title: Nitric oxide releasing d-α-tocopheryl polyethylene glycol succinate for enhancing antitumor activity of doxorubicin.
abstract: Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when codelivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized d-α-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release ∼90% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO3 could also serve as an enhancer for the common chemotherapeutic drug doxorubicin (DOX). Codelivering TNO3 with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (∼6.25-fold lower IC50). Moreover, for DOX-based chemotherapy in tumor-bearing mice, coadministration with TNO3 significantly extended the blood circulation time of DOX (14.7-fold t1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO3, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.
authors.affiliation: Tongji School of Pharmacy and ‡National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology , Wuhan 430030, China.
authors.forename: Qingle
authors.initials: Q
authors.lastname: Song
authors.forename: Songwei
authors.initials: S
authors.lastname: Tan
authors.forename: Xiangting
authors.initials: X
authors.lastname: Zhuang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Guo
authors.forename: Yongdan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.forename: Qi
authors.initials: Q
authors.lastname: Ye
authors.forename: Luqin
authors.initials: L
authors.lastname: Si
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D005260:Female; D006207:Half-Life; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008823:Micelles; D009569:Nitric Oxide / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D014810:Vitamin E; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D004317:Doxorubicin; C014225:tocophersolan
keywords: TPGS; antitumor; doxorubicin; nitric oxide