Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates.

ABSTRACT

Thyrotropin-releasing hormone (TRH) and TRH-like peptides carry a therapeutic potential for neurological conditions. Nanoparticles (NP) made of the biodegradable polymer, Poly(Sebacic Anhydride) (PSA), have been developed to carry TRH, intended for intranasal administration to patients. There is limited information on the safety of biodegradable polymers when given intranasally, and therefore, we have performed two preclinical safety and toxicity studies in cynomolgus monkeys and rats using TRH-PSA nanoparticles. The rats and monkeys were dosed intranasally for 42 days or 28 days, respectively, and several animals were followed for additional 14 days. Animals received either placebo, vehicle (PSA), or different concentrations of TRH-PSA. No systemic adverse effects were seen. Changes in T3 or T4 concentrations were observed in some TRH-PSA-treated animals, which did not have clinical or microscopic correlates. No effect was seen on TSH or prolactin concentrations. In the monkey study, microscopic changes in the nasal turbinates were observed, which were attributed to incidental mechanical trauma caused during administration. Taken together, the TRH-loaded PSA NPs have proven to be safe, with no local or systemic adverse effects attributed to the drug loaded nanoparticles. These findings provide additional support to the growing evidence of the safety of peptide-loaded NPs for intranasal delivery and pave the way for future clinical trials in humans.