

Research output: Contribution to journalArticle

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Abstract

We evaluated the in vivo biodistribution of indium- and yttrium-labeled second-generation polyamidoamine dendrimer (PAMAM) conjugated with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), a derivative of DTPA. In addition, we conjugated PAMAM-1B4M to humanized anti-Tac IgG (HuTac) and evaluated its in vitro and in vivo properties. PAMAM-1B4M was labeled with 111In at 37-48 MBq/mg (1.0-1.3 mCi/mg) or with 88Y at 3.7-4.8 MBq/mg (0.1-0.13 mCi/mg), and an aliquot of radiolabeled conjugate was saturated with the corresponding stable yttrium or indium. Nontumor-bearing nude mice were injected intravenously with 55.5-66.6 kBq (1.5-1.8 mCi) of 88Y-labeled PAMAM-1B4M or with 185 kBq (5 μCi) of 111In-labeled PAMAM-1B4M. The mice were then sacrificed at 15 min, 90 min, 1 day, and 4 days postinjection. Then the PAMAM-1B4M was conjugated with HuTac and labeled with 111In at 111-259 MBq/mg (3-7 mCi/mg). Another preparation of 111In-labeled HuTac-PAMAM-1B4M was saturated with stable indium. Immunoreactivity of both preparations and biodistribution in normal mice 1 h after injection and in ATAC4 and A431 tumorbearing mice 18 h after injection were evaluated and compared with those of 111In-labeled 1B4MHuTac. We noted significantly higher accumulations (p < 0.05) of 111In-labeled and 88Y-labeled unsaturated PAMAM-1B4M than saturated preparations in the liver, kidney, spleen, and bone at most time points. The whole-body clearance times of unsaturated preparations were significantly slower than those of saturated preparations at all time points, with the exception of 168 h for 111In-labeled PAMAM-1B4M. The saturated preparation of 111In-labeled HuTac-PAMAM-1B4M showed lower hepatic uptake (27 ± 2%ID/g) than the unsaturated (32 ± 2%ID/g), but greater than the HuTac1B4M control (10 ± 0%ID/g). The splenic uptake showed 15 ± 1, 38 ± 5, and 8 ± 1%ID/g for the saturated, unsaturated, and control, respectively. The biodistribution of the dendrimer conjugated HuTac in normal organs of tumor-bearing mice was similar to nontumor-bearing mice. Specific tumor (ATAC4) uptake was higher than that in nonspecific tumor (A431). In conclusion, we evaluated the biodistribution of radiolabeled PAMAM-1B4M. We noted high accumulation in the liver, kidney, and spleen, which significantly decreased when the chelates were saturated with the stable element. A similar phenomenon was observed between unsaturated and saturated 111In-labeled HuTac-PAMAM-1B4M, indicating that the PAMAM dendrimer had a detrimental effect on biodistribution.

Original languageEnglish
Pages (from-to)103-111
Number of pages9
JournalBioconjugate Chemistry
Volume10
Issue number1
DOIs
Publication statusPublished - 1999 Jan 1
Externally publishedYes

Fingerprint

Yttrium
Dendrimers
Indium
Monoclonal antibodies
Monoclonal Antibodies
Bearings (structural)
Tumors
2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid
Liver
Poly(amidoamine)
Spleen
Kidney
Neoplasms
Pentetic Acid
Injections

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Evaluation of the in vivo biodistribution of indium-111 and yttrium-88 labeled dendrimer-1B4M-DTPA and its conjugation with anti-tac monoclonal antibody. / Kobayashi, Hisataka; Wu, Chuanchu; Kim, Meyoung-Kon; Paik, Chang H.; Carrasquillo, Jorge A.; Brechbiel, Martin W.

In: Bioconjugate Chemistry, Vol. 10, No. 1, 01.01.1999, p. 103-111.

