Abstract |
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, 10958-65). 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.
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Authors | Ying Li, Yang Lei, Ernst Wagner, Cao Xie, Weiyue Lu, Jianhua Zhu, Jie Shen, Jing Wang, Min Liu |
Journal | Bioconjugate chemistry
(Bioconjug Chem)
Vol. 24
Issue 1
Pg. 133-43
(Jan 16 2013)
ISSN: 1520-4812 [Electronic] United States |
PMID | 23241015
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibiotics, Antineoplastic
- Drug Carriers
- Peptides
- Phosphatidylethanolamines
- polyethylene glycol-distearoylphosphatidylethanolamine
- Polyethylene Glycols
- Doxorubicin
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Topics |
- Amino Acid Sequence
- Animals
- Antibiotics, Antineoplastic
(administration & dosage, pharmacokinetics, therapeutic use)
- Cell Line
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Doxorubicin
(administration & dosage, pharmacokinetics, therapeutic use)
- Drug Carriers
(chemistry, metabolism)
- Drug Delivery Systems
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Neoplasms
(blood supply, drug therapy, pathology)
- Peptides
(chemistry, metabolism)
- Phosphatidylethanolamines
(chemistry, metabolism)
- Polyethylene Glycols
(chemistry, metabolism)
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