title: Dual pH-sensitive oxidative stress generating micellar nanoparticles as a novel anticancer therapeutic agent.
abstract: Cancer cells are under oxidative stress due to a large production of reactive oxygen species (ROS), which involve in cell proliferation and cancer promotion and progression. On the other hand, ROS promotes cell death, depending on the rate of ROS production and the activity of antioxidant systems. Recently, "oxidation therapy" has arisen as a promising anticancer strategy, which can be achieved by inducing the generation of cytotoxic level of ROS or inhibiting the antioxidant systems in tumor cells. Here, we report oxidative stress amplifying nanoplatforms as novel anticancer therapeutics, which are able not only to suppress antioxidant but also to generate ROS simultaneously in acidic tumor microenvironments. The oxidative stress amplifying nanoplatforms are composed of dual pH-sensitive PBCAE copolymer, polymeric prodrug of BCA (benzoyloxycinnamaldehyde) and heme oxygenase-1 (HO-1) inhibiting zinc protoporphyrin (ZnPP). PBCAE was designed to incorporate ROS-generating BCA in its backbone via acid-cleavable acetal linkages and self-assemble to form micelles that encapsulate ZnPP. In vitro proof-of-concept studies revealed that ZnPP encapsulated in PBCAE micelles suppressed HO-1 to make cancer cells more vulnerable to BCA-induced ROS, leading to enhanced apoptotic cell death. In addition, ZnPP-loaded PBCAE micelles significantly suppressed the tumor growth in human cancer xenograft mouse models. We believe that oxidative stress amplifying micellar nanoparticles have a great potential as novel redox anticancer therapeutics.
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Baekje-daero 567, Jeonju, Chonbuk, 561-756, Republic of Korea.
authors.forename: Sanga
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Baekje-daero 567, Jeonju, Chonbuk, 561-756, Republic of Korea.
authors.forename: Byeongsu
authors.initials: B
authors.lastname: Kwon
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Baekje-daero 567, Jeonju, Chonbuk, 561-756, Republic of Korea.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Baekje-daero 567, Jeonju, Chonbuk, 561-756, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Han
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Baekje-daero 567, Jeonju, Chonbuk, 561-756, Republic of Korea.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Yoo
authors.affiliation: Laboratory of Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, 125 Gwahakro Daejeon 305-806, Republic of Korea.
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Baekje-daero 567, Jeonju, Chonbuk, 561-756, Republic of Korea; Polymer Fusion Research Center, Department of Polymer Nano Science and Technology, Chonbuk National University, Baekje-daero 567,Jeonju, Chonbuk, 561-756, Republic of Korea. Electronic address: dlee@chonbuk.ac.kr.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles; D018384:Oxidative Stress / Q000187:drug effects*; D011108:Polymers; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C484327:2'-benzoyloxycinnamaldehyde; D000970:Antineoplastic Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D008823:Micelles; D011108:Polymers; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D000171:Acrolein; D051547:Heme Oxygenase-1
keywords: Apoptosis; Cancer; Micelles; Oxidative stress; Reactive oxygen species