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LIPID MEMBRANE STRUCTURE meetings

Foreign code F120006481
File No. S2010-0171-C0
Posted date May 7, 2012
Country WIPO
International application number 2011JP053963
International publication number WO 2011135905
Date of international filing Feb 23, 2011
Date of international publication Nov 3, 2011
Priority data
  • P2010-103333 (Apr 28, 2010) JP
Title LIPID MEMBRANE STRUCTURE meetings
Abstract Disclosed is a lipid membrane structure which fulfils intracellular migration properties, selectivity for target cells and in vivo stability and can be used for the delivery of a substance to a target cell. In the lipid membrane structure, a lipid membrane is modified with (a) polyalkylene glycol having a target-cell-selective ligand bound thereto and (b) a polypeptide containing multiple arginine residues.
Outline of related art and contending technology BACKGROUND ART
Drag, delivery, system (DDS) used as is to a membrane structure such as a lipid of the liposome, the ability to retain the drug, in vivo stability, drug should be delivered to a particular cell (target cell) selectivity, a target cell to go, the release of the drug within the target cells and the like various performance are required. In particular, in the nucleus or the cytoplasm of the target for delivery of a drug or nucleic acid in the lipid membrane structure, as well as selectivity to target cells, within the cell, in particular of the specific organelle such as nucleus inside the target cell and thus an excellent migration.
The inventors have found that, previously, such as octaarginine (R8) a peptide having consecutive arginine residues of the lipid membrane by modifying the surface of the structure, transfer from the cells of the lipid membrane structure, in particular nuclear import can be improved are found (International Publication WO2005/032593; Journal of Controlled Release, 98, pp.317-323, 2004). However, modifications can comprise R8, specificity for a particular cell is not provide internalization. In addition, due to a cationic R8, R8 modified lipid membrane structure may be easily and quickly evacuated from the living body, lipid modified R8 film structure is selected to be within the delivery to target cells is thought to be difficult.
On the other hand, the in vivo stability of the lipid membrane structure, particularly as a method of increasing blood stability, polyalkylene glycol, typically polyethylene glycol (PEG) modified the surface of the lipid membrane structure is widely known (for example, JP-1-249717 publication, JP-2-149512 publication, JP-4-346918 publication, JP-2004-10481 are described in Japanese Patent Application). The method, a lipid membrane structure PEG hydration layer covering the carrier particles such as opsonization and serum protein adsorption is suppressed and the like, as a result, phagocytosis by macrophages and uptake by the reticuloendothelial system based on the tissue can be avoided.
However, R8 was modified with the lipid membrane structure for the purpose of enhancing the in vivo stability of the lipid membrane structure further PEG and modify the surface, by modification of R8 internalization ability is lost and there is a problem. That is, lipid membrane structure R8 and simultaneous modifications PEG, modified PEG the lipid membrane structure to improve the in vivo stability of the other hand, that lower the cell transition in a contradicting problem (also referred to as the dilemma PEG) has been altered.
This PEG as an attempt to solve the dilemma, the present inventor et al. further phospholipid PEG residues between residues of the matrix metalloproteinase can be a substrate peptide comprising substrate arranged phospholipid derivatives is created, the lipid membrane structure lipid derivatives are proposed (Japanese Patent Application JP-2007-099750). The lipid membrane structure is a matrix metalloproteinase by cleavage of the peptide portion PEG for a property of being desorbed and, in the blood is stable due to the presence of the site of modification on the other hand, malignant tumor cells secrete matrix metalloprotease in the vicinity of the site of modification in the lipid membrane structure being detached from the characteristic of lowering the stability of the has. Due to this characteristic, the lipid membrane structure held in the anti-tumor agent and a nucleic acid is released at the outside of the malignant tumor cells, or the site of modification in the dissociation of the lipid membrane structure in the malignant tumor cells efficiently taken up by, or nucleic acid of the drug in malignant tumor cells can be introduced efficiently.
However, in Japanese Patent Application Laid-open 2007-099750 the technique, as malignant tumor cells secrete matrix metalloprotease DDS of even though it is effective, other target cells, or that do not secrete matrix metalloprotease in particular, the amount of secretion or less relative to the effectiveness as DDS cannot be hardly expected, other than the malignant tumor cells to improve the selectivity in the cells is not particularly limited.
In addition, the lipid membrane structure as a method of increasing the selectivity towards the target cells, such as the cell membrane surface receptors that are present in a particular cell-specific expression of the living body to the substance or ligand can selectively bind to the lipid membrane structure of the surface-modifying methods have been known. In this method, the in vivo stability of the lipid membrane structure to improve the selectivity for the target cell in order to satisfy at the same time, via PEG ligand is generally arranged on the surface of the lipid membrane structure in many cases. However, the lipid membrane structure is a target cell specific ligand selectivity for the modification of the performance improves, mediated endocytosis into cells of the saturation property due to uptake, intracellular migration property of the lipid membrane structure is the upper limit, the uptake of the drug or the like is expected at the high medicinal effect cannot be enhanced and has a problem. In this way, conventional, intracellular migration, selectivity for target cells, and in vivo stability of the lipid membrane structure is satisfactory at the same time has yet to be provided in.
Scope of claims (In Japanese)請求の範囲 [請求項1]
標的細胞に物質を送達するための脂質膜構造体であって、脂質膜が下記の(a)及び(b):
(a)標的細胞選択性リガンドが結合したポリアルキレングリコール;及び
(b)複数個のアルギニン残基を含むポリペプチド
で修飾された脂質膜構造体。

