Potent Retro-Inverso d-Peptide for Simultaneous Targeting of Angiogenic Blood Vasculature and Tumor Cells

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• 作者：Ying Li ; Yang Lei ; Ernst Wagner ; Cao Xie ; Weiyue Lu ; Jianhua Zhu ; Jie Shen ; Jing Wang ; Min Liu
• 刊名：Bioconjugate Chemistry
• 出版年：2013
• 出版时间：January 16, 2013
• 年：2013
• 卷：24
• 期：1
• 页码：133-143
• 全文大小：540K
• 年卷期：v.24,no.1(January 16, 2013)
• ISSN：1520-4812

文摘

The application of tumor targeting ligands for the treatment of cancer holds the promise of enhanced efficacy and reduced toxicity. L-SP5 (_L(SVSVGMKPSPRP)) is a peptide that recognizes tumor neovasculature but not normal blood vessels (Lee et al., Cancer Res.2007, 67, 10958鈥?5). The current report presents the design and application of D-SP5 (_D(PRPSPKMGVSVS)), a novel retro-inverso analogue of L-SP5. Peptides D-SP5 and parental L-SP5 are shown to compete for the same target sites of a yet unknown cellular target and possess a dual-targeting bioactivity for both activated endothelial cells (HUVEC) and several tumor cell lines. Cellular uptake experiments showed superior in vitro targeting abilities of D-SP5 compared with L-SP5, such as enhanced internalization into stimulated HUVEC or KB, U87, and SGC tumor cells. A radioligand receptor binding assay revealed a higher cell affinity of D-SP5 in all tested cell lines, with K_d values for D-SP5 about 2-fold lower than for L-SP5. An up to 3-fold higher maximum binding capacity (B_max) to cells of D-SP5 was noted. Fluorescein-labeled D-SP5 upon intravenous administration displayed strong association with tumor endothelium. D-SP5-conjugated PEG-DSPE micelles displayed enhanced tumor homing (evidenced by near-infrared in vivo imaging). When loaded with doxorubicin, D-SP5 micelles could markedly suppress tumor growth with higher efficacy than L-SP5 micelles both in vitro and in vivo in KB tumor xenografts. In summary, the data demonstrate that D-SP5 displays higher binding affinities toward tumor endothelium as well as tumor cells and enhanced tumor targeting capability in vitro and in vivo.