Research output: Contribution to journalArticle

Kobayashi, Hisataka ; Wu, Chuanchu ; Kim, Meyoung-Kon ; Paik, Chang H. ; Carrasquillo, Jorge A. ; Brechbiel, Martin W. / Evaluation of the in vivo biodistribution of indium-111 and yttrium-88 labeled dendrimer-1B4M-DTPA and its conjugation with anti-tac monoclonal antibody. In: Bioconjugate Chemistry. 1999 ; Vol. 10, No. 1. pp. 103-111.
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abstract = "We evaluated the in vivo biodistribution of indium- and yttrium-labeled second-generation polyamidoamine dendrimer (PAMAM) conjugated with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), a derivative of DTPA. In addition, we conjugated PAMAM-1B4M to humanized anti-Tac IgG (HuTac) and evaluated its in vitro and in vivo properties. PAMAM-1B4M was labeled with 111In at 37-48 MBq/mg (1.0-1.3 mCi/mg) or with 88Y at 3.7-4.8 MBq/mg (0.1-0.13 mCi/mg), and an aliquot of radiolabeled conjugate was saturated with the corresponding stable yttrium or indium. Nontumor-bearing nude mice were injected intravenously with 55.5-66.6 kBq (1.5-1.8 mCi) of 88Y-labeled PAMAM-1B4M or with 185 kBq (5 μCi) of 111In-labeled PAMAM-1B4M. The mice were then sacrificed at 15 min, 90 min, 1 day, and 4 days postinjection. Then the PAMAM-1B4M was conjugated with HuTac and labeled with 111In at 111-259 MBq/mg (3-7 mCi/mg). Another preparation of 111In-labeled HuTac-PAMAM-1B4M was saturated with stable indium. Immunoreactivity of both preparations and biodistribution in normal mice 1 h after injection and in ATAC4 and A431 tumorbearing mice 18 h after injection were evaluated and compared with those of 111In-labeled 1B4MHuTac. We noted significantly higher accumulations (p < 0.05) of 111In-labeled and 88Y-labeled unsaturated PAMAM-1B4M than saturated preparations in the liver, kidney, spleen, and bone at most time points. The whole-body clearance times of unsaturated preparations were significantly slower than those of saturated preparations at all time points, with the exception of 168 h for 111In-labeled PAMAM-1B4M. The saturated preparation of 111In-labeled HuTac-PAMAM-1B4M showed lower hepatic uptake (27 ± 2{\%}ID/g) than the unsaturated (32 ± 2{\%}ID/g), but greater than the HuTac1B4M control (10 ± 0{\%}ID/g). The splenic uptake showed 15 ± 1, 38 ± 5, and 8 ± 1{\%}ID/g for the saturated, unsaturated, and control, respectively. The biodistribution of the dendrimer conjugated HuTac in normal organs of tumor-bearing mice was similar to nontumor-bearing mice. Specific tumor (ATAC4) uptake was higher than that in nonspecific tumor (A431). In conclusion, we evaluated the biodistribution of radiolabeled PAMAM-1B4M. We noted high accumulation in the liver, kidney, and spleen, which significantly decreased when the chelates were saturated with the stable element. A similar phenomenon was observed between unsaturated and saturated 111In-labeled HuTac-PAMAM-1B4M, indicating that the PAMAM dendrimer had a detrimental effect on biodistribution.",
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T1 - Evaluation of the in vivo biodistribution of indium-111 and yttrium-88 labeled dendrimer-1B4M-DTPA and its conjugation with anti-tac monoclonal antibody

AU - Kobayashi, Hisataka

AU - Wu, Chuanchu

AU - Kim, Meyoung-Kon

AU - Paik, Chang H.

AU - Carrasquillo, Jorge A.

