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Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL-003
- Source :
- Oxidative Medicine and Cellular Longevity, Oxidative Medicine and Cellular Longevity, Vol 2021 (2021)
- Publication Year :
- 2020
-
Abstract
- Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.
- Subjects :
- Male
Aging
Time Factors
Article Subject
Radioprotective Agent
DNA damage
Administration, Oral
Apoptosis
Radiation-Protective Agents
Pharmacology
Biochemistry
Histones
Rats, Sprague-Dawley
Amifostine
Pharmacokinetics
Oral administration
Intestine, Small
medicine
Toxicity Tests, Acute
Animals
Regeneration
Cell Proliferation
Mice, Inbred ICR
QH573-671
Chemistry
Cell Differentiation
Dose-Response Relationship, Radiation
Cell Biology
General Medicine
DNA
Free Radical Scavengers
Survival Analysis
Acute toxicity
In vitro
Mice, Inbred C57BL
Treatment Outcome
Toxicity
Cytology
Whole-Body Irradiation
medicine.drug
DNA Damage
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 19420994
- Volume :
- 2021
- Database :
- OpenAIRE
- Journal :
- Oxidative medicine and cellular longevity
- Accession number :
- edsair.doi.dedup.....d0d267033a2fa2896a8de4e6a6ebddee