Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

Abstract

Background:Integrins α v β 3 and α v β 5 , both of which specifically recognize the Arg-Gly-Asp (RGD) motif, are overexpressed on many solid tumors and in tumor neovasculature. Thus, coupling the RGD motif to the liposomal surface for achieving active targeting can be a promising strategy for the treatment of tumors. Methods: Cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGD) was covalently coupled with the liposomal membrane surface, followed by coating with poly(ethylene glycol) (PEG) using the post-insertion technique. The coupling efficiency of cRGD was determined. Doxorubicin as a model anticancer drug was loaded into liposomes using an ammonium sulfate gradient method to investigate the encapsulation efficiency, cellular uptake by the integrin-overexpressing human glioma cell line U87MG in vitro, and pharmacokinetic properties in Sprague-Dawley rats. Results: cRGD was conjugated to the liposomal surface by a thiol-maleimide coupling reaction. The coupling efficiency reached 98%. The encapsulation efficiency of doxorubicin in liposomes was more than 98%. The flow cytometry test result showed that cRGD-modified liposomes (RGD-DXRL-PEG) had higher cell uptake by U87MG cells, compared with nontargeted liposomes (DXRL-PEG). The cellular uptake was significantly inhibited in the presence of excess free cRGD. Both the targeted (t 1/2 = 24.10 hours) and non-targeted (t 1/2 = 25.32 hours) liposomes showed long circulating properties in rat plasma. The area under the curve of the targeted and nontargeted liposomes was 6.4-fold and 8.3-fold higher than that of doxorubicin solution, respectively. Conclusion: This study indicates preferential targeting and long circulating properties for cRGD-modified liposomes in vivo, which could be used as a potential targeted liposomal drug delivery system to treat human glioma.

A new target ligand Ser–Glu for PEPT1-overexpressing cancer imaging

“…16 In peptides functionalized NP fields, RGD (arginine-glycine-aspartic acid) peptide family maybe the most widely applied peptide ligand, which can specifically bind to cancer overexpressed α v β 3 integrin receptors. 17,18 Peptide transporter 1 (PEPT1) is a member of peptide transporters. 19 Under healthy conditions, PEPT1 restrictedly existed in the epithelial cells of small intestine, kidney and bile duct, and nuclei and lysosomes of pancreas.…”

The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation

“…4,5 For example, Arg-Gly-Asp (RGD) -or Asn-Gly-Arg (NGR)-modified targeting drug delivery systems have been extensively investigated. [6][7][8][9][10] [CRGDK/RGPD/EC]), has been reported to enhance vascularity and tissue permeability in a tumor-specific and neuropilin-1 (NRP-1)-dependent manner. 11 The mechanism for how iRGD homes to tumor sites has been explained in detail.…”

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects

“…Furthermore, according to recent reports, when cRGD 31 and other targeted ligands (folate, transferrin, and others) 32,33 are used to modify liposomes, these are usually cleared faster than nontargeted liposomes.…”