{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:31:58Z","timestamp":1793431918909,"version":"4.5.0"},"reference-count":58,"publisher":"Radiation Research Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2022,8,1]]},"abstract":"<jats:p>The release of actinides into the environment represents a significant potential public health concern. Chelation therapy utilizing diethylenetriamine pentaacetate (DTPA) is a U.S. Food and Drug Administration (FDA)-approved therapy capable of mitigating the deposition of some absorbed actinides in the body. However, the pharmacokinetic profile of DTPA is not ideal for prophylactic applications. In this study, we examine the incorporation of DTPA into a HPMA copolymer (P-DTPA) to investigate if the enhanced blood circulation time can offer superior prophylactic protection and of improving in vivo radiometal decorporation. Utilizing lutetium-177 (177Lu) as an actinide model, the performance of P-DTPA and DTPA (control) were evaluated using selectivity studies in the presence of competing biological metals, chelation and stability assays in human serum and cytotoxicity studies using human umbilical vein endothelial cells (HUVEC). The in vivo decorporation efficiency of P-DTPA relative to DTPA and untreated controls was also evaluated over two weeks in CF-1 mice. In the experimental groups, the mice were prophylactically treated with P-DTPA or DTPA (30 \u00b5mol\/kg) 6 or 24 h prior to 177LuCl3 administration. The in vitro results reveal that P-DTPA gives efficient complexation yields relative to DTPA with a tolerable cytotoxicity profile and good serum stability. The in vivo decorporation studies demonstrated enhanced total excretion of the 177Lu using P-DTPA compared to DTPA in both the 6 and 24 h prophylactic treatment study arms. This enhanced decorporation effect is certainly attributable to the expected prolonged biological half-life of DTPA when grafted to the HPMA polymer.<\/jats:p>","DOI":"10.1667\/rade-21-00244.1","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T13:07:12Z","timestamp":1659359232000},"page":"357-367","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro and In Vivo Evaluation of DTPA-HPMA Copolymers as Potential Decorporating Agents for Prophylactic Therapy of Actinide Contamination"],"prefix":"10.1667","volume":"198","author":[{"given":"Sameer","family":"Alshehri","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jered C.","family":"Garrison","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"11","doi-asserted-by":"crossref","unstructured":"O Gr\u00e9my, L Miccoli, F Lelan, et al.  \"Radiat Res.\"  189, \"Delivery of DTPA through liposomes as a good strategy for enhancing plutonium decorporation regardless of treatment regimen.\" 477 (2018)","DOI":"10.1667\/RR14968.1"},{"key":"46","doi-asserted-by":"crossref","unstructured":"O Gr\u00e9my, D Laurent, S Coudert, et al.  \"Radiat Res.\"  185, \"Decorporation of Pu\/Am actinides by chelation therapy: New arguments in favor of an intracellular component of DTPA action.\" 568 (2016)","DOI":"10.1667\/RR14193.1"},{"key":"31","doi-asserted-by":"crossref","unstructured":"RD Lloyd, GN Taylor, CW Mays, et al.  \"Radiat Res.\"  78, \"Dependency of chelation efficacy upon time after first DTPA injection.