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LIPID MEMBRANE STRUCTURE FOR DELIVERY INTO SIRNA CELL NEW 新技術説明会

外国特許コード F190009750
整理番号 (S2017-0830-N0)
掲載日 2019年5月7日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2018JP022940
国際公開番号 WO 2018230710
国際出願日 平成30年6月15日(2018.6.15)
国際公開日 平成30年12月20日(2018.12.20)
優先権データ
  • 特願2017-117708 (2017.6.15) JP
発明の名称 (英語) LIPID MEMBRANE STRUCTURE FOR DELIVERY INTO SIRNA CELL NEW 新技術説明会
発明の概要(英語) A lipid membrane structure contains, as a lipid component, a lipid compound represented by formula (I): (R1)(R2)C(OH)-(CH2)a-(O-CO)b-X [wherein a represents an integer of 3 to 5; b represents an integer of 0 or 1; R1 and R2 independently represent a linear hydrocarbon group that may have -CO-O-; and X represents a 5- to 7-membered non-aromatic heterocyclic group or a group represented by formula (B) (wherein d represents an integer of 0 to 3; and R3 and R4 independently represent a C1-4 alkyl group or a C2-4 alkenyl group, wherein R3 and R4 may be bonded together to form a 5- to 7-membered non-aromatic hetero ring (wherein one or two C1-4 alkyl groups or C2-4 alkenyl groups may be present as substituents on the ring))].
従来技術、競合技術の概要(英語) BACKGROUND ART
Agent specific to the diseased part of the lipid membrane as a means of transporting an agent is a liposome structure has been proposed a method of encapsulating. In particular, the treatment of malignant tumors filled with anti-tumor agents in the art that the effectiveness of the liposomes are many reported. In addition, the available gene expression as a multi-functional lipid membrane structure enveloped nanostructures (MEND: Multifunctional envelope-type nano device; hereinafter, abbreviated as' MEND ' is used herein. For example see Non-Patent Document 1 or the like) is proposed. This structure is, in a particular cell such as a gene for the selective delivery can be used as a drug, for example, such as gene therapy of a tumor is known to be useful.
Lipid drug using the film structure, nucleic acid, peptide, polypeptide, a sugar such as the target organ or tumor tissue such as the target substance to a specific site as a means for delivering, to the surface of the lipid membrane structure is modified with functional molecules have been proposed many methods. Anti-tumor agents of an agent such as a lipid containing membrane structure may be, reaches to a target cell within the cell by endocytosis incorporated in the state and are encompassed within the endosome, thereafter, a lysosomal enzyme hydrolysis action or the like included in the receiving agent has been released into the cytoplasm. Endosome incorporated into the liposome in order to enhance the release of drug from, the surface of the liposome (GALA: Non-Patent Document 2) the peptide in the liposome (Non-Patent Document 3) or (Patent Document 4) the MEND has been proposed.
In addition, the nucleic acid containing a target substance such as a lipid film structure is transferred into the nucleus of the target cell as a means for, for example, the external surface of the liposome in the liposome octaarginine (Patent Document 1, Non-Patent Document 4), nuclear translocation peptides modified with a lipid membrane (Patent Document 2) has a membrane of two 2, galactose or mannose surface of monosaccharides such as liposome (Patent Document 3) has been proposed. Modified saccharide multiple lipid membrane structure is a lipid membrane and nucleus (T-MEND) of the fuzed film, in the in vitro test results and thereby improving the efficiency of gene expression have been reported. Further, (non-patent document 5) by modifying the KALA peptide lipid film structure of a material such as nucleic acid into the nucleus of the cell efficiently deliver (Patent Document 5) have been reported.
On the other hand, dendritic cells, the center of the immune response from the responsible for antigen presenting cell, a cancer immunotherapy is one of significant target cell 1. Dendritic cells from a cancer patient collected, outside the activation is conducted after introduction of an antigen, an immune cell therapy is administered to the patient again (dendritic cell therapy) have also been carried out. In recent years, in a dendritic cell has been found from immunosuppressive factors, dendritic cells are also attracting attention as a target of the siRNA and pharmaceutical, dendritic cells can be combined with therapies therapy, cancer immunity inducing the more powerful and can be expected.
