Preclinical toxicological study of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in synergic ratio

• Published in: Biomedicine & pharmacotherapy Vol. 144; p. 112307
• Main Authors: Roque, Marjorie Coimbra, da Silva, Caroline Dohanik, Lempek, Marthin Raboch, Cassali, Geovanni Dantas, de Barros, André Luís Branco, Melo, Marília Martins, Oliveira, Mônica Cristina
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.12.2021; Elsevier
• Subjects: Action Potentials - drug effects; Acute toxicity; Administration, Intravenous; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - toxicity; Breast cancer; Cardiotoxicity; Co-administration; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - toxicity; Drug Compounding; Drug Synergism; Electrocardiography; Female; Heart Diseases - chemically induced; Heart Diseases - metabolism; Heart Diseases - pathology; Lethal Dose 50; Lipids - chemistry; Liposomes; Mice; Mice, Inbred BALB C; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Paclitaxel - toxicity; Co-administration; Breast cancer; Liposomes; Doxorubicin; Paclitaxel; Acute toxicity
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112307

Combination therapy between paclitaxel (PTX) and doxorubicin (DXR) is applied as the first-line treatment of breast cancer. Co-administration of drugs at synergistic ratio for treatment is facilitated with the use of nanocarriers, such as liposomes. However, despite the high response rate of solid tumors to this combination, a synergism of cardiotoxicity may limit the use. Thus, the objective of this work was to investigate the toxicity of long-circulating and fusogenic liposomes co-encapsulating PTX and DXR at the synergistic molar ratio (1:10) (LCFL-PTX/DXR). For this, clinical chemistry, histopathological analysis and electrocardiographic exams were performed on female Balb/c mice that received a single intravenous dose of LCFL-PTX/DXR. The results of the study indicated that the LD50 dose range (lethal dose for 50% of animals) of the LCFL-PTX/DXR treatment (28.9–34.7 mg/kg) is much higher than that found for free PTX/DXR treatment (20.8–23.1 mg/kg). In addition, liposomes promoted cardiac protection by not raising CK-MB levels in animals, keeping cardiomyocytes without injury or electrocardiographic changes. After 14 days of treatment, free PTX/DXR caused prolongation of the QRS interval when compared to LCFL-PTX/DXR treatment at the same dose (37.0 ± 5.01 ms and 30.83 ± 2.62 ms, respectively, with p = 0.017). The survival rate of animals treated with LCFL-PTX/DXR was three times higher than that of those treated with free drugs. Thus, it was established that the toxicity of LCFL-PTX/DXR is reduced compared to the combination of free PTX/DXR and this platform has advantages for the clinical treatment of breast cancer. [Display omitted] •LCFL-PTX/DXR reduced in vivo toxicity compared to free PTX/DXR.•ECG showed that LCFL-PTX/DXR induced lower cardiac toxicity compared to free PTX/DXR.•Survival of animals treated with LCFL-PTX/DXR is three times higher than free PTX/DXR.•The dose of LCFL-PTX/DXR tolerated by mice is 27% higher than that of free drugs.