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1. 发明申请

WO2005055980A2 POLYMALIC ACID-BASED MULTIFUNCTIONAL DRUG DELIVERY SYSTEM 审中-公开
标题翻译：基于聚合酸的多功能药物递送系统
公开(公告)号：WO2005055980A2
公开(公告)日：2005-06-23
申请号：PCT/US2004/040660
申请日：2004-12-03
申请人： ARROGENE, INC. , LJUBIMOVA, Julia, Y. , BLACK, Keith, L. , HOLLER, Eggehard
发明人： LJUBIMOVA, Julia, Y. , BLACK, Keith, L. , HOLLER, Eggehard
IPC分类号： A61K9/00
CPC分类号： A61K47/6883 , A61K47/593 , A61K47/60
摘要： A structured drug system that is useful for delivering a drug payload to a specific tissue or cell type is disclosed. The system is based on purified polymalic acid. This polymer isolated from natural sources is biocompatible, biodegradable and of very low toxicity. The polymer is extremely water soluble and contains a large number of free carboxyl groups which can used to attach a number of different active molecules. In the examples disclosed N-hydroxysuccinimide esters of the carboxyl groups are used to attach such molecules. The active molecules include monoclonal antibodies to promote specific cellular uptake and specific pro-drugs such as antisense nucleic acids designed to modify the cellular metabolism of a target cell. The pro-drugs are advantageously linked by a somewhat labile bond so that they will be released under specific conditions. In addition, the system contains amide-linked valine to encourage membrane disruption under lysosomal conditions. Polyethylene glycol groups are attached to extend the drug system's circulation half-life. In addition, fluorescent reported groups can be readily included to aid in visualizing and confirming drug system targeting. The drug system can deliver treatments for a wide range of diseases and is specially advantageous for treatment of neoplasms.
摘要翻译：公开了一种用于将药物有效载荷递送到特定组织或细胞类型的结构化药物系统。该系统基于纯化的聚丙酸。从天然来源分离的聚合物是生物相容的，可生物降解的，毒性非常低。聚合物极易水溶，并含有大量游离羧基，可用于连接许多不同的活性分子。在实施例中，羧基的N-羟基琥珀酰亚胺酯用于附着这些分子。活性分子包括促进特异性细胞摄取的单克隆抗体和特异性前体药物，例如旨在修饰靶细胞的细胞代谢的反义核酸。前药有利地通过稍微不稳定的键连接，使得它们将在特定条件下释放。此外，该系统含有酰胺键缬氨酸，以促进溶酶体条件下的膜破坏。连接聚乙二醇基团以延长药物系统的循环半衰期。此外，可以容易地包括荧光报告的组以帮助可视化和确认药物系统靶向。药物系统可以为广泛的疾病提供治疗，特别有利于治疗肿瘤。

