Antimetastatic activity of polymeric RGDT peptides conjugated with poly(ethylene glycol).
Polymeric peptides containing defined repetitive or cyclic structures of RGDT sequence, (RGDT)n (n = 1 to 11) and cyclo(RGDT)n (n = 2 to 4), at a dose of 500 micrograms exhibited an inhibitory effect on experimental lung metastasis upon co-injection with tumor cells and the magnitude of the effect increased in parallel with the increase of degree of repetition of the RGDT sequence. The conjugation of (RGDT)n (n = 1, 5, 11) with poly(ethylene glycol), PEG as a polymeric carrier led to enhanced inhibition of lung metastasis in proportion to the degree of RGDT sequence repetition and in a dose-dependent manner. Multiple i.v. administrations of PEG-(RGDT)11, at 2-day and 3-day intervals before the excision of primary tumors, effectively inhibited spontaneous lung metastasis by s.c. inoculation of tumors, whereas (RGDT)11 exhibited inhibition of lung metastasis only when given at 2-day intervals. This indicates that the conjugation of PEG with (RGDT)n allowed the prolongation of administration interval, implying a sustained inhibitory effect on tumor metastasis. In support of this supposition, a decrease in the arrest of radiolabeled tumor cells in the lungs was observed when PEG-(RGDT)11 was co-injected i.v. with tumor cells, or injected i.v. one day before tumor inoculation. In contrast, (RGDT)11 significantly inhibited the tumor cell arrest in the lungs only upon co-injection with tumor cells. We also noted that (RGDT)n, cyclo(RGDT)n and PEG-(RGDT)11 inhibited tumor cell invasion into Matrigel in a concentration-dependent manner and in proportion to the degree of RGDT sequence repetition, indicating that the peptide-mediated antimetastatic effect is partly associated with the anti-invasive potential. Thus, the conjugation of anti-cell adhesive and anti-metastatic RGDT peptide with PEG might provide a therapeutically promising basis for the prevention of cancer metastasis ("anti adhesion therapy").
Saiki
I
I
Institute of Immunological Science, Hokkaido University, Sapporo.
Yoneda
J
J
Igarashi
Y
Y
Aoki
M
M
Kusunose
N
N
Ono
K
K
Azuma
I
I
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms
D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011092:Polyethylene Glycols; C065722:poly (arginyl-glycyl-aspartyl-threonine)