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Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.

Ahlstedt, Jonas LU ; Tran, Thuy LU ; Strand, Filip; Holmqvist, Bo; Strand, Sven-Erik LU ; Gram, Magnus LU and Åkerström, Bo LU (2015) In American journal of nuclear medicine and molecular imaging 5(4). p.333-347
Abstract
Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming... (More)
Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT. (Less)
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organization
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Contribution to journal
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published
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in
American journal of nuclear medicine and molecular imaging
volume
5
issue
4
pages
333 - 347
publisher
e-Century Publishing Corporation
external identifiers
  • pmid:26269772
ISSN
2160-8407
language
English
LU publication?
yes
id
0de31dee-3006-4542-8bb3-11eb681d6e31 (old id 7841218)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26269772?dopt=Abstract
http://www.ajnmmi.us/ajnmmi_V5N4.html
date added to LUP
2015-09-05 19:02:18
date last changed
2016-04-16 00:26:02
@article{0de31dee-3006-4542-8bb3-11eb681d6e31,
  abstract     = {Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.},
  author       = {Ahlstedt, Jonas and Tran, Thuy and Strand, Filip and Holmqvist, Bo and Strand, Sven-Erik and Gram, Magnus and Åkerström, Bo},
  issn         = {2160-8407},
  language     = {eng},
  number       = {4},
  pages        = {333--347},
  publisher    = {e-Century Publishing Corporation},
  series       = {American journal of nuclear medicine and molecular imaging},
  title        = {Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.},
  volume       = {5},
  year         = {2015},
}