公开(公告)号：US5336762A

公开(公告)日：1994-08-09

申请号：US642033

申请日：1991-01-16

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K49/00 ,  A61K49/08 ,  A61K51/06 ,  A61K51/12 ,  C08B37/02

CPC分类号： A61K51/1255 ,  A61K49/085 ,  A61K49/128 ,  A61K49/143 ,  A61K49/1818 ,  A61K51/065 ,  A61K2123/00 ,  Y10S977/738 ,  Y10S977/788 ,  Y10S977/895 ,  Y10S977/902 ,  Y10S977/915 ,  Y10S977/927 ,  Y10S977/93

摘要： The present invention includes an image-enhancing agent comprising a biodegradable, water-soluble polymer, synthetic or naturally derived and having repeating hydrophilic monomeric units with amino or hydroxyl groups. This agent also includes chelating agents comprising functional groups bound to an amino or hydroxyl group of the monomeric units. These chelating agents have a formation constant for divalent or trivalent metal cations of at least about 10.sup.8 at physiological temperature and pH. This image-enhancing agent is biodegradable to intermediary metabolites, excretable chelates, oligomers, monomers or combinations thereof of low toxicity. These image-enhancing agents may further comprise a paramagnetic metal ion for enhancement of the image arising from induced magnetic resonance signals. Images resulting from scanning of gamma particle emissions may be enhanced when the image-enhancing agent of the present invention comprises radioisotopic metal ions emitting gamma particles. The physical conversion of these image-enhancing agents into microspheres (or, less optimally, microaggregates) allows further internal directioning of the image-enhancing agents to organs with phagocytic capabilities. Dextran is a preferred polymer; DTPA and gadolinium are respectively preferred chelating agents and paramagnetic metal ions.

摘要翻译： 本发明包括一种图像增强剂，其包含可合成或天然衍生的可生物降解的水溶性聚合物，并具有具有氨基或羟基的重复亲水性单体单元。 该试剂还包括螯合剂，其包含与单体单元的氨基或羟基结合的官能团。 这些螯合剂在生理温度和pH下具有至少约108的二价或三价金属阳离子的形成常数。 该成像增强剂可生物降解为低毒性的中间体代谢物，可分解的螯合物，低聚物，单体或其组合。 这些图像增强剂可以进一步包含用于增强由感应磁共振信号引起的图像的顺磁金属离子。 当本发明的图像增强剂包含发射γ粒子的放射性同位素金属离子时，可以增强扫描γ粒子发射产生的图像。 将这些增强剂物理转化成微球体（或者更不优选的是微团聚体）允许图像增强剂进一步内部定向具有吞噬能力的器官。 葡聚糖是优选的聚合物; DTPA和钆分别是螯合剂和顺磁金属离子。

公开(公告)号：US5672334A

公开(公告)日：1997-09-30

申请号：US160085

申请日：1993-11-29

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K49/00 ,  A61K49/08 ,  A61K49/12 ,  A61K49/18 ,  A61K51/06 ,  C08B37/00 ,  A61B5/055

CPC分类号： A61K49/126 ,  A61K49/085 ,  A61K49/10 ,  A61K49/103 ,  A61K49/1881 ,  A61K51/065 ,  C08B37/0069 ,  A61K2123/00 ,  Y10S436/806 ,  Y10T436/24

摘要： This application concerns novel agents comprising cationic or chemically basic metal chelators in association with hydrophilic carriers of anionic or chemically acidic saccharides, sulfatoids and glycosaminoglycans. In certain embodiments, the agents comprise metals and metal ions. Covalent and non-covalent chemical and physical means are described for stabilizing the binding of the metal chelators to the carriers. Novel non-covalently bound compositions are described which give uniquely high payloads and ratio of metal chelator to carrier, ranging from a low of about 15% metal chelator by weight, to a characteristic range of 70% to 90% metal chelator by weight. Specific embodiments are described comprising deferoxamine, ferrioxamine, iron-basic porphine, iron-triethylenetetraamine, gadolinium DTPA-lysine, gadolinium DOTA-lysine and gadolinium with basic derivatives of porphyrins, porphines, expanded porphyrins, Texaphyrins and sapphyrins as the basic or cationic metal chelators, which are in turn, bound to acidic or anionic carriers, including one or more of acidic or anionic saccharides, and including sulfated sucrose, pentosan polysulfate, dermatan sulfate, oversulfated dermatan sulfate, chondroitin sulfate, oversulfated chondroitin sulfate, heparan sulfate, beef heparin, porcine heparin, non-anticoagulant heparins, and other native and modified acidic saccharides and glycosaminoglycans. Also disclosed are methods of enhancing in vivo imgages arising from induced magnetic resonance signals, methods of enhancing in vivo images in conjunction with ultrasound or X-rays and methods of obtaining in vivo body images utilizing radioisotope containing agents. Methods of treating vasular disease are also disclosed.

