ES2660906T3 - Nanopartículas de ácido nucleico y usos de las mismas - Google Patents
Nanopartículas de ácido nucleico y usos de las mismas Download PDFInfo
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- ES2660906T3 ES2660906T3 ES08756527.1T ES08756527T ES2660906T3 ES 2660906 T3 ES2660906 T3 ES 2660906T3 ES 08756527 T ES08756527 T ES 08756527T ES 2660906 T3 ES2660906 T3 ES 2660906T3
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- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- AFBXRHFIVUFPES-UHFFFAOYSA-N 5-methyl-1h-pyrimidine-2,4-dione Chemical compound CC1=CNC(=O)NC1=O.CC1=CNC(=O)NC1=O AFBXRHFIVUFPES-UHFFFAOYSA-N 0.000 description 1
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- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
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- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
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- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
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- 238000004166 bioassay Methods 0.000 description 1
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- 210000003855 cell nucleus Anatomy 0.000 description 1
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- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
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- 125000003835 nucleoside group Chemical group 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
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- 108091092562 ribozyme Proteins 0.000 description 1
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- 229940104230 thymidine Drugs 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
Una suspensión o dispersión de nanopartículas que comprende una población de partículas, donde la suspensión o dispersión de nanopartículas comprende una nanoemulsión, donde la mayoría de partículas tienen diámetros entre 10 nanómetros y 300 nanómetros, y donde las nanopartículas comprenden al menos un ácido nucleico de hasta 30 nucleótidos de longitud que tiene actividad biológica en la piel, tejido subcutáneo, músculo contiguo o tejido distante, donde la nanoemulsión comprende una premezcla de al menos un aceite, un tensioactivo, agua y el ácido nucleico, donde el aceite es un triglicérido de cadena media o aceite de soja y el tensioactivo es TWEEN.
Description
En algunas realizaciones, la composición de nanopartículas consiste esencialmente en agua, un aceite, un tensioactivo y al menos un agente biológicamente activo (p.ej., un ácido nucleico). En algunas realizaciones, la composición de nanopartículas consiste esencialmente en agua, un aceite, un tensioactivo, al menos un agente biológicamente activo y al menos una sustancia usada para producir y/o conservar la composición de
5 nanopartículas.
En algunas realizaciones, la composición de nanopartículas consiste en agua, un aceite, un tensioactivo y un ácido nucleico. En algunas realizaciones, la composición de nanopartículas consiste en agua, un aceite, un tensioactivo, un ácido nucleico y al menos una sustancia usada para producir y/o conservar las nanopartículas.
10
Ácidos nucleicos
Puede incorporarse cualquiera de una variedad de ácidos nucleicos a composiciones de nanopartículas de acuerdo con la presente invención. En algunas realizaciones, el ácido nucleico para incorporar a una composición de
15 nanopartículas es un polinucleótido. En algunas realizaciones, el ácido nucleico para incorporar a una composición de nanopartículas es un nucleótido. En algunas realizaciones, el ácido nucleico para incorporar a una composición de nanopartículas es un nucleósido.
En algunas realizaciones, un ácido nucleico es menor de alrededor de 50 nucleótidos de longitud. En algunas
20 realizaciones, un ácido nucleico es menor de alrededor de 90, alrededor de 80, alrededor de 70, alrededor de 65, alrededor de 60, alrededor de 55, alrededor de 50, alrededor de 45, alrededor de 40, alrededor de 35, alrededor de 30, alrededor de 25, alrededor de 20, alrededor de 15, alrededor de 13, alrededor de 12, alrededor de 10, alrededor de 9, alrededor de 8, alrededor de 7, alrededor de 6, alrededor de 5, alrededor de 4, alrededor de 3 o alrededor de 2 nucleótidos de longitud. En algunas realizaciones específicas, un ácido nucleico es un único residuo de ácido
25 nucleico (p.ej., un único nucleótido o un único nucleósido). En algunas realizaciones, el ácido nucleico para incorporar a una composición de nanopartículas comprende solo residuos de ácido nucleico de origen natural (p.ej., nucleótidos, nucleósidos). En algunas realizaciones, un ácido nucleico comprende uno o más residuos de ácido nucleico de origen no natural.