\" 448 (1979)","DOI":"10.2307\/3574971"},{"key":"12","doi-asserted-by":"crossref","unstructured":"G Phan, B Le Gall, G Grillon, et al.  \"Biochimie.\"  88, \"Enhanced decorporation of plutonium by DTPA encapsulated in small PEG-coated liposomes.\" 1843 (2006)","DOI":"10.1016\/j.biochi.2006.06.010"},{"key":"13","doi-asserted-by":"crossref","unstructured":"G Phan, A Herbet, S Cholet, et al.  \"J Control Release.\"  110, \"Pharmacokinetics of DTPA entrapped in conventional and long-circulating liposomes of different size for plutonium decorporation.\" 177 (2005)","DOI":"10.1016\/j.jconrel.2005.09.029"},{"key":"1","doi-asserted-by":"crossref","unstructured":"RO. McClellan,  \"Handbook of Toxicology of Chemical Warfare Agents.\"  2020, \"Health effects of nuclear weapons and releases of radioactive materials.\" 707","DOI":"10.1016\/B978-0-12-819090-6.00043-X"},{"key":"2","doi-asserted-by":"crossref","unstructured":"RJ. Abergel,  \"Metal Chelation in Medicine: Royal Society of Chemistry.\"  \"CHAPTER 6 Chelation of Actinides.\" 183 (2017)","DOI":"10.1039\/9781782623892-00183"},{"key":"3","doi-asserted-by":"crossref","unstructured":"\u00c9 Ansoborlo, B Amekraz, C Moulin, et al.  \"CR Chim.\"  10, \"Review of actinide decorporation with chelating agents.\" 1010 (2007)","DOI":"10.1016\/j.crci.2007.01.015"},{"key":"4","doi-asserted-by":"crossref","unstructured":"L Grappin, P B\u00e9rard, F M\u00e9n\u00e9trier, et al.  \"Radioprotection.\"  42, \"Exposure to actinides: report on Ca-DTPA injections in CEA-AREVA centres.\" 163 (2007)","DOI":"10.1051\/radiopro:2006031"},{"key":"5","doi-asserted-by":"crossref","unstructured":"F M\u00e9n\u00e9trier, L Grappin, P Raynaud, et al.  \"Appl Radiat Isotopes.\"  62, \"Treatment of accidental intakes of plutonium and americium: guidance notes.\" 829 (2005)","DOI":"10.1016\/j.apradiso.2005.01.005"},{"key":"6","unstructured":"\"Guidance for industry on pentetate calcium trisodium and pentetate zinc trisodium for treatment of internal contamination with plutonium, americium, or curium; Availability.\"  68 FR, 53984 (2003)"},{"key":"7","doi-asserted-by":"crossref","unstructured":"CS Kang, Y Chen, E Dadachova, et al.  \"J Radioanal Nucl Chem.\"  303, \"Evaluation of benzyl-substituted DTPA analogues as decorporation agents of radionuclides.\" 2407 (2015)","DOI":"10.1007\/s10967-014-3714-9"},{"key":"8","doi-asserted-by":"crossref","unstructured":"F Lahrouch, B Siberchicot, J F\u00e8vre, et al.  \"Inorg Chem.\"  59, \"Carboxylate-and phosphonate-modified polyethylenimine: Toward the design of actinide decorporation agents.\" 128 (2019)","DOI":"10.1021\/acs.inorgchem.9b02014"},{"key":"9","unstructured":"JG McAfee, G Gagne, HL Atkins, et al.  \"J Nucl Med.\"  20, \"Biological distribution and excretion of DTPA labeled with Tc-99m and In-111.\" 1273 (1979)"},{"key":"10","doi-asserted-by":"crossref","unstructured":"J Stather, H Smith, M Bailey, et al.  \"Health Phys.\"  44, \"The retention of 14C-DTPA in human volunteers after inhalation or intravenous injection.\" 45 (1983)","DOI":"10.1097\/00004032-198301000-00006"},{"key":"14","doi-asserted-by":"crossref","unstructured":"L L\u00e9ost, J Roques, A Van Der Meeren, et al.  \"Dalton Trans.\"  47, \"Towards the development of chitosan nanoparticles for plutonium pulmonary decorporation.