'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded With Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice

Glioma is one of the fatal intracranial cancers that is a huge challenge to decrease the death rate currently. The deep penetration and high accumulation of therapeutic inorganic ions into the tumor site are extremely impeded due to the existence of physiological barriers, which limits to widen the indication of some drugs such as arsenic trioxide. The previous data have confirmed that the mannose substrate (MAN) without acetyl groups facilitates vesicles to go into the brain. Given that deacetylation of AC(4)MAN groups on the surface of liposomes under the enzyme incubation occurred, namely 'prodrug-like' features of vesicles, the liposomes could more easily penetrate the BBB, target the glioma site, release arsenic trioxide, and inhibit the growth of glioma cells in the brain. Besides, the possibility of AC(4)MAN binding to Gluts could be reduced due to the steric hindrance of acetyl groups, decreasing the off-target effects of vesicles. Here, we developed 'prodrug-like' arsenic trioxide (AS(2)O(3), ATO)-loaded liposomes inserted with distearoyl phospho-ethanolaminepolyethylene glycol-1000-p-carboxylpheny-alpha-D-acetylmannosamine (DSPE-PEG-1000-AC(4)MAN), which was named AC(4)MAN-ATO-LIP. Cytotoxic experiments of liposomes indicated that the toxicity of AC(4)MAN-ATO-LIP was lower than that of free ATO but stronger than that of ATO-LIP (without insertion of DSPE-PEG-1000-AC(4)MAN). The uptake of vesicles by U87 glioma cells displayed that the cellular uptake of AC(4)MAN-Rho-LIP (labeled by rhodamine) was remarkably improved, compared with Rho-LIP. The in vivo biodistribution results showed the superiority of AC(4)MAN-Rho-LIP in enhanced intracranial accumulation. Furthermore, the treatment of orthotopic glioma in Balb/c nude mice with AC(4)MAN-ATO-LIP elongated the survival time of the animals than that with physiological saline, free ATO, or ATO-LIP, respectively. All the results suggested that the AC(4)MAN-ATO-LIP had stronger anti-glioma effects as well as lower toxicities, and may be a promising approach for the treatment of brain cancer. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.