Abstract

Liposomes with peptides motifs have been widely applied for targeted delivery of anticancer drugs . However, few studies have questioned whether peptide modification on liposomes may induce serious toxicity associated with immune stimulation. Here, we report that display of a tumor targeting cyclic RGD peptide ( e.g. c(RGDyK) and c(RGDfK) on the surface of liposomes can be a potent inducer of lethal hypersensitivity-like reactions in mice upon re-administration, with the main symptom a sudden drop in body temperature. The hypothermia usually abates within 4 h but is sometimes lethal with death happening within 30 min post injection. This reaction has been proven to be IgE-independent acute systemic anaphylaxis , which may due to IgG immune complex triggered complement activation, anaphylatoxin and cytokine release, etc. , leading to acute conspicuous organ damage. Results from an exploration of influence factors showed that the immunotoxicity of c(RGDyK)-liposomes could not be eliminated by minimizing the c(RGDyK) motif ratio, or by decreasing injection doses in the normal dose range, or by increasing the mPEG-DSPE motif ratio. However, encapsulation of a strong cytotoxic drug completely shut off this unwanted immune response. Investigation with a series of peptides containing the RGD sequence suggested that the lethal immunotoxicity of the cyclic RGD peptide was RGD sequence and peptide cyclization dependent. This study provides a valuable alert for the utilization of peptide modified liposomes in drug delivery, especially when carrying low-toxicity drugs.