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1. 发明申请

US20110020371A1 POLY(BETA MALIC ACID) WITH PENDANT LEU-LEU-LEU TRIPEPTIDE FOR EFFECTIVE CYTOPLASMIC DRUG DELIVERY 有权
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：US20110020371A1
公开(公告)日：2011-01-27
申请号：US12935110
申请日：2009-04-10
申请人： Hui Ding , Julia Y. Ljubimova , Eggehard Holler , Keith L. Black
发明人： Hui Ding , Julia Y. Ljubimova , Eggehard Holler , Keith L. Black
IPC分类号： A61K39/395 , C08G63/91 , C12N5/07 , A61P35/00
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，本发明提供药物递送分子，其包含共价连接至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。

2. 发明授权

US08309614B2 Poly(beta malic acid) with pendant leu-leu-leu tripeptide for effective cytoplasmic drug delivery 有权
标题翻译：聚（β-苹果酸）与悬浮的leu-leu-leu三肽有效的细胞质药物递送
公开(公告)号：US08309614B2
公开(公告)日：2012-11-13
申请号：US12935110
申请日：2009-04-10
申请人： Hui Ding , Julia Y. Ljubimova , Eggehard Holler , Keith L. Black
发明人： Hui Ding , Julia Y. Ljubimova , Eggehard Holler , Keith L. Black
IPC分类号： A61K47/14 , C07H21/02
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，本发明提供药物递送分子，其包含共价连接至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。

3. 发明申请

US20140161762A1 DRUG DELIVERY OF TEMOZOLOMIDE FOR SYSTEMIC BASED TREATMENT OF CANCER 有权
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：US20140161762A1
公开(公告)日：2014-06-12
申请号：US14179195
申请日：2014-02-12
申请人： Rameshwar Patil , Eggehard Holler , Keith L. Black , Julia Y. Ljubimova
发明人： Rameshwar Patil , Eggehard Holler , Keith L. Black , Julia Y. Ljubimova
IPC分类号： A61K47/48
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。

4. 发明授权

US07935677B2 Polymalic acid-based multi-functional drug delivery system 有权
标题翻译：聚马来酸多功能药物输送系统
公开(公告)号：US07935677B2
公开(公告)日：2011-05-03
申请号：US10580999
申请日：2004-12-03
申请人： Julia Y. Ljubimova , Keith L. Black , Eggehard Holler
发明人： Julia Y. Ljubimova , Keith L. Black , Eggehard Holler
IPC分类号： C12N15/11 , A61K47/30 , 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。

5. 发明授权

US08785371B2 Drug delivery of temozolomide for systemic based treatment of cancer 有权
标题翻译：用于系统性治疗癌症的替莫唑胺的药物递送
公开(公告)号：US08785371B2
公开(公告)日：2014-07-22
申请号：US13513145
申请日：2010-12-10
申请人： Rameshwar Patil , Eggehard Holler , Keith L. Black , Julia Y. Ljubimova
发明人： Rameshwar Patil , Eggehard Holler , Keith L. Black , Julia Y. Ljubimova
IPC分类号： A61K38/00 , A61K31/74 , A61K47/48 , C08G63/48 , C08G63/91 , C08L89/00 , C08F283/00 , C08G69/48 , C08L67/00 , C08L77/00
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

US20120328555A1 DRUG DELIVERY OF TEMOZOLOMIDE FOR SYSTEMIC BASED TREATMENT OF CANCER 有权
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：US20120328555A1
公开(公告)日：2012-12-27
申请号：US13513145
申请日：2010-12-10
申请人： Rameshwar Patil , Eggehard Holler , Keith L. Black , Julia Y. Ljubimova
发明人： Rameshwar Patil , Eggehard Holler , Keith L. Black , Julia Y. Ljubimova
IPC分类号： A61K47/48 , C08G63/91 , A61P31/00
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。

7. 发明申请

US20110212048A1 POLYMALIC ACID-BASED MULTIFUNCTIONAL DRUG DELIVERY SYSTEM 有权
标题翻译：基于聚合酸的多功能药物递送系统
公开(公告)号：US20110212048A1
公开(公告)日：2011-09-01
申请号：US13097364
申请日：2011-04-29
申请人： Julia Y. Ljubimova , Keith Black , Eggehard Holler
发明人： Julia Y. Ljubimova , Keith Black , Eggehard Holler
IPC分类号： A61K47/48 , C08F8/30 , A61P35/00
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。

8. 发明授权

US08562964B2 Polymalic acid-based multifunctional drug delivery system 有权
标题翻译：聚肌酸多功能药物输送系统
公开(公告)号：US08562964B2
公开(公告)日：2013-10-22
申请号：US13097364
申请日：2011-04-29
申请人： Julia Y. Ljubimova , Keith Black , Eggehard Holler
发明人： Julia Y. Ljubimova , Keith Black , Eggehard Holler
IPC分类号： A61K47/48 , A61P35/00 , C08F8/30
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。

9. 发明申请

US20120258049A1 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：US20120258049A1
公开(公告)日：2012-10-11
申请号：US13441599
申请日：2012-04-06
申请人： Keith L. Black , Julia Ljubimova , Alexander Ljubimov , Eggehard Holler
发明人： Keith L. Black , Julia Ljubimova , Alexander Ljubimov , Eggehard Holler
IPC分类号： A61B5/055 , C08G63/91
CPC分类号： A61K49/16 , A61K47/593 , A61K49/128
摘要： Nanoconjugates that include a polymalic-based molecular scaffold with one or more imaging moiety and one or more targeting modules attached to the scaffold are provided. Methods of targeting a diseased cell or a diseased tissue in a subject by administering the nanoconjugate are described. Methods of synthesizing the nanoconjugate are also provided.
摘要翻译：提供包括具有一个或多个成像部分的聚丙烯基分子支架和连接到支架上的一个或多个靶向模块的纳结合物。描述了通过施用纳米缀合物靶向受试者中患病细胞或患病组织的方法。还提供了合成纳米缀合物的方法。

10. 发明授权

US10383958B2 Polymalic acid based nanoconjugates for imaging 有权
公开(公告)号：US10383958B2
公开(公告)日：2019-08-20
申请号：US13441599
申请日：2012-04-06
申请人： Keith L. Black , Julia Ljubimova , Alexander Ljubimov , Eggehard Holler
发明人： Keith L. Black , Julia Ljubimova , Alexander Ljubimov , Eggehard Holler
IPC分类号： A61K49/16 , A61K49/12 , A61K47/59
摘要： Nanoconjugates that include a polymalic-based molecular scaffold with one or more imaging moiety and one or more targeting modules attached to the scaffold are provided. Methods of targeting a diseased cell or a diseased tissue in a subject by administering the nanoconjugate are described. Methods of synthesizing the nanoconjugate are also provided.

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