30 En general, un nucleósido comprende un azúcar pentosa (p.ej., ribosa o desoxirribosa) y una base nitrogenada heterocíclica (p.ej., purinas: citosina, timidina y uracilo; y pirimidinas: guanina y adenina; véase la Tabla 1) ligados covalentemente por un enlace glicosídico. En general, un nucleótido comprende un nucleósido y de uno a tres grupos 5’ fosfato. Tabla 1: Bases nitrogenadas heterocíclicas
- Nombre trivial
- Símbolo Nombre sistemático Fórmula
- Adenina (6-aminopurina)
- A 7H-purin-6-amina
- Citosina
- C 4-amino-3H-pirimidin2-ona
- Guanina (2-amino-6-oxopurina; 2aminohipoxantina)
- G 2-amino-1H-purin6(9H)-ona
- Timina (5-metiluracilo)
- T 5-metilpirimidin2,4(1H,3H)-diona
- Uracilo (2-oxi-4-oxipirimidina; 2,4-(1H,3H)pirimidindiona; 2,4-dihidroxipirimidina; 2,4pirimidindiol)
- U pirimidin-2,4(1H,3H)diona
15
5
15
25
35
45
55
65
menudo no contribuyen significativamente a la especificidad del reconocimiento de diana y pueden ser menos críticos para la escisión de diana.
Los microARN (miARN) son ARN no codificantes codificados genómicamente de alrededor de 21-23 nucleótidos de longitud que ayudan a regular la expresión génica, particularmente durante el desarrollo (véanse, p.ej., Bartel, 2004, Cell, 116: 281; Novina y Sharp, 2004, Nature, 430: 161 y la publicación de patente de EE.UU. 2005/0059005; también revisada en Wang y Li, 2007, Front. Biosci., 12: 3975 y Zhao, 2007, Trends Biochem. Sci., 32: 189. El fenómeno de la interferencia de ARN, ampliamente definido, incluye los efectos de silenciamiento génico inducido endógenamente de miARN así como silenciamiento desencadenado por dsARN extraño. Los miARN maduros son estructuralmente similares a los siARN producidos a partir de dsARN exógeno, pero antes de alcanzar la madurez, los miARN experimentan primero una extensa modificación postranscripcional. Un miARN se expresa típicamente a partir de un gen codificante de ARN mucho más largo como transcrito primario conocido como primiARN, que se procesa en el núcleo celular hasta una estructura de tallo-bucle de 70 nucleótidos denominada premiARN por el complejo microprocesador. Este complejo consiste en una enzima ARNasa III denominada Drosha y una proteína de unión a dsARN Pasha. La porción de dsARN de este premiARN se une y escinde por Dicer, produciendo la molécula de miARN madura que puede integrarse en el complejo RISC; por tanto, miARN y siARN comparten la misma maquinaria celular posteriormente a su procesamiento inicial (Gregory et al., 2006, Meth. Mol. Biol., 342: 33. En general, los miARN no son perfectamente complementarios de sus transcritos diana.
En algunas realizaciones, los miARN pueden oscilar en el intervalo entre 18 nt-26 nt de longitud. Típicamente, los miARN son monocatenarios. Sin embargo, en algunas realizaciones, los miARN pueden ser al menos parcialmente bicatenarios. En ciertas realizaciones, los miARN pueden comprender un dúplex de ARN (al que se hace referencia en la presente memoria como una “región de dúplex”) y pueden comprender opcionalmente además uno o dos salientes monocatenarios. En algunas realizaciones, un agente de iARN comprende una región de dúplex que oscila de 15 pb a 29 pb de longitud y que comprende opcionalmente además uno a tres salientes monocatenarios. Un miARN puede formarse a partir de dos moléculas de ARN que hibridan conjuntamente, o puede generarse como alternativa a partir de una sola molécula de ARN que incluye una porción de autohibridación. La porción de dúplex de un miARN comprende habitualmente, pero no necesariamente, una o más protuberancias consistentes en uno o más nucleótidos no apareados. Una hebra de un miARN incluye una porción que hibrida con un ARN diana. En ciertas realizaciones, una hebra del miARN no es exactamente complementaria de una región del ARN diana, lo que significa que el miARN hibrida con el ARN diana con uno o más desapareamientos. En algunas realizaciones, una hebra del miARN es exactamente complementaria de una región del ARN diana, lo que significa que el miARN hibrida con el ARN diana sin desapareamientos. Típicamente, se cree que los miARN median la inhibición de la expresión génica al inhibir la traducción de transcritos diana. Sin embargo, en algunas realizaciones, los miARN pueden mediar la inhibición de la expresión génica causando la degradación de los transcritos diana.