2. 发明申请

WO2012139030A1 POLYMALIC ACID BASED NANOCONJUGATES FOR IMAGING 审中-公开
标题翻译：基于聚合酸的纳米颗粒成像
公开(公告)号：WO2012139030A1
公开(公告)日：2012-10-11
申请号：PCT/US2012/032573
申请日：2012-04-06
申请人： CEDARS-SINAI MEDICAL CENTER , BLACK, Keith L. , LJUBIMOVA, Julia Y. , LJUBIMOV, Alexander V. , HOLLER, Eggehard
发明人： BLACK, Keith L. , LJUBIMOVA, Julia Y. , LJUBIMOV, Alexander V. , HOLLER, Eggehard
IPC分类号： A61K49/00 , C07C211/00
CPC分类号： A61K49/16 , A61K47/593 , A61K49/128
摘要： Nanoconjugates include a polymalic-based molecular scaffold with one or more imaging moiety and one or more targeting modules attached to the scaffold. At least one imaging moiety and at least one targeting module is conjugated to the polymalicacid based molecular scaffold. Methods of synthesizing the nanoconjugate involve providing a polymalic acid having a plurality of pendant carboxyi groups. The method reacts a compound containing sulfhydryl groups and amino acid groups through the pendant carboxyi groups to add sulfhydryl groups to the polymalic acid to form an activated polymalic acid. The method reacts at least one imaging moiety containing a sulfhydryl binding group to the activated polymalic acid to form a preconjugate. The method may involve administering to the subject a nanoconjugate that includes a polymalic acid-based molecular scaffold, at least one imaging moiety, and at least one targeting module.
摘要翻译：纳米缀合物包括具有一个或多个成像部分和连接到支架的一个或多个靶向模块的基于聚丙烯的分子支架。至少一个成像部分和至少一个靶向模块与基于聚缩水甘油的分子支架缀合。合成纳米缀合物的方法涉及提供具有多个侧链羧基的聚丙酸。该方法通过侧基羧基将含有巯基和氨基酸的化合物反应，以向聚丙酸中加入巯基以形成活化的聚丙酸。该方法将含有巯基结合基团的至少一个成像部分与活化的聚丙酸反应形成预共轭物。该方法可以包括向受试者施用包括基于聚丙酸的分子支架，至少一个成像部分和至少一个靶向模块的纳米缀合物。

3. 发明申请

WO2012091718A1 POLYMALIC ACID-BASED NANOBIOPOLYMER COMPOSITIONS AND METHODS FOR TREATING CANCER 审中-公开
标题翻译：基于聚合酸的纳米聚酰亚胺组合物和治疗癌症的方法
公开(公告)号：WO2012091718A1
公开(公告)日：2012-07-05
申请号：PCT/US2010/062515
申请日：2010-12-30
申请人： CEDARS-SINAI MEDICAL CENTER , INOUE, Satoshi , DING, Hui , HOLLER, Eggehard , BLACK, Keith , LJUBIMOVA, Julia
发明人： INOUE, Satoshi , DING, Hui , HOLLER, Eggehard , BLACK, Keith , LJUBIMOVA, Julia
IPC分类号： A61K39/395 , A61K38/16 , A61K47/30 , A61P35/00
CPC分类号： C07K16/32 , A61K39/39558 , A61K47/593 , A61K47/60 , A61K47/6855 , A61K47/6883 , A61K2039/505 , C12N15/113 , C12N15/1138 , C12N2310/11 , C12N2310/14 , C12N2310/3233 , C12N2320/31 , C12N2320/32 , A61K2300/00
摘要： Nanobiopolymeric conjugates based on biodegradable, non-toxic and non- immunogenic poly (β-L-malic acid) PMLA covalently linked to molecular modules that include morpholino antisense oligonucleotides (AONa), an siRNA or an antibody specific for an oncogenic protein in a cancer cell, and an antibody specific for a transferrin receptor protein, are efficient for treatment a cancer in a subject.
摘要翻译：基于可生物降解，无毒和非免疫原性的聚（β-L-苹果酸）PMLA的纳米生物共轭物共价连接到分子模块，分子模块包括吗啉代反义寡核苷酸（AONa），siRNA或对癌症中致癌蛋白质特异的抗体细胞和特异于转铁蛋白受体蛋白的抗体对于治疗受试者的癌症是有效的。

