title: pH-Responsive Polymer Conjugate of Pirarubicin With Styrene Maleic Acid Copolymer as a Potential Therapeutic for Ovarian Cancer.
abstract: Previous studies indicated the potential of styrene maleic acid copolymer (SMA)-conjugated pirarubicin (4'-O-tetrahydropyranyldoxorubicin [THP]) for targeted anticancer therapy based on the enhanced permeability and retention effect. In this study, to achieve further improved therapeutic efficacy, a pH-responsive SMA-conjugated THP-containing hydrazone bond (SMA-hyd-THP) was synthesized and evaluated in vitro and ex vivo using human ovarian cancer cells and tissues. SMA-hyd-THP showed good water solubility, forming micelles with a mean particle size of 48.0 nm, which is applicable for enhanced permeability and retention-based tumor accumulation. The THP loading in this preparation was 15% (wt/wt), and release rate of free THP from SMA-hyd-THP at physiological pH (7.4) was approximately 10% in 72 h. However, it increased rapidly at pH 6.5 (42%) and 5.5 (83%), which indicates that tumor environment of weak acidic condition (pH 6.5-6.9) is favorable for release of THP. This notion was partly proved by incubating SMA-hyd-THP with tumor tissues from ovarian cancer patients. In addition, release of THP was not affected by serum, suggesting that SMA-hyd-THP is relatively stable in circulation. Finally, SMA-hyd-THP showed much increased cytotoxicity against various ovarian cancer cells at acidic tumor pH (6.5). These findings may provide an option for targeted therapy against ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Dalian Municipal Central Hospital, Dalian Medical University, Dalian, 116033, People's Republic of China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Sheng Jing Hospital, China Medical University, Shenyang, 110004, People's Republic of China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Yin
authors.affiliation: School of Public Health, Anhui Medical University, 81th Meishan Road, Hefei City, Anhui Province, 230032, People's Republic of China; Institute of Drug Delivery Science, Sojo University, Ikeda 4-22-1, Kumamoto Nishi-ku, 860-0082, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Obstetrics and Gynecology, Dalian Municipal Central Hospital, Dalian Medical University, Dalian, 116033, People's Republic of China.
authors.forename: Xianyu
authors.initials: X
authors.lastname: Jin
keywords: EPR effect; antitumor therapy; ovarian cancer; pirarubicin; styrene maleic acid copolymer; tumor targeting