Development of PEGylated Histone Deacetylase Inhibitor Having Prolonged Blood Retention and EPR effect

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kansai University
• Principal Investigator: NAGAOKA Yasuo 関西大学, 化学生命工学部, 教授 (90243039)
• Co-Investigator(Kenkyū-buntansha): HATTORI Yoshiyuki 星薬科大学, 薬学部, 准教授 (90350222)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: ヒストン脱アセチル化酵素阻害剤 / HDAC / PEG / 抗がん剤

Outline of Final Research Achievements

Since the hydroxamate type histone deacetylase inhibitor (HDI) like SAHA is readily degraded in physiological conditions, it has low bioavailability and is not applicable to the solid cancer so far. In order to overcome this drawback, we protected hydroxamic acid moiety with a polyethylene glycol (PEG) peptide conjugate and form micelle expecting to provide stealth effect and EPR (enhanced permeability and retention) effect to prolong the blood retention and to enhance the drug accumulation to the cancer tissue. PEG-peptide-SAHA is synthesized with coupling of SAHA with PEG-peptide prepared by solid-phase method. Micelles, whose average diameter is 40 nm, were formed and the molecules in the micelles were linked each other with S-S bonds to stabilize them. Retention of the molecule in blood, as well as anti-proliferative activity of PEG-peptide-SAHA micelle was higher than that of intact SAHA, indicating that PEGylated SAHA can efficiently act as prodrug of HDI.

Free Research Field

医薬品化学