4. 发明申请

WO2005055980A3 POLYMALIC ACID-BASED MULTIFUNCTIONAL DRUG DELIVERY SYSTEM 审中-公开
标题翻译：基于聚合酸的多功能药物递送系统
公开(公告)号：WO2005055980A3
公开(公告)日：2006-01-05
申请号：PCT/US2004040660
申请日：2004-12-03
申请人： ARROGENE INC , LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD
发明人： LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD
IPC分类号： A61K47/48
CPC分类号： A61K47/6883 , A61K47/593 , A61K47/60
摘要： A structured drug system that is useful for delivering a drug payload to a specific tissue or cell type is disclosed. The system is based on purified polymalic acid. This polymer isolated from natural sources is biocompatible, biodegradable and of very low toxicity. The polymer is extremely water soluble and contains a large number of free carboxyl groups which can used to attach a number of different active molecules. In the examples disclosed N-hydroxysuccinimide esters of the carboxyl groups are used to attach such molecules. The active molecules include monoclonal antibodies to promote specific cellular uptake and specific pro-drugs such as antisense nucleic acids designed to modify the cellular metabolism of a target cell. The pro-drugs are advantageously linked by a somewhat labile bond so that they will be released under specific conditions. In addition, the system contains amide-linked valine to encourage membrane disruption under lysosomal conditions. Polyethylene glycol groups are attached to extend the drug system's circulation half-life. In addition, fluorescent reported groups can be readily included to aid in visualizing and confirming drug system targeting. The drug system can deliver treatments for a wide range of diseases and is specially advantageous for treatment of neoplasms.
摘要翻译：公开了一种用于将药物有效载荷递送到特定组织或细胞类型的结构化药物系统。该系统基于纯化的聚丙酸。从天然来源分离的聚合物是生物相容的，可生物降解的和非常低的毒性。聚合物极易水溶，并含有大量游离羧基，可用于连接许多不同的活性分子。在实施例中，羧基的N-羟基琥珀酰亚胺酯用于附着这些分子。活性分子包括促进特异性细胞摄取的单克隆抗体和特异性前体药物，例如旨在修饰靶细胞的细胞代谢的反义核酸。前药有利地通过稍微不稳定的键连接，使得它们将在特定条件下释放。此外，该系统含有酰胺键缬氨酸，以促进溶酶体条件下的膜破坏。连接聚乙二醇基团以延长药物系统的循环半衰期。此外，可以容易地包括荧光报告的组以帮助可视化和确认药物系统靶向。药物系统可以为广泛的疾病提供治疗，特别有利于治疗肿瘤。

5. 发明申请

WO2011072240A1 DRUG DELIVERY OF TEMOZOLOMIDE FOR SYSTEMIC BASED TREATMENT OF CANCER 审中-公开
标题翻译：药物输送用于基于系统的癌症治疗的TEMOZOLOMIDE
公开(公告)号：WO2011072240A1
公开(公告)日：2011-06-16
申请号：PCT/US2010/059919
申请日：2010-12-10
申请人： CEDARS-SINAI MEDICAL CENTER , PATIL, Rameshwar , HOLLER, Eggehard , BLACK, Keith L. , LJUBIMOVA, Julia, Y.
发明人： PATIL, Rameshwar , HOLLER, Eggehard , BLACK, Keith L. , LJUBIMOVA, Julia, Y.
IPC分类号： A01N43/52 , A61K31/425
CPC分类号： A61K47/593 , A61K31/4188 , A61K31/425 , A61K47/48061 , A61K47/48215 , A61K47/48246 , A61K47/48338 , A61K47/48384 , A61K47/48561 , A61K47/48584 , A61K47/48623 , A61K47/48669 , A61K47/48692 , A61K47/545 , A61K47/60 , A61K47/64 , A61K47/65 , A61K47/6803 , A61K47/6849 , A61K47/6851 , A61K47/6855 , A61K47/6865 , A61K47/6877 , A61K47/6883 , A61K47/6889 , A61K47/6898 , C07K16/2881 , C07K16/3015 , C07K16/3053 , C07K2317/24 , C07K2317/77
摘要： The present invention relates to methods of drug delivery for the treatment of a condition or disease, such as cancer. In one embodiment, the invention provides a method of preparing a multifunctional nanoconjugate of temozolomide (TMZ) by conjugating TMZ in its hydrazide form to a polymalic acid platform. In another embodiment, the polymalic acid platform is conjugated to a monoclonal antibody to transferrin receptor, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety. The present invention relates to methods of drug delivery for the treatment of a condition or disease, such as cancer. In one embodiment, the invention provides a method of preparing a multifunctional nanoconjugate of temozolomide (TMZ) by conjugating TMZ in its hydrazide form to a polymalic acid platform. In another embodiment, the polymalic acid platform is conjugated to a monoclonal antibody to transferrin receptor, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety.
摘要翻译：本发明涉及用于治疗诸如癌症的疾病或疾病的药物递送方法。在一个实施方案中，本发明提供了通过将其酰肼形式的TMZ与聚马来酸平台结合来制备替莫唑胺（TMZ）的多功能纳米缀合物的方法。在另一个实施方案中，聚马来酸平台与转铁蛋白受体的单克隆抗体，三聚亮氨酸（LLL）部分和/或聚乙二醇（PEG）部分缀合。本发明涉及用于治疗诸如癌症的疾病或疾病的药物递送方法。在一个实施方案中，本发明提供了通过将其酰肼形式的TMZ与聚马来酸平台结合来制备替莫唑胺（TMZ）的多功能纳米缀合物的方法。在另一个实施方案中，聚马来酸平台与转铁蛋白受体的单克隆抗体，三聚亮氨酸（LLL）部分和/或聚乙二醇（PEG）部分缀合。

