HM-3, An RGD (Arg-Gly-Asp)-modified polypeptide derived from endostatin, is a potent angiogenesis inhibitor. Its robust inhibitory effects on endothelial cell migration and tumor growth have been demonstrated by activity assay both in vitro and in vivo. However, HM-3 has relatively short half-life in vivo. In order to prolong its half-life and retain its safety and efficacy, previous studies modified HM-3 with four types of PEG (site-specific N-terminal modification), and the results showed that mPEG-SC20k-HM-3 was the most ideal modification product via activity evaluation in vivo. In the present study, we determined the pharmacokinetic properties, immunogenicity and binding targets of mPEG-SC20k-HM-3. The results showed that mPEG-SC20k-HM-3 had good linear pharmacokinetic properties in SD rats. The half-life of mPEG-SC20k-HM-3 was 43.76-fold longer than that of unmodified HM-3 after intravenous injection in SD rats. The administration frequency of the modified product (mPEG-SC20k-HM-3) was reduced from twice a day to once every 2 days, while the safety and efficacy were retained. The immunogenicity of mPEG-SC20k-HM-3 was significantly lower than that of HM-3 in BALB/c mice. Histochemical and immunohistochemical results showed that mPEG-SC20k-HM-3 could significantly inhibit angiogenesis and tumor growth, induce continuous necrosis, and reduce vessel density within tumor tissues. Furthermore, mPEG-SC20k-HM-3 could bind multi-target αvβ3 and α5β1 of integrin, and the major binding target was integrin αvβ3. All of these results indicated that PEGylated HM-3 had a good application prospect.
Keywords: PEGylation, anti-tumor, integrin, polypeptide, pharmacokinetics, immunogenicity, targets, mechanism, endostatin, angiogenesis inhibitor
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