ASSESSMENT OF THE TOXICOLOGICAL PROPERTIES OF DOCETAXEL LOADED FOLATE-MODIFIED POLYMER PARTICLES IN VIVO
A. A. Krasheninnikova,
V. V. Zavarzina,
D. S. Panova,
N. V. Gukasova,
S. L. Kuznetsov,
I. A. Tubasheva,
V. Yu. Balabanyan,
Yu. I. Poltavets https://doi.org/10.17650/1726-9784-2019-19-2-55-64
Abstract
Introduction One of the perspective approaches to the development of anticancer chemotherapy drugs is the use of submicron vectorizeddelivery systems that increase the selectivity of action and reduce the toxic side effects of chemotherapy. A delivery system of docetaxel(DOC) loaded poly(lactide-co-glycolide) (PLGA) particles modified with folic acid dodecylamide (FAD) was developed (PLGA-DOC-FAD).
The aim of the research was a comparative toxicological study of DOC-loaded particles and standard docetaxel solution form in acuteand subchronic experiments in mice after intravenous administration.
Materials and methods The research was conducted in female C57BL/6 mice. During the study of acute toxicity, drugs were administeredin the following dose range: 20, 60, 90, 120, 160 mg/kg. Over 30 days, mortality and body weight were evaluated, pathomorphologicalstudies were performed. The study of toxicity in conditions of subchronic administration of medicine was conducted using three timesdaily administration in single doses of 11 and 22 mg/kg. Subchronic toxicity of the drugs was studied with three times daily administrationin single doses of 11 and 22 mg/kg. The necessary studies were performed within 30 days.
Results With a single injection of PLGA-DOC-FAD in doses of 20, 60, 90 mg/kg, the death of animals wasn’t observed; at doses of 120 and160 mg/kg, the death of animals was detected in 1–4 days. In the case of administration of the DOC substance, the death of animalsoccurred within a day after the administration of doses of 60, 90, 120, 160 mg/kg. The pattern of intoxication was similar in case of compared drugs and manifested in hypodynamia, impaired movement coordination, hind limbs paresis, though the manifestation degreethereof was more expressed in the groups with the introduction of DOC than in the case of the introduction of PLGA-DOC-FAD. It wasdetected that the LD50 for PLGA-DOC-FAD is 140 mg/kg, and for the DOC substance – 112 mg/kg. In case of subchronic administration, the detected toxic properties of drug depend on the size of the dose applied. The administration of a single dose of 22 mg/kg of PLGA-DOC-FAD caused lethal effects (2/10), reversible delay in weight gain and leucopenia in surviving animals, and an increase in the relativemass of the spleen. The use of PLGA-DOC-FAD in a single dose of 11 mg/kg didn’t cause death, was well tolerated and characterizedby similar toxicity with the docetaxel substance.
Conclusion Based on experimental data, the toxic dose levels of PLGA-DOC-FAD were determined under acute and subchronic administration. The results obtained allowed us to recommend PLGA-DOC-FAD for further examination.
The aim of the research was a comparative toxicological study of DOC-loaded particles and standard docetaxel solution form in acuteand subchronic experiments in mice after intravenous administration.
Materials and methods The research was conducted in female C57BL/6 mice. During the study of acute toxicity, drugs were administeredin the following dose range: 20, 60, 90, 120, 160 mg/kg. Over 30 days, mortality and body weight were evaluated, pathomorphologicalstudies were performed. The study of toxicity in conditions of subchronic administration of medicine was conducted using three timesdaily administration in single doses of 11 and 22 mg/kg. Subchronic toxicity of the drugs was studied with three times daily administrationin single doses of 11 and 22 mg/kg. The necessary studies were performed within 30 days.
Results With a single injection of PLGA-DOC-FAD in doses of 20, 60, 90 mg/kg, the death of animals wasn’t observed; at doses of 120 and160 mg/kg, the death of animals was detected in 1–4 days. In the case of administration of the DOC substance, the death of animalsoccurred within a day after the administration of doses of 60, 90, 120, 160 mg/kg. The pattern of intoxication was similar in case of compared drugs and manifested in hypodynamia, impaired movement coordination, hind limbs paresis, though the manifestation degreethereof was more expressed in the groups with the introduction of DOC than in the case of the introduction of PLGA-DOC-FAD. It wasdetected that the LD50 for PLGA-DOC-FAD is 140 mg/kg, and for the DOC substance – 112 mg/kg. In case of subchronic administration, the detected toxic properties of drug depend on the size of the dose applied. The administration of a single dose of 22 mg/kg of PLGA-DOC-FAD caused lethal effects (2/10), reversible delay in weight gain and leucopenia in surviving animals, and an increase in the relativemass of the spleen. The use of PLGA-DOC-FAD in a single dose of 11 mg/kg didn’t cause death, was well tolerated and characterizedby similar toxicity with the docetaxel substance.
Conclusion Based on experimental data, the toxic dose levels of PLGA-DOC-FAD were determined under acute and subchronic administration. The results obtained allowed us to recommend PLGA-DOC-FAD for further examination.
Supporting agencies: The study was supported by the Scientific Program of the NRC “Kurchatov institute” and Agreement No 14.607.21.0198 (RFMEFI60717X0198) of Ministry of Science and Higher Education of the Russian Federation.
About the Authors
A. A. Krasheninnikova
National Research Center “Kurchatov Institute”;
Institute of General Pathology and Pathophysiology
Russian Federation
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
8 Baltiyskaya St., Moscow 125315
V. V. Zavarzina
National Research Center “Kurchatov Institute”
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
D. S. Panova
National Research Center “Kurchatov Institute”
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
N. V. Gukasova
National Research Center “Kurchatov Institute”
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
S. L. Kuznetsov
National Research Center “Kurchatov Institute”
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
I. A. Tubasheva
National Research Center “Kurchatov Institute”
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
V. Yu. Balabanyan
M.V. Lomonosov Moscow State University
Russian Federation
1 Leninskie Gory, Moscow 119991
Russian Federation
1 Leninskie Gory, Moscow 119991
Yu. I. Poltavets
National Research Center “Kurchatov Institute”
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
Russian Federation
1 Akademika Kurchatova ploshchad’, Moscow 123182
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For citations:
Krasheninnikova A.A., Zavarzina V.V., Panova D.S., Gukasova N.V., Kuznetsov S.L., Tubasheva I.A., Balabanyan V.Yu., Poltavets Yu.I. ASSESSMENT OF THE TOXICOLOGICAL PROPERTIES OF DOCETAXEL LOADED FOLATE-MODIFIED POLYMER PARTICLES IN VIVO. Russian Journal of Biotherapy. 2020;19(2):55-64. (In Russ.) https://doi.org/10.17650/1726-9784-2019-19-2-55-64
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