AU - Brechbiel, Martin W.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - We evaluated the in vivo biodistribution of indium- and yttrium-labeled second-generation polyamidoamine dendrimer (PAMAM) conjugated with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), a derivative of DTPA. In addition, we conjugated PAMAM-1B4M to humanized anti-Tac IgG (HuTac) and evaluated its in vitro and in vivo properties. PAMAM-1B4M was labeled with 111In at 37-48 MBq/mg (1.0-1.3 mCi/mg) or with 88Y at 3.7-4.8 MBq/mg (0.1-0.13 mCi/mg), and an aliquot of radiolabeled conjugate was saturated with the corresponding stable yttrium or indium. Nontumor-bearing nude mice were injected intravenously with 55.5-66.6 kBq (1.5-1.8 mCi) of 88Y-labeled PAMAM-1B4M or with 185 kBq (5 μCi) of 111In-labeled PAMAM-1B4M. The mice were then sacrificed at 15 min, 90 min, 1 day, and 4 days postinjection. Then the PAMAM-1B4M was conjugated with HuTac and labeled with 111In at 111-259 MBq/mg (3-7 mCi/mg). Another preparation of 111In-labeled HuTac-PAMAM-1B4M was saturated with stable indium. Immunoreactivity of both preparations and biodistribution in normal mice 1 h after injection and in ATAC4 and A431 tumorbearing mice 18 h after injection were evaluated and compared with those of 111In-labeled 1B4MHuTac. We noted significantly higher accumulations (p < 0.05) of 111In-labeled and 88Y-labeled unsaturated PAMAM-1B4M than saturated preparations in the liver, kidney, spleen, and bone at most time points. The whole-body clearance times of unsaturated preparations were significantly slower than those of saturated preparations at all time points, with the exception of 168 h for 111In-labeled PAMAM-1B4M. The saturated preparation of 111In-labeled HuTac-PAMAM-1B4M showed lower hepatic uptake (27 ± 2%ID/g) than the unsaturated (32 ± 2%ID/g), but greater than the HuTac1B4M control (10 ± 0%ID/g). The splenic uptake showed 15 ± 1, 38 ± 5, and 8 ± 1%ID/g for the saturated, unsaturated, and control, respectively. The biodistribution of the dendrimer conjugated HuTac in normal organs of tumor-bearing mice was similar to nontumor-bearing mice. Specific tumor (ATAC4) uptake was higher than that in nonspecific tumor (A431). In conclusion, we evaluated the biodistribution of radiolabeled PAMAM-1B4M. We noted high accumulation in the liver, kidney, and spleen, which significantly decreased when the chelates were saturated with the stable element. A similar phenomenon was observed between unsaturated and saturated 111In-labeled HuTac-PAMAM-1B4M, indicating that the PAMAM dendrimer had a detrimental effect on biodistribution.

AB - We evaluated the in vivo biodistribution of indium- and yttrium-labeled second-generation polyamidoamine dendrimer (PAMAM) conjugated with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), a derivative of DTPA. In addition, we conjugated PAMAM-1B4M to humanized anti-Tac IgG (HuTac) and evaluated its in vitro and in vivo properties. PAMAM-1B4M was labeled with 111In at 37-48 MBq/mg (1.0-1.3 mCi/mg) or with 88Y at 3.7-4.8 MBq/mg (0.1-0.13 mCi/mg), and an aliquot of radiolabeled conjugate was saturated with the corresponding stable yttrium or indium. Nontumor-bearing nude mice were injected intravenously with 55.5-66.6 kBq (1.5-1.8 mCi) of 88Y-labeled PAMAM-1B4M or with 185 kBq (5 μCi) of 111In-labeled PAMAM-1B4M. The mice were then sacrificed at 15 min, 90 min, 1 day, and 4 days postinjection. Then the PAMAM-1B4M was conjugated with HuTac and labeled with 111In at 111-259 MBq/mg (3-7 mCi/mg). Another preparation of 111In-labeled HuTac-PAMAM-1B4M was saturated with stable indium. Immunoreactivity of both preparations and biodistribution in normal mice 1 h after injection and in ATAC4 and A431 tumorbearing mice 18 h after injection were evaluated and compared with those of 111In-labeled 1B4MHuTac. We noted significantly higher accumulations (p < 0.05) of 111In-labeled and 88Y-labeled unsaturated PAMAM-1B4M than saturated preparations in the liver, kidney, spleen, and bone at most time points. The whole-body clearance times of unsaturated preparations were significantly slower than those of saturated preparations at all time points, with the exception of 168 h for 111In-labeled PAMAM-1B4M. The saturated preparation of 111In-labeled HuTac-PAMAM-1B4M showed lower hepatic uptake (27 ± 2%ID/g) than the unsaturated (32 ± 2%ID/g), but greater than the HuTac1B4M control (10 ± 0%ID/g). The splenic uptake showed 15 ± 1, 38 ± 5, and 8 ± 1%ID/g for the saturated, unsaturated, and control, respectively. The biodistribution of the dendrimer conjugated HuTac in normal organs of tumor-bearing mice was similar to nontumor-bearing mice. Specific tumor (ATAC4) uptake was higher than that in nonspecific tumor (A431). In conclusion, we evaluated the biodistribution of radiolabeled PAMAM-1B4M. We noted high accumulation in the liver, kidney, and spleen, which significantly decreased when the chelates were saturated with the stable element. A similar phenomenon was observed between unsaturated and saturated 111In-labeled HuTac-PAMAM-1B4M, indicating that the PAMAM dendrimer had a detrimental effect on biodistribution.

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