En ciertas realizaciones, un ácido nucleico es o comprende una ribozima diseñada para escindir catalíticamente transcritos de ARNm diana que puede usarse para evitar la traducción de un ARNm diana y/o la expresión de una diana (véanse, p.ej., la publicación PCT WO 90/11364 y Sarver et al., 1990, Science 247: 1222).
En ciertas realizaciones, un ácido nucleico es o comprende un ácido nucleico que participa en la formación de estructuras de triple hélice. La expresión endógena del gen diana puede reducirse orientándose a secuencias desoxirribonucleotídicas complementarias de la región reguladora del gen diana (p.ej., el promotor y/o potenciadores del gen diana), formando estructuras de triple hélice que previenen la transcripción del gen diana en células musculares diana del cuerpo (véanse en general, Helene, 1991, Anticancer Drug Des. 6: 569; Helene et al., 1992, Ann. NY Acad. Sci. 660: 27 y Maher, 1992, Bioassays 14: 807).
En algunos aspectos, el mecanismo mediante el cual un ácido nucleico particular ejerce un efecto terapéutico y/o afecta a una actividad biológica es desconocido. La presente invención contempla el uso de tales ácidos nucleicos. En algunas realizaciones, pueden usarse los procedimientos de la presente invención para el suministro (p.ej., suministro transdérmico) de ácidos nucleicos biológicamente activos (p.ej., polinucleótidos y/o residuos de ácido nucleico) que no se han identificado ni caracterizado todavía.
En algunas realizaciones, los ácidos nucleicos para usar de acuerdo con la presente invención mejoran la curación de heridas. Tales ácidos nucleicos incluyen ADN codificante del factor de crecimiento de queratinocitos 1 (KGF-1) (Lin et al., 2006, Wound Repair Regen., 14: 618). En algunas realizaciones, los ácidos nucleicos que codifican KGF1 se caracterizan por toda o una porción de una secuencia como se expone en la secuencia de GenBank NC_000015. En algunas realizaciones, los ácidos nucleicos para usar de acuerdo con la presente invención pueden promover la curación de heridas cutáneas. Tales ácidos nucleicos incluyen oligonucleótidos anticodificantes de Conexina43 (Cx43), agentes de iARN, siARN, shARN y/o miARNA (Mori et al., 2006, J Cell Sci., 119: 5193). En algunas realizaciones, los oligonucleótidos anticodificantes, agentes de iARN, siARN, shARNA y/o miARN pueden orientarse a una o más regiones y/o porciones características de un ácido nucleico que tiene una secuencia tal como la expuesta en la secuencia de GenBank AK312324.
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-
2008
- 2008-05-30 CN CN200880100579.1A patent/CN101765423B/zh not_active Expired - Fee Related
- 2008-05-30 US US12/671,693 patent/US10016451B2/en not_active Expired - Fee Related
- 2008-05-30 KR KR1020097027262A patent/KR20100050443A/ko not_active Withdrawn
- 2008-05-30 CN CN201410153149.3A patent/CN103961315A/zh active Pending
- 2008-05-30 EP EP08756527.1A patent/EP2162117B1/en not_active Not-in-force
- 2008-05-30 WO PCT/US2008/065329 patent/WO2008151022A2/en not_active Ceased
- 2008-05-30 KR KR1020157005113A patent/KR20150028856A/ko not_active Ceased
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- 2008-05-30 ES ES08756527.1T patent/ES2660906T3/es active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| KR20150028856A (ko) | 2015-03-16 |
| CA2688415A1 (en) | 2008-12-11 |
| CN103961315A (zh) | 2014-08-06 |
| WO2008151022A3 (en) | 2009-04-30 |
| WO2008151022A2 (en) | 2008-12-11 |
| CN101765423B (zh) | 2014-08-06 |
| IL202345A0 (en) | 2010-06-30 |
| EP2162117B1 (en) | 2018-02-21 |
| CA2688415C (en) | 2015-11-10 |
| KR20100050443A (ko) | 2010-05-13 |
| CN101765423A (zh) | 2010-06-30 |
| US10016451B2 (en) | 2018-07-10 |
| US20110305734A1 (en) | 2011-12-15 |
| EP2162117A2 (en) | 2010-03-17 |
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