title: Injectable supramolecular hydrogel formed from α-cyclodextrin and PEGylated arginine-functionalized poly(l-lysine) dendron for sustained MMP-9 shRNA plasmid delivery.
abstract: Hydrogels have attracted much attention in cancer therapy and tissue engineering due to their sustained gene delivery ability. To obtain an injectable and high-efficiency gene delivery hydrogel, methoxypolyethylene glycol (MPEG) was used to conjugate with the arginine-functionalized poly(l-lysine) dendron (PLLD-Arg) by click reaction, and then the synthesized MPEG-PLLD-Arg interacted with α-cyclodextrin (α-CD) to form the supramolecular hydrogel by the host-guest interaction. The gelation dynamics, hydrogel strength and shear viscosity could be modulated by α-CD content in the hydrogel. MPEG-PLLD-Arg was confirmed to bind and deliver gene effectively, and its gene transfection efficiency was significantly higher than PEI-25k under its optimized condition. After gelation, MMP-9 shRNA plasmid (pMMP-9) could be encapsulated into the hydrogel matrix in situ and be released from the hydrogels sustainedly, as the release rate was dependent on α-CD content. The released MPEG-PLLD-Arg/pMMP-9 complex still showed better transfection efficiency than PEI-25k and induced sustained tumor cell apoptosis. Also, in vivo assays indicated that this pMMP-9-loaded supramolecular hydrogel could result in the sustained tumor growth inhibition meanwhile showed good biocompatibility. As an injectable, sustained and high-efficiency gene delivery system, this supramolecular hydrogel is a promising candidate for long-term gene therapy.
  
  
  
  To realize the sustained gene delivery for gene therapy, a supramolecular hydrogel with high-efficiency gene delivery ability was prepared through the host-guest interaction between α-cyclodextrin and PEGylated arginine-functionalized poly(l-lysine) dendron. The obtained hydrogel was injectable and biocompatible with adjustable physicochemical property. More importantly, the hydrogel showed the high-efficiency and sustained gene transfection to our used cells, better than PEI-25k. The supramolecular hydrogel resulted in the sustained tumor growth inhibition meanwhile keep good biocompatibility. As an injectable, sustained and high-efficiency gene delivery system, this supramolecular hydrogel is a promising candidate in long-term gene therapy and tissue engineering.
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Otolaryngology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: The School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: 3D Imaging and Bioengineering Laboratory, Department of Mechanical Engineering, Curtin University, Australia.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wu
authors.affiliation: 3D Imaging and Bioengineering Laboratory, Department of Mechanical Engineering, Curtin University, Australia.
authors.forename: Thomas Brett
authors.initials: TB
authors.lastname: Kirk
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China. Electronic address: madong_jnu@163.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China. Electronic address: weixue_jnu@aliyun.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000737:chemistry*; D001672:Biocompatible Materials / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D050091:Dendrimers / Q000737:chemistry; D004587:Electrophoresis, Agar Gel; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007267:Injections; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D010957:Plasmids / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011107:Polylysine / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection; D014961:X-Ray Diffraction; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D050091:Dendrimers; D034741:RNA, Small Interfering; D047391:alpha-Cyclodextrins; D049452:Green Fluorescent Proteins; D011107:Polylysine; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D001120:Arginine; D020780:Matrix Metalloproteinase 9; C032613:alpha-cyclodextrin
keywords: Arginine; Poly(l-lysine) dendrimer; Supramolecular hydrogels; Sustained gene delivery