6. 发明申请

WO2009126913A1 POLY(BETA MALIC ACID) WITH PENDANT LEU-LEU-LEU TRIPEPTIDE FOR EFFECTIVE CYTOPLASMIC DRUG DELIVERY 审中-公开
标题翻译：用于有效的CYTOPLASMIC药物递送的寡核苷酸（抗坏血酸）与寡核苷酸寡核苷酸
公开(公告)号：WO2009126913A1
公开(公告)日：2009-10-15
申请号：PCT/US2009/040252
申请日：2009-04-10
申请人： CEDARS-SINAI MEDICAL CENTER , DING, Hui , LJUBIMOVA, Julia, Y. , HOLLER, Eggehard , BLACK, Keith, L.
发明人： DING, Hui , LJUBIMOVA, Julia, Y. , HOLLER, Eggehard , BLACK, Keith, L.
IPC分类号： A61K47/48 , A61K9/00
CPC分类号： A61K47/48238 , A61K9/0019 , A61K9/0024 , A61K9/0095 , A61K9/4866 , A61K31/711 , A61K47/593 , A61K47/60 , A61K49/0041 , A61K49/0054
摘要： The invention relates to the use of Polycefin-LLL nanoconjugate as a means of cytoplasmic delivery of drugs. In one embodiment, the present invention provides a drug delivery molecule, comprising a polymerized carboxylic acid molecular scaffold covalently linked to L-leucylleucylleucine. In another embodiment, the Polycefin-LLL includes drug antisense morpholino oligos, targeting antibodies, and a pH-sensitive endosome escape unit. In addition, the drug could be siRNA, microRNA, and aptamer.
摘要翻译：本发明涉及Polycefin-LLL纳米缀合物作为药物细胞质递送手段的用途。在一个实施方案中，本发明提供了药物递送分子，其包含共价连接到L-亮氨酰基亮氨酸亮氨酸的聚合的羧酸分子支架。在另一个实施方案中，Polycefin-LLL包括药物反义吗啉代寡核苷酸，靶向抗体和pH敏感的内体逃逸单元。此外，该药物可以是siRNA，microRNA和适体。

7. 发明专利

IL261438D0 Polymalic acid based nanoimmunoconjugates and uses thereof 未知
公开(公告)号：IL261438D0
公开(公告)日：2018-10-31
申请号：IL26143818
申请日：2018-08-28
申请人： CEDARS SINAI MEDICAL CENTER , LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD , LJUBIMOV ALEXANDER , DING HUI
发明人： LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD , LJUBIMOV ALEXANDER , DING HUI
IPC分类号： A61K20060101
摘要： Nanoimmunoconjugates including a polymalic acid-based molecular scaffold, targeting ligands, anti-tumor immune response stimulators and anti-cancer agents are provided. Methods for treating cancer in a subject by administering the nanoimmunoconjugates that provide both systemic and local immune responses and synergistic anticancer effect are described.

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