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 μg 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 antimetastatic RGDT peptide with PEG might provide a therapeutically promising basis for the prevention of cancer metastasis (“anti adhesion therapy”).