\" 11605 (2018)","DOI":"10.1039\/C8DT02419G"},{"key":"15","unstructured":"S. Chen,  \"Improving Decorporation Efficacy of DTPA and HOPO Using Chitosan\/TPP Nanoparticles: Preparation, Characterization and Release Testing [dissertation].\"  (2016)"},{"key":"16","unstructured":"B Pelaz, C Alexiou, RA Alvarez-Puebla, et al.  \"ACS Nano.\"  11, \"Diverse Applications of Nanomedicine.\" 2313 (2017)"},{"key":"17","doi-asserted-by":"crossref","unstructured":"B \u0158\u00edhov\u00e1  and M Kov\u00e1\u0159  \"Adv Drug Deliver Rev.\"  62, \"Immunogenicity and immunomodulatory properties of HPMA-based polymers.\" 184 (2010)","DOI":"10.1016\/j.addr.2009.10.005"},{"key":"18","doi-asserted-by":"crossref","unstructured":"J Kope\u010dek  and P Kope\u010dkov\u00e1  \"Adv Drug Deliver Rev.\"  62, \"HPMA copolymers: origins, early developments, present, and future.\" 122 (2010)","DOI":"10.1016\/j.addr.2009.10.004"},{"key":"19","doi-asserted-by":"crossref","unstructured":"L Seymour, R Duncan, J Strohalm, et al.  \"J Biomed Mater Res.\"  21, \"Effect of molecular weight (Mw) of N-(2-hydroxypropyl) methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats.\" 1341 (1987)","DOI":"10.1002\/jbm.820211106"},{"key":"20","doi-asserted-by":"crossref","unstructured":"X-M Liu, SC Miller, D Wang,  \"Adv Drug Deliver Rev.\"  62, \"Beyond oncology\u2014application of HPMA copolymers in non-cancerous diseases.\" 258 (2010)","DOI":"10.1016\/j.addr.2009.10.006"},{"key":"21","doi-asserted-by":"crossref","unstructured":"P Chytil, E Koziolov\u00e1, T Etrych, et al.  \"Macromol Biosci.\"  18, \"HPMA copolymer\u2013drug conjugates with controlled tumor-specific drug release.\" 1700209 (2018)","DOI":"10.1002\/mabi.201700209"},{"key":"22","doi-asserted-by":"crossref","unstructured":"RM Smith  and AE Martell  \"Sci Total Environ.\"  64, \"Critical stability constants, enthalpies and entropies for the formation of metal complexes of aminopolycarboxylic acids and carboxylic acids.\" 125 (1987)","DOI":"10.1016\/0048-9697(87)90127-6"},{"key":"23","doi-asserted-by":"crossref","unstructured":"W M\u00fcller, U Linzner, E Sch\u00e4ffer,  \"Int J Nucl Med Biol.\"  5, \"Organ distribution studies of lutetium-177 in mouse.\" 29 (1978)","DOI":"10.1016\/0047-0740(78)90087-6"},{"key":"24","doi-asserted-by":"crossref","unstructured":"A Mitra, A Nan, JC Papadimitriou, et al.  \"Nucl Med Biol.\"  33, \"Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy.\" 43 (2006)","DOI":"10.1016\/j.nucmedbio.2005.09.005"},{"key":"25","doi-asserted-by":"crossref","unstructured":"V Omelyanenko, P Kopeckova, C Gentry, et al.  \"J Control Release.\"  53, \"Targetable HPMA copolymer-adriamycin conjugates. Recognition, internalization, and subcellular fate.\" 25 (1998)","DOI":"10.1016\/S0168-3659(97)00235-6"},{"key":"26","doi-asserted-by":"crossref","unstructured":"S Alshehri, W Fan, W Zhang, et al.  \"Pharm Res.\"  37, \"in vitro evaluation and biodistribution studies of HPMA copolymers targeting the gastrin releasing peptide receptor in prostate cancer.\" 229 (2020)","DOI":"10.1007\/s11095-020-02952-3"},{"key":"27","doi-asserted-by":"crossref","unstructured":"A Kratz, M Ferraro, PM Sluss, et al.  \"New Engl J Med.\"  351, \"Laboratory reference values.