Single Acute-Dose and Repeat-Doses Toxicity of anti-HIV-1 PNATAR–Penetratin Conjugate after Intraperitoneal Administration to Mice

ABSTRACT Polyamide (peptide) nucleic acids conjugated with membrane-penetrating peptide are potential antisense therapeutic agents because of their unique chemical properties, high target specificity, and efficient cellular uptake. However, studies of their potential toxicity in animal models are lacking. In this study, we evaluated the toxicity of the response of Balb/C mice to anti-HIV-1 PNATAR–penetratin conjugate targeted against the transactivation response (TAR) element of HIV-1 LTR. A single i.p. dose of 600 mg/kg of body weight was lethal, killing all mice within 72 hours. However, death did not occur after single doses of 100 and 300 mg/kg, although all mice experienced initial and transitory diarrhea and loss of agility. Repeated daily doses of 10, 30, and 100 mg/kg were well tolerated by mice during 8 days of treatment, although daily doses of 100 mg/kg caused diarrhea during the first 4 days of treatment. During 8 weeks of follow-up, mice fully recuperated. Serositis was observed in the spleen...