Abstract
HM-3, designed by our laboratory, is a polypeptide composed of 18 amino acids. Pharmacodynamic studies in vivo and in vitro indicated that HM-3 could inhibit endothelial cell migration and angiogenesis, thereby inhibiting tumor growth. However, the half-life of HM-3 is short. In this study, we modified HM-3 with different polyethylene glycols (PEG) in order to reduce the plasma clearance rate, extend the half-life in the body, maintain a high concentration of HM-3 in the blood and increase the therapeutic efficiency. HM-3 was modified with four different types of PEG with different molecular weights (ALD-mPEG5k, ALD-mPEG10k, SC-mPEG10k and SC-mPEG20k), resulting in four modified products (ALD-mPEG5k-HM-3, ALD-mPEG10k-HM-3, SC-mPEG10k-HM-3 and SC-mPEG20k-HM-3, respectively). Anti-tumor activity of these four modified HM-3 was determined in BALB/c mice with Taxol as a positive control and normal saline as a negative control. Tumor weight inhibition rates of mice treated with Taxol, HM-3, ALD-mPEG5k-HM-3, ALD-mPEG10k-HM-3, SC-mPEG10k-HM-3 and SC-mPEG20k-HM-3 were 44.50%, 43.92%, 37.95%, 31.64%, 20.27% and 50.23%, respectively. Tumor inhibition rates in the Taxol, HM-3 and SC-mPEG20k-HM-3 groups were significantly higher than that in the negative control group. The efficiency of tumor inhibition in the SC-mPEG20k-HM-3 group (drug treatment frequency: once per two days) was better than that in the HM-3 group (drug treatment frequency: twice per day). In addition, tumor inhibition rate in the SC-mPEG20k-HM-3 group was higher than that in the taxol group. We conclude that SC-mPEG20k-HM-3 had a low plasma clearance rate and long half-life, resulting in high anti-tumor therapeutic efficacy in vivo. Therefore, SC-mPEG20k-HM-3 could be potentially developed as new anti-tumor drugs.
Highlights
HM-3 is a new anti-tumor polypeptide developed in our laboratory, which is composed of 18 amino acids and previous studies showed that the target of HM-3 is integrin [1]
Our results showed that the modified product, SC-mPEG20k-HM-3, had a low plasma clearance rate, long half-life and retained its anti-tumor activity excellently
RP-high-performance liquid chromatography (HPLC) analysis showed that the purity of the four polyethylene glycol (PEG)-modified HM-3 products (ALD-mPEG5k-HM-3, ALD-mPEG10k- HM-3, SC-mPEG10k-HM-3 and SC-mPEG20k-HM-3) was over
Summary
HM-3 is a new anti-tumor polypeptide developed in our laboratory, which is composed of 18 amino acids and previous studies showed that the target of HM-3 is integrin (αvβ3) [1]. In vivo and in vitro studies have shown that HM-3 could inhibit endothelial cell migration and angiogenesis, thereby inhibiting tumor growth. HM-3 is expected to be developed as therapeutic drugs for the treatment of solid tumors including gastric and liver cancer [2]. HM-3 has been authorized as a national invention patent and declared for an international patent [3]. Similar to other peptide drugs, the half-life of HM-3 is short (approximately 25 min). Animal studies suggested that the optimal therapeutic efficiency could be obtained by administration of the drug twice a day
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