PMID- 25818409 OWN - NLM STAT- MEDLINE DCOM- 20151214 LR - 20171021 IS - 1878-5905 (Electronic) IS - 0142-9612 (Linking) VI - 52 DP - 2015 Jun TI - Gene therapy for nucleus pulposus regeneration by heme oxygenase-1 plasmid DNA carried by mixed polyplex micelles with thermo-responsive heterogeneous coronas. PG - 1-13 LID - S0142-9612(15)00134-9 [pii] LID - 10.1016/j.biomaterials.2015.02.024 [doi] AB - Safe and high-efficiency gene therapy for nucleus pulposus (NP) regeneration was urgently desired to treat disc degeneration-associated diseases. In this work, an efficient nonviral cationic block copolymer gene delivery system was used to deliver therapeutic plasmid DNA (pDNA), which was prepared via complexation between the mixed cationic block copolymers, poly(ethylene glycol)-block-polyN-[N-(2-aminoethyl)-2-aminoehtyl]aspartamide [PEG-b-PAsp(DET)] and poly(N-isopropylacrylamide)-block-PAsp(DET) [PNIPAM-b-PAsp(DET)], and pDNA at 25 degrees C. The mixed polyplex micelles (MPMs) containing heterogeneous coronas with hydrophobic and hydrophilic microdomains coexisting could be obtained upon heating from 25 to 37 degrees C, which showed high tolerability against nuclease and strong resistance towards protein adsorption. The gene transfection efficiency of MPMs in NP cells was significantly higher than that of regular polyplex micelles prepared from sole block copolymer of PEG-b-PAsp(DET) (SPMs) in in vitro and in vivo evaluation due to the synergistic effect of improved colloidal stability and low cytotoxicity. High expression of heme oxygenase-1 (HO-1) in NP cells transfected by MPMs loading HO-1 pDNA significantly decreased the expression activity of matrix metalloproteinases 3 (MMP-3) and cyclo-oxygenase-2 (COX-2) induced by interleukin-1beta (IL-1beta), and simultaneously increased the NP phenotype-associated genes such as aggrecan, type II collagen, and SOX-9. Moreover, the therapeutic effects of MPMs loading pDNA were tested to treat disc degeneration induced by stab injury. The results demonstrated that administration of HO-1 pDNA carried by MPMs in rat tail discs apparently reduced inflammatory responses induced by need stab and increased glycosaminoglycan (GAG) content, finally achieving better therapeutic efficacy as compared with SPMs. Consequently, MPMs loading HO-1 pDNA were demonstrated to be potential as a safe and high-efficiency nonviral gene delivery system for retarding or regenerating the degenerative discs. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Feng, Ganjun AU - Feng G AD - Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Chen, Hongying AU - Chen H AD - Technology Center for Public Research, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Li, Junjie AU - Li J AD - CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China. FAU - Huang, Qiang AU - Huang Q AD - Technology Center for Public Research, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Gupte, Melanie J AU - Gupte MJ AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Liu, Hao AU - Liu H AD - Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Song, Yueming AU - Song Y AD - Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Ge, Zhishen AU - Ge Z AD - CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China. Electronic address: gezs@ustc.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150218 PL - Netherlands TA - Biomaterials JT - Biomaterials JID - 8100316 RN - 0 (Acrylic Resins) RN - 0 (Micelles) RN - 25189-55-3 (poly-N-isopropylacrylamide) RN - 9007-49-2 (DNA) RN - EC 1.14.14.18 (Heme Oxygenase-1) SB - IM MH - Acrylic Resins/chemistry MH - Animals MH - Cells, Cultured MH - Cervical Vertebrae/metabolism/*physiology MH - DNA/*administration & dosage/genetics/therapeutic use MH - Gene Expression Regulation MH - Genetic Therapy/*methods MH - Genetic Vectors/administration & dosage/genetics/therapeutic use MH - Heme Oxygenase-1/*genetics MH - Micelles MH - Plasmids/*administration & dosage/genetics/therapeutic use MH - Rabbits MH - Rats MH - Rats, Sprague-Dawley MH - *Regeneration MH - Temperature MH - Transfection OTO - NOTNLM OT - Gene therapy OT - Nonviral gene carrier OT - Nucleus pulposus regeneration OT - Polyplex micelles OT - Thermo-responsive EDAT- 2015/03/31 06:00 MHDA- 2015/12/15 06:00 CRDT- 2015/03/31 06:00 PHST- 2014/12/06 00:00 [received] PHST- 2015/01/28 00:00 [revised] PHST- 2015/02/01 00:00 [accepted] PHST- 2015/03/31 06:00 [entrez] PHST- 2015/03/31 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - S0142-9612(15)00134-9 [pii] AID - 10.1016/j.biomaterials.2015.02.024 [doi] PST - ppublish SO - Biomaterials. 2015 Jun;52:1-13. doi: 10.1016/j.biomaterials.2015.02.024. Epub 2015 Feb 18.