Polymer complex of WR 2721. Synthesis and radioprotective efficiency

Koseva, Neli; Tsacheva, Ivelina; Mitova, Violeta; Vodenicharova, Elitsa; Molkentine, Jessica M.; Mason, Kathryn A.; Troev, K.

doi:10.1016/j.ejps.2014.08.006

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…In this work, the formation of the adduct was confirmed by FT-IR spectroscopy. In further studies, the effect of the use of polymer complex was examined in comparison with amifostine alone [ 130 ], visible positive effects can be seen in Figure 14 .…”

Section: Properties and Applications Of Polyphosphodiestersmentioning

confidence: 99%

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Design, Synthesis and Actual Applications of the Polymers Containing Acidic P–OH Fragments: Part 1. Polyphosphodiesters

Nifant’ev

Ivchenko

2022

IJMS

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Among natural and synthetic polymers, main-chain phosphorus-containing polyacids (PCPAs) (polyphosphodiesters), stand in a unique position at the intersection of chemistry, physics, biology and medicine. The structural similarity of polyphosphodiesters PCPAs to natural nucleic and teichoic acids, their biocompatibility, mimicking to biomolecules providing the ‘stealth effect’, high bone mineral affinity of polyphosphodiesters resulting in biomineralization at physiological conditions, and adjustable hydrolytic stability of polyphosphodiesters are the basis for various biomedical, industrial and household applications of this type of polymers. In the present review, we discuss the synthesis, properties and actual applications of polyphosphodiesters.

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Section: Properties and Applications Of Polyphosphodiestersmentioning

confidence: 99%

“…Three groups of 10 mice each were exposed to 9 Gy WBI alone (black circles), WR2721 ip at a dose of 50 mg/kg 30 min prior to WBI (blue circles), or the polymer complex of WR2721 at an ip dose of 50 mg/kg 30 min prior to WBI (red circles). Reprinted with permission from [ 130 ]. Copyright (2014) Elsevier B. V.…”

Section: Figures Schemes and Tablementioning

confidence: 99%

Design, Synthesis and Actual Applications of the Polymers Containing Acidic P–OH Fragments: Part 1. Polyphosphodiesters

Nifant’ev

Ivchenko

2022

IJMS

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“…Systemic dosing of WR-2721 by intraperitoneal (IP) injection has already been shown to be effective at radioprotecting the gut of C3Hf/KamLaw mice receiving whole body irradiation 11,12 , but we wanted to determine if oral (PO) administration of WR-2721 would be similarly efficacious. We tested a range of doses of oral WR-2721 from 0 to 1,000 mg/kg, followed either 15 or 30 minutes after by a morbid dose of whole body irradiation (WBI).…”

Section: Resultsmentioning

confidence: 99%

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

Molkentine

Fujimoto

Horvath

et al. 2019

Sci Rep

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Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.

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“…C57BL/6 mice treated with total body irradiation (TBI) were then used to assess the survival benefit of CCM-Ami compared to amifostine. Previously published studies utilized TBI from 5-12 Gy mostly for 10 minutes (0.6-2.2 Gy/min) [14,22,23]. However, longer radiation exposure times with lower dose rates are more representative of a nuclear accident.…”

Section: Acute Toxicity and Total Body Irradiationmentioning

confidence: 99%

“…The efficacy of its use for alleviating the side effects of chemotherapy and space travel is also limited by the extremely short half-life. Re-formulations including microcapsules and polymer complex were investigated to assess the efficacy for radioprotection, but no better result was found [14][15][16]. This article describes the preparation and characterization of amifostine-loaded CCM (CCM-Ami).…”

Section: Introductionmentioning

confidence: 99%

Chelating Complex Micelles for Delivering Cytoprotectant Amifostine and its Application in Radiation Protection

Wang¹,

Cheng²,

Chen³

et al. 2018

J Pharmacovigil

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Polymer complex of WR 2721. Synthesis and radioprotective efficiency

Cited by 10 publications

References 27 publications

Design, Synthesis and Actual Applications of the Polymers Containing Acidic P–OH Fragments: Part 1. Polyphosphodiesters

Design, Synthesis and Actual Applications of the Polymers Containing Acidic P–OH Fragments: Part 1. Polyphosphodiesters

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

Chelating Complex Micelles for Delivering Cytoprotectant Amifostine and its Application in Radiation Protection

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