A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo

Abstract

Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents.

Co-delivery of Bmi1 small interfering RNA with ursolic acid by folate receptor-targeted cationic liposomes enhances anti-tumor activity of ursolic acid in vitro and in vivo

“…Therefore, many folate-targeted ligands were used to functionalized liposomes and any other nanocarrier drug delivery systems (Xiang et al., 2008; Jiang et al., 2009). In our previous and this study, we also successfully designed folate-targeted ligands as active targeting moieties (Huang et al., 2014). The cellular uptake of Bmi1 siRNA could be substantially enhanced through Folate-targeted liposomes delivery (Figure 2), suggesting the effectiveness of folate-targeted ligands.…”

Honokiol-loaded polymeric nanoparticles: an active targeting drug delivery system for the treatment of nasopharyngeal carcinoma

“…FR is a glycosyl phosphatidylinositol-anchored membrane protein, which is over-expressed in more than 90% of ovarian carcinomas and in other epithelial cancers to varying degrees. The distinct expression pattern of FR between normal and malignant tissues makes it an ideal target for drug delivery (Huang et al, 2014 ). A recent study showed that FR is over-expressed in the HNE-1 cell lines (Xie et al, 2013 ).…”