Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

Chong Li,^1,2 Yixin Wang,³ Xiaolin Zhang,¹ Li Deng,¹ Yan Zhang,¹ Zhangbao Chen<sup>1

1</sup>Key Laboratory on Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China; ²School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Fudan University, Shanghai, People's Republic of China; ³Department of Pharmacy, the Second People's Hospital of Sichuan Province and Sichuan Cancer Hospital, Chengdu, People's Republic of China

Abstract: Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting.

Keywords: tumor targeting, liposome, cyclic peptide, selenopeptide