title: Azo polymeric micelles designed for colon-targeted dimethyl fumarate delivery for colon cancer therapy.
abstract: Colon-targeted drug delivery and circumventing drug resistance are extremely important for colon cancer chemotherapy. Our previous work found that dimethyl fumarate (DMF), the approved drug by the FDA for the treatment of multiple sclerosis, exhibited anti-tumor activity on colon cancer cells. Based on the pharmacological properties of DMF and azo bond in olsalazine chemical structure, we designed azo polymeric micelles for colon-targeted dimethyl fumarate delivery for colon cancer therapy. We synthesized the star-shape amphiphilic polymer with azo bond and fabricated the DMF-loaded azo polymeric micelles. The four-arm polymer star-PCL-azo-mPEG (sPCEG-azo) (constituted by star-shape PCL (polycaprolactone) and mPEG (methoxypolyethylene glycols)-olsalazine) showed self-assembly ability. The average diameter and polydispersity index of the DMF-loaded sPCEG-azo polymeric micelles were 153.6nm and 0.195, respectively. In vitro drug release study showed that the cumulative release of DMF from the DMF-loaded sPCEG-azo polymeric micelles was no more than 20% in rat gastric fluid within 10h, whereas in the rat colonic fluids, the cumulative release of DMF reached 60% in the initial 2h and 100% within 10h, indicating that the DMF-loaded sPCEG-azo polymeric micelles had excellent colon-targeted property. The DMF-loaded sPCEG-azo polymeric micelles had no significant cytotoxicity on colon cancer cells in phosphate buffered solution (PBS) and rat gastric fluid. In rat colonic fluid, the micelles showed significant cytotoxic effect on colon cancer cells. The blank sPCEG-azo polymeric micelles (without DMF) showed no cytotoxic effect on colon cancer cells in rat colonic fluids. In conclusion, the DMF-loaded sPCEG-azo polymeric micelles show colon-targeted DMF release and anti-tumor activity, providing a novel approach potential for colon cancer therapy.
  
  
  
  Colon-targeted drug delivery and circumventing drug resistance are extremely important for colon cancer chemotherapy. Our previous work found that dimethyl fumarate (DMF), the approved drug by the FDA for the treatment of multiple sclerosis, exhibited anti-tumor activities on colon cancer cells (Br J Pharmacol. 2015 172(15):3929-43.). Based on the pharmacological properties of DMF and azo bond in olsalazine chemical structure, we designed azo polymeric micelles for colon-targeted dimethyl fumarate delivery for colon cancer therapy. We found that the DMF-loaded sPCEG-azo polymeric micelles showed colon-targeted DMF release and anti-tumor activities, providing a novel approach potential for colon cancer therapy.
authors.affiliation: Institute of Materials Processing and Intelligent Manufacturing & Center for Biomedical Materials and Engineering, Harbin Engineering University, PR China.
authors.forename: Zhen-Gang
authors.initials: ZG
authors.lastname: Ma
authors.affiliation: Institute of Materials Processing and Intelligent Manufacturing & Center for Biomedical Materials and Engineering, Harbin Engineering University, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, PR China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, PR China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, PR China.
authors.forename: Xin-Zi
authors.initials: XZ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, PR China.
authors.forename: Jin-Lai
authors.initials: JL
authors.lastname: Gao
authors.affiliation: Institute of Materials Processing and Intelligent Manufacturing & Center for Biomedical Materials and Engineering, Harbin Engineering University, PR China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, PR China.
authors.forename: De-Li
authors.initials: DL
authors.lastname: Dong
authors.affiliation: Institute of Materials Processing and Intelligent Manufacturing & Center for Biomedical Materials and Engineering, Harbin Engineering University, PR China. Electronic address: zhijiesun@hrbeu.edu.cn.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Sun
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D065546:Drug Liberation; D000067493:Dynamic Light Scattering; D006801:Humans; D008297:Male; D008823:Micelles; D011108:Polymers / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D001391:Azo Compounds; D008823:Micelles; D011108:Polymers; D000069462:Dimethyl Fumarate
keywords: Colon cancer cells; Colon-targeted; Dimethyl fumarate; Micelles; Olsalazine