\" 1548 (2004)","DOI":"10.1056\/NEJMcpc049016"},{"key":"28","doi-asserted-by":"crossref","unstructured":"S Watanabe, K Hashimoto, NS Ishioka,  \"J Radioanal Nucl Chem.\"  303, \"Lutetium-177 complexation of DOTA and DTPA in the presence of competing metals.\" 1519 (2015)","DOI":"10.1007\/s10967-014-3590-3"},{"key":"29","doi-asserted-by":"crossref","unstructured":"MM. Vora,  \"Int J Rad Appl Instr A.\"  42, \"HPLC analysis of indium-111 diethylenetriaminepentaacetic acid (111In-DTPA) radiopharmaceutical.\" 19 (1991)","DOI":"10.1016\/0883-2889(91)90119-L"},{"key":"30","doi-asserted-by":"crossref","unstructured":"W Fan, W Zhang, S Alshehri, et al.  \"Eur J Med Chem.\"  177, \"Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor.\" 386 (2019)","DOI":"10.1016\/j.ejmech.2019.05.068"},{"key":"32","doi-asserted-by":"crossref","unstructured":"K Sueda, MP Sadgrove, M Jay, et al.  \"Health Phys.\"  105, \"Species-dependent effective concentration of DTPA in plasma for chelation of 241Am.\" 208 (2013)","DOI":"10.1097\/HP.0b013e318290ca33"},{"key":"33","doi-asserted-by":"crossref","unstructured":"S Rani  and U Gupta  \"Drug Discov Today.\"  25, \"HPMA-based polymeric conjugates in anticancer therapeutics.\" 997 (2020)","DOI":"10.1016\/j.drudis.2020.04.007"},{"key":"34","doi-asserted-by":"crossref","unstructured":"T Lammers, R Kuhnlein, M Kissel, et al.  \"J Control Release.\"  110, \"Effect of physicochemical modification on the biodistribution and tumor accumulation of HPMA copolymers.\" 103 (2005)","DOI":"10.1016\/j.jconrel.2005.09.010"},{"key":"35","doi-asserted-by":"crossref","unstructured":"MW Brechbiel  and OA Gansow  \"Bioconjugate Chem.\"  2, \"Backbone-substituted DTPA ligands for yttrium-90 radioimmunotherapy.\" 187 (1991)","DOI":"10.1021\/bc00009a008"},{"key":"36","doi-asserted-by":"crossref","unstructured":"DE Owens  and NA Peppas  \"Int J Pharm.\"  307, \"Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles.\" 93 (2006)","DOI":"10.1016\/j.ijpharm.2005.10.010"},{"key":"37","doi-asserted-by":"crossref","unstructured":"U Pandey, N Gamre, SP Lohar, et al.  \"Appl Radiat Isotopes.\"  127, \"A systematic study on the utility of CHX-A\u201d-DTPA-NCS and NOTA-NCS as bifunctional chelators for 177Lu radiopharmaceuticals.\" 1 (2017)","DOI":"10.1016\/j.apradiso.2017.04.028"},{"key":"38","unstructured":"L Camera, S Kinuya, K Garmestani, et al.  \"J Nucl Med.\"  35, \"Evaluation of the serum stability and in vivo biodistribution of CHX-DTPA and other ligands for yttrium labeling of monoclonal antibodies.\" 882 (1994)"},{"key":"39","doi-asserted-by":"crossref","unstructured":"H-S Chong, DE Milenic, K Garmestani, et al.  \"Nucl Med Biol.\"  33, \"In vitro and in vivo evaluation of novel ligands for radioimmunotherapy.\" 459 (2006)","DOI":"10.1016\/j.nucmedbio.2006.03.004"},{"key":"40","doi-asserted-by":"crossref","unstructured":"P Barta, A Laznickova, M Laznicek, et al.  \"J Labelled Compd Rad.\"  56, \"Preclinical evaluation of radiolabelled nimotuzumab, a promising monoclonal antibody targeting the epidermal growth factor receptor.\" 280 (2013)","DOI":"10.1002\/jlcr.2988"},{"key":"41","unstructured":"LR Perk, GW Visser, MJ Vosjan, et al.  \"J Nucl Med.\"  46, \"89Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals 90Y and 177Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab.