Interaction of Pu and Am with Bone Mineral In Vitro

Guilmette, R.A.; Lindhorst, P.S.; Hanlon, L.L.

doi:10.1093/oxfordjournals.rpd.a032448

Cited by 14 publications

(25 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Octadentate 3,4,3-LI(1,2-HOPO) removed 4% of the sorbed 238 Pu(IV); the hexadentate and tetradentate Me-3,2-HOPO ligands removed, on average, 0.5%; ZnNa 3 -DTPA removed Ͻ0.1% (Guilmette et al 1998(Guilmette et al , 2003.…”

Section: Removal Of Pu(iv) From Bone Mineral In Vitromentioning

confidence: 99%

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Durbin¹

2008

Health Physics

106

View full text Add to dashboard Cite

All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

show abstract

Section: Removal Of Pu(iv) From Bone Mineral In Vitromentioning

confidence: 99%

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Durbin¹

2008

Health Physics

106

View full text Add to dashboard Cite

show abstract

“…This effect could be due to the possible saturation at higher contamination levels of the pathways participating in the transfer of Pu from blood to hepatocytes and intracellular spaces of other nonparenchymal cells, involving cellular membrane‐associated proteins and receptor‐mediated endocytosis [Ansoborlo et al., ; Durbin, ; Jensen et al., ]. In addition, while the 238 Pu skeleton deposits seem reduced in control animals injected with low doses, they appear difficult to remove through chelation, which may be due to concentration‐dependent Pu speciation and sorption equilibrium at the bone surface [Guilmette et al., ; Ansoborlo et al., ; Durbin, ].…”

Section: Discussionmentioning

confidence: 99%

“…concentration-dependent Pu speciation and sorption equilibrium at the bone surface [Guilmette et al, 1998;Ansoborlo et al, 2006;Durbin, 2006].…”

Section: Figurementioning

confidence: 99%

Significance of Single Variables in Defining Adequate Animal Models to Assess the Efficacy of New Radionuclide Decorporation Agents: Using the Contamination Dose as an Example

Jarvis

Kullgren

et al. 2012

Drug Development Research

View full text Add to dashboard Cite

Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I‐III Regulatory, Quality, ManufacturingPostmarketing Phase IV Internal radioactive contamination can arise in different ways, from accidents affecting nuclear sites and industrial or medical sources, to the possible terrorist use of radiological dispersal devices. In all cases, internalized radionuclides may pose significant health risks and must be removed from the body. The need for safe, practical, and efficacious actinide chelation therapy options has motivated the current preclinical development of new hydroxypyridinone‐based actinide decorporation agents. In order to seek regulatory approval for such new decorporation agents, a number of efficacy studies must be performed and, in principle, must respond to selective criteria of the Animal Efficacy Rule from the US Food and Drug Administration (FDA). While many in vivo decorporation efficacy studies have been conducted over the past few decades using different animal species and contamination procedures, there is no designated standard animal model for the evaluation of new actinide chelation drugs. This study aims at probing the influence of a single variable such as the contamination dose on the efficacy of the chelators 3,4,3‐LI(1,2‐HOPO) and 5‐LIO(Me‐3,2‐HOPO) at removing plutonium‐238 administered as a soluble citrate complex. The dependence of body burden on contamination dose observed in untreated animals was reduced with the hydroxypyridinonate chelators, more so than with the commercially available diethylenetriaminepentaacetic acid chelator. This study demonstrates how a slight change in the design of decorporation experiments can remarkably impact the efficacy profile of the tested drug, and thus the path a sponsor might take to gain FDA approval.

show abstract

“…This unfortunate circumstance means that individuals with systemic burdens of Pu and/or Am would incur a risk of dose-dependent bone cancer for which the only dose and risk reduction possible would be interception of actinide released by structural skeletal remodeling. In vitro studies with bone mineral surrogates show that binding of Pu and Am occurs relatively rapidly (< 8 h), is tenacious, and Pu is not amenable to removal by the chelating agent of choice today, DTPA (diethylenetriaminepentaacetic acid), whether in Ca or Zn chelate forms (2) . Chelating agents that can remove Pu and/or Am from bone surfaces would be valuable.…”

Section: Introductionmentioning

confidence: 99%

“…All of these ligands, with their different backbones, denticities and functional groups, have been tested primarily in mice for efficacy in decorporating intravenously injected Pu (3)(4)(5)(6)(7)(8) and some have been tested for in vivo chelation of Am (9)(10)(11)(12)(13) . Using a previously described in vitro system in which Pu or Am were allowed to bind to a crystalline bone mineral surrogate, calcium hydroxyapatite (2) (HAP), a test ligand was added at various concentrations, and its ability to solubilize the HAP-bound Pu or Am was determined as functions of concentration and incubation time. Because the chemistry of actinide binding to bone mineral has yet to be elucidated, it was not reasonable to predict which compounds would be more or less effective; nevertheless, the structural features encompassed by this set of compounds were expected to influence their binding affinities for the actinides.…”

Section: Introductionmentioning

confidence: 99%

Competitive binding of Pu and Am with bone mineral and novel chelating agents

Guilmette¹,

Hakimi²,

Durbin³

et al. 2003

Radiation Protection Dosimetry

View full text Add to dashboard Cite

Effective direct removal of actinides such as Pu and Am from bone in vivo has not been accomplished to date, even with the strong chelating agents CaNa3DTPA or ZnNa3DTPA. This study, using an established in vitro system, compared removal of Pu and Am bound to bone mineral by ZnNa3DTPA and 10 chelating agents designed specifically to sequester actinides, including Pu and Am. Ligands tested were tetra, hexa, and octadentate, with linear or branched backbones containing sulfocatechol [CAM(S)], hydroxycatechol [CAM(C)], hydroxipyridinone (1,2-HOPO, Me-3,2-HOPO), or hydroxamate functional groups. The wide range of Pu and Am removal exhibited by the test ligands generally agreed with their metal coordination and chemical properties. The most effective agents for Pu (100 microM concentration, 24-48 h contact) are all octadentate as follows: 3,4,3-LICAM(S) (54% unbound); 3,4,3-LICAM(C) (6.2%); 3,4,3-LI(1,2-HOPO) (3.8%); H(2,2)-(Me-3,2-HOPO) (2.2%) and DFO-(1,2-HOPO) (1.8%). The other ligands removed less than 1% of the bound Pu; and ZnNa3DTPA removed only 0.086%. The most effective ligands for Am removal (100 microM, 24-48 h contact) are as follows: octadentate H(2,2)-(Me-3,2-HOPO) (21% unbound); 3,4,3-LI(1,2-HOPO) (14.5%) and 3,4,3-LICAM(C) (5.9%); hexadentate TREN-(Me-3,2-HOPO) and TREN-(1,2-HOPO) (9.6%); and tetradentate 5-LIO(Me-3,2-HOPO) (5.2%). Am removal by ZnNa3DTPA was about 1.4%. Among the ligands presently considered for possible human use, only 3,4,3-LI(1,2-HOPO) removed potentially useful amounts of both Pu and Am from bone mineral.

show abstract

Interaction of Pu and Am with Bone Mineral In Vitro

Cited by 14 publications

References 0 publications

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Significance of Single Variables in Defining Adequate Animal Models to Assess the Efficacy of New Radionuclide Decorporation Agents: Using the Contamination Dose as an Example

Competitive binding of Pu and Am with bone mineral and novel chelating agents

Contact Info

Product

Resources

About