Conventional, dendritic cells for introducing RNA into the nucleus, a lentiviral vector expressing the shRNA used immunosuppressive factors knocked down are reported (Non-Patent Document 6, Non-Patent Document 7) is present. However, artificial delivery systems using siRNA introduction to the dendritic cells is hardly reported. The use of viral vectors of the target gene knockdown be achieved in a high efficiency, there is a problem in safety.
SiRNA delivery system is introduced as an artificial R8/GALA-D-MEND(D-MEND) have been reported (Non-Patent Document 8). D-MEND is, the cell affinity (R8) peptide octaarginine element in the endosome escape element GALA MEND modified peptide, the number of the envelope film nano MEND control carrier. D-MEND is, commonly used in cancer cells are HeLa cells at concentrations as low as about 12 nm 70% the concentration of the siRNA knockdown of shown, its activity is introduced into the general purpose as a reagent (LFN2000) compared to 2 2000 Appropriate times more activity.
However, the mouse bone marrow cells derived from transfected with dendritic cells in the case D-MEND, 70-80% siRNA knockdown efficiency in order to achieve a higher concentration (80-120 nm) is necessary, the target of the siRNA knockdown efficiency by a factor of about 40% is also a problem that remains in the (non-patent document 9). In this way a conventional artificial in the case of using a delivery system, a typical cancer cells than in the dendritic cells tend to knock down efficiency is largely lowered, deployed in the field of pharmaceutical immune therapy siRNA are prevented.
So far, the functional nucleic acid, in particular of a given target gene expression in vivo delivery of siRNA capable of suppressing in order to achieve efficient, the number of cationic lipids have been developed. In particular, physiological pH is electrically neutral, mildly acidic endosomal pH environment such as changes in pH sensitive cationic significant development of the cationic lipid. Jayaraman et al. developed DLin-MC3-DMA, the first (F7) in mouse liver ED50 in the knock-down factors in 7 to achieve a 0.005 mg siRNA/kg (non-patent document 10). The present inventors so far unique pH sensitive cationic lipid and has developed a YSK13-C3 YSK05, F7 knockdown in achieving 0.06,0.015 mg siRNA/kg as the ED50 (non-patent document 11, Non-Patent Document 12, Non-Patent Document 13). In addition, a biodegradable Maier et al. MC3-DMA was developed to provide L319, ED50 and 0.01 mg siRNA/kg in both the high safety was reported (Non-Patent Document 14, Non-Patent Document 15, Non-Patent Document 16). However, these lipid-containing lipid nanoparticles of the endosome escape efficiency is still only about % number and not the (non-patent document 17), to further improve the bioavailability of the development of technology has been desired.
Further, Dong et al. is a lipid-like material through a high-found unique cKK-E12, F7 knockdown in ED50 was achieved in 0.002 mg siRNA/kg (non-patent document 18). On the active surface of the art literature is the most excellent, high dose toxicity in lipid biosynthesis and degradation in the safety and the like is not found.
In recent years, many cancer tissue, especially a human patient is cancerous tissue, collagen including interstitial component is very abundant, the components of the nanoparticles in cancer tissue significantly interfere with the permeability being revealed. The size of the nanoparticles in order to solve this problem very thought of as an effective strategy. In fact, Cabral et al., the diameter of the micelle polymer in the formulation of platinum about 30 nm to the sealing is controlled to be small in the cancerous tissue in the improved permeability, anti-tumor effect can be enhanced (Non-Patent Document 19) reports. SiRNA delivery in the same strategy is considered to be very effective, lipid nanoparticles (Lipid Nanoparticle: LNP) is technically difficult to be small, the report is very poor. 2 Liquid mixture can be achieved at the moment of the built-in micro flow path of the mixer which has a diameter of about 30 nm can be manufactured with good reproducibility in the LNP, in recent years have been reported (Non-Patent Document 20, Non-Patent Document 21). On the other hand, in the size of the LNP, the siRNA delivery activity has been found to significantly reduce the (non-patent document 22, Non-Patent Document 23). To overcome this problem for the treatment of cancer or siRNA delivery technique is excellent in order to achieve a very important role on the other hand, at present no knowledge about the method to overcome this is.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • HOKKAIDO UNIVERSITY
  • 発明者(英語)
  • HARASHIMA Hideyoshi
  • SATO Yusuke
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA 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 RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ 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 KM ML MR NE SN ST TD TG
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