[請求項2]
脂質膜構造体がリポソームである請求項1に記載の脂質膜構造体。

[請求項3]
脂質膜構造体の表面が上記(a)ポリアルキレングリコール及び(b)ポリペプチドで修飾された請求項1又は2に記載の脂質膜構造体。

[請求項4]
標的細胞選択性リガンドが標的細胞の細胞膜外側に発現しているレセプターに特異的に結合可能なリガンドである請求項1ないし3のいずれか1項に記載の脂質膜構造体。

[請求項5]
上記(a)ポリアルキレングリコールの先端部に標的細胞選択性リガンドが結合した請求項1ないし4のいずれか1項に記載の脂質膜構造体。

[請求項6]
上記(a)ポリアルキレングリコール及び(b)ポリペプチドが疎水性基で修飾されており、前記疎水性基が脂質膜に挿入された請求項1ないし5のいずれか1項に記載のの脂質膜構造体。

[請求項7]
上記(b)ポリペプチドが4ないし20個の連続したアルギニン残基を含むポリペプチドである請求項1ないし6のいずれか1項に記載の脂質膜構造体。

[請求項8]
上記(a)ポリアルキレングリコールがポリエチレングリコールである請求項1ないし7のいずれか1項に記載の脂質膜構造体。

[請求項9]
送達すべき物質が内部に封入された請求項1ないし8のいずれか1項に記載の脂質膜構造体。

[請求項10]
内部に遺伝子を含む核酸及びカチオン性ポリマーが封入された請求項9に記載の脂質膜構造体。

[請求項11]
内部に抗腫瘍剤が封入された請求項9に記載の脂質膜構造体。

[請求項12]
抗腫瘍剤がドキソルビシンである請求項11に記載の脂質膜構造体。

[請求項13]
標的細胞選択性リガンドがリガンドペプチドである請求項11に記載の脂質膜構造体。

[請求項14]
リポソーム形態である請求項11ないし13のいずれか1項に記載の脂質膜構造体。

[請求項15]
粒子径が約200 nm~400 nmの範囲である請求項14に記載の脂質膜構造体。

[請求項16]
請求項9ないし15のいずれか1項に記載の脂質膜構造体を有効成分として含む医薬組成物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION HOKKAIDO UNIVERSITY
  • Inventor
  • HARASHIMA Hideyoshi
  • HATAKEYAMA Hiroto
  • KHALIL Ikramy
  • TAKARA Kazuhiro
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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