title: Hypoxia-responsive ionizable liposome delivery siRNA for glioma therapy.
abstract: Here, we report the hypoxia-responsive ionizable liposomes to deliver small interference RNA (siRNA) anticancer drugs, which can selectively enhance cellular uptake of the siRNA under hypoxic and low-pH conditions to cure glioma. For this purpose, malate dehydrogenase lipid molecules were synthesized, which contain nitroimidazole groups that impart hypoxia sensitivity and specificity as hydrophobic tails, and tertiary amines as hydrophilic head groups. These malate dehydrogenase molecules, together with DSPE-PEG2000 and cholesterol, were self-assembled into O'1,O1-(3-(dimethylamino)propane-1,2-diyl) 16-bis(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl) di(hexadecanedioate) liposomes (MLP) to encapsulate siRNA through electrostatic interaction. Our study showed that the MLP could deliver polo-like kinase 1 siRNA (siPLK1) into glioma cells and effectively enhance the cellular uptake of MLP/siPLK1 because of increased positive charges induced by hypoxia and low pH. Moreover, MLP/siPLK1 was shown to be very effective in inhibiting the growth of glioma cells both in vitro and in vivo. Therefore, the MLP is a promising siRNA delivery system for tumor therapy.
authors.affiliation: Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University; Department of Neurosurgery, Institute of Nervous System Diseases, Xuzhou Medical University.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University; Department of Neurosurgery, Institute of Nervous System Diseases, Xuzhou Medical University.
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University; Department of Neurosurgery, Institute of Nervous System Diseases, Xuzhou Medical University.
authors.forename: Yan-Dong
authors.initials: YD
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University; Department of Neurosurgery, Institute of Nervous System Diseases, Xuzhou Medical University.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University; Department of Neurosurgery, Institute of Nervous System Diseases, Xuzhou Medical University.
authors.forename: Bai-Yang
authors.initials: BY
authors.lastname: Li
authors.affiliation: Department of Hematology, Affiliated Hospital of Xuzhou Medical University.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Chemistry, School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, Jiangsu, People's Republic of China.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Zeng
authors.affiliation: Department of Chemistry, School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, Jiangsu, People's Republic of China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University; Department of Neurosurgery, Institute of Nervous System Diseases, Xuzhou Medical University.
authors.forename: Ru-Tong
authors.initials: RT
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D051381:Rats; D013057:Spectrum Analysis; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008081:Liposomes; D008291:Malate Dehydrogenase; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
keywords: cellular uptake; hypoxia responsive; hypoxic conditions; ionizable liposome; siRNA delivery