LAUSR

The stability and binding affinity of targeting ligands are very important in active targeting drug delivery. Herein we used LyP-1 peptide as a model peptide to investigate chemical-biology-based strategies in the design of peptide ligands for active targeting. LyP-1 is a short peptide cyclized with a disulfide bond. It can specifically bind to tumor cells and tumor lymphatics through the interaction with cell-surface protein p32/gC1qR. Lc(LyP-1), with a same sequence of LyP-1, is coupled by amide bond. It showed better cellular uptake and stability in blood in our previous research. Further, usually d-peptide demonstrates higher stability than l-peptide, and it may contribute to better active targeting ability in vivo. Herein, we designed a retro-inverso isomer of Lc(LyP-1), termed Dc(LyP-1), expecting to inspire brain metastatic tumor targeted drug delivery. However, although Lc(LyP-1) showed lower stability than Dc(LyP-1) in fresh rat bold serum, both the 4T1 cellular uptake capacity (89.20%) and p32 protein binding affinity (7.39 × 10-6) were significantly higher than those (33.41%, 1.37 × 10-5) of Dc(LyP-1). Further, Lc(LyP-1) modified PEG-PLA micelles displayed much higher in vivo distribution in brain metastatic tumor than Dc(LyP-1). All results suggested that Lc(LyP-1) had a better performance than Dc(LyP-1) in brain metastatic tumor-targeted drug delivery.