\" 1898 (2005)"},{"key":"42","doi-asserted-by":"crossref","unstructured":"Y Cao, Y Gong, L Liu, et al.  \"J Appl Toxicol.\"  37, \"The use of human umbilical vein endothelial cells (HUVECs) as an in vitro model to assess the toxicity of nanoparticles to endothelium: a review.\" 1359 (2017)","DOI":"10.1002\/jat.3470"},{"key":"43","doi-asserted-by":"crossref","unstructured":"C. Lucke-Huhle,  \"Health Phys.\"  31, \"Proliferation-dependent cytotoxicity of diethylenetriaminepentaacetate (DTPA) in vitro.\" 349 (1976)","DOI":"10.1097\/00004032-197610000-00006"},{"key":"44","doi-asserted-by":"crossref","unstructured":"D Pissuwan, C Boyer, K Gunasekaran, et al.  \"Biomacromolecules.\"  11, \"In vitro cytotoxicity of RAFT polymers.\" 412 (2010)","DOI":"10.1021\/bm901129x"},{"key":"45","doi-asserted-by":"crossref","unstructured":"A Mitra, T Coleman, M Borgman, et al.  \"J Control Release.\"  114, \"Polymeric conjugates of mono-and bi-cyclic \u03b1V\u03b23 binding peptides for tumor targeting.\" 175 (2006)","DOI":"10.1016\/j.jconrel.2006.06.014"},{"key":"47","doi-asserted-by":"crossref","unstructured":"L-D Quan, F Yuan, X-M Liu, et al.  \"Mol Pharm.\"  7, \"Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl) methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.\" 1041 (2010)","DOI":"10.1021\/mp100132h"},{"key":"48","doi-asserted-by":"crossref","unstructured":"X Wei, F Li, G Zhao, et al.  \"Mol Pharm.\"  14, \"Pharmacokinetic and biodistribution studies of HPMA copolymer conjugates in an aseptic implant loosening mouse model.\" 1418 (2017)","DOI":"10.1021\/acs.molpharmaceut.7b00045"},{"key":"49","doi-asserted-by":"crossref","unstructured":"PJ Julyan, LW Seymour, DR Ferry, et al.  \"J Control Release.\"  57, \"Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine.\" 281 (1999)","DOI":"10.1016\/S0168-3659(98)00124-2"},{"key":"50","doi-asserted-by":"crossref","unstructured":"Y-E Rahman, MW Rosenthal, EA Cerny,  \"Science.\"  180, \"Intracellular plutonium: removal by liposome-encapsulated chelating agent.\" 300 (1973)","DOI":"10.1126\/science.180.4083.300"},{"key":"51","doi-asserted-by":"crossref","unstructured":"G Sahay, DY Alakhova, AV Kabanov,  \"J Control Release.\"  145, \"Endocytosis of nanomedicines.\" 182 (2010)","DOI":"10.1016\/j.jconrel.2010.01.036"},{"key":"52","doi-asserted-by":"crossref","unstructured":"G Boocock, C Danpure, D Popplewell, et al.  \"Radiat Res.\"  42, \"The subcellular distribution of plutonium in rat liver.\" 381 (1970)","DOI":"10.2307\/3572805"},{"key":"53","doi-asserted-by":"crossref","unstructured":"R Gruner, A Seidel, R Winter,  \"Radiat Res.\"  85, \"The initial early distribution of monomeric 239Pu and 241Am in rat liver as determined by Triton WR 1339 injection.\" 367 (1981)","DOI":"10.2307\/3575570"},{"key":"54","doi-asserted-by":"crossref","unstructured":"A Seidel, M Wiener, E Kr\u00fcger, et al.  \"Int J Rad Appl Instr B.\"  13, \"Studies on the lysosomal binding of 141Ce, 239Np, 239Pu and 241Am in rat and Syrian hamster liver using carrier-free electrophoresis.\" 515 (1986)","DOI":"10.1016\/0883-2897(86)90130-3"},{"key":"55","doi-asserted-by":"crossref","unstructured":"Y Nakamura, Y Tsumura, Y Tonogai, et al.  \"Toxicol Sci.\"  37, 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