摘要翻译： 本申请涉及包含阳离子或化学碱性金属螯合剂与阴离子或化学酸性糖，硫酸酯和糖胺聚糖的亲水载体相关的新型试剂。 在某些实施方案中，试剂包含金属和金属离子。 描述了用于稳定金属螯合剂与载体的结合的共价和非共价化学和物理手段。 描述了新的非共价结合的组合物，其赋予独特的高有效载荷和金属螯合剂与载体的比例，范围从约15重量％的金属螯合剂的低至特征范围为70重量％至90重量％的金属螯合剂。 描述了具体的实施方案，其包括去铁胺，铁草胺，铁 - 碱性卟吩，铁三亚乙基四胺，钆DTPA-赖氨酸，钆DOTA-赖氨酸和钆与卟啉，卟吩，扩增的卟啉，Texaphyrins和sap with的碱性衍生物作为碱性或阳离子金属螯合剂 其又与酸性或阴离子载体结合，包括一种或多种酸性或阴离子糖类，并且包括硫酸化蔗糖，戊聚糖多硫酸盐，硫酸皮肤素，硫酸硫酸皮肤素，硫酸软骨素，硫酸硫酸软骨素，硫酸乙酰肝素，牛肝素 ，肝素肝素，非抗凝血素肝素和其他天然和改性的酸性糖和糖胺聚糖。 还公开了增强由诱导磁共振信号产生的体内成像的方法，结合超声或X射线增强体内图像的方法以及使用含放射性同位素的试剂获得体内体形图像的方法。 还公开了治疗血管疾病的方法。

公开(公告)号：US5155215A

公开(公告)日：1992-10-13

申请号：US613465

申请日：1990-11-07

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K51/00 ,  A61K49/00 ,  A61K49/08 ,  A61K51/12

CPC分类号： A61K49/128 ,  A61K49/085 ,  A61K49/1818 ,  A61K51/065 ,  A61K51/1255 ,  A61K2123/00

摘要： The present invention includes an image-enhancing agent comprising a biodegradable, water-soluble polymer, synthetic or naturally derived and having repeating hydrophilic monomeric units with amino or hydroxyl groups. This agent also includes chelating agents comprising functional groups bound to an amino or bydroxyl group of the monomeric units. These chelating agents have a formation constant for divalent or trivalent metal cations of at least about 10.sup.8 at physiological temperature and pH. This image-enhancing agent is biodegradable to intermediary metabolites, excretable chelates, oligomers, monomers or combinations thereof of low toxicity.These image-enhancing agents may further comprise a paramagnetic metal ion for enhancement of the image arising from induced magnetic resonance signals.Images resulting from scanning of gamma particle emissions may be enhanced when the image-enhancing agent of the present invention comprise radioisotopic metal ions emitting gamma particles.The physical conversion of these image enhancing agents into microspheres allows further internal directioning of the image-enhancing agents to organs with phogocytic capabilities.Dextran is a preferred polymer DTPA and gadoliniium are respectively preferred chelating agents and paramagnetic metal ions.

摘要翻译： 本发明包括一种图像增强剂，其包含可合成或天然衍生的可生物降解的水溶性聚合物，并具有具有氨基或羟基的重复亲水性单体单元。 该试剂还包括螯合剂，其包含与单体单元的氨基或邻羟基结合的官能团。 这些螯合剂在生理温度和pH下具有至少约108的二价或三价金属阳离子的形成常数。 该成像增强剂可生物降解为低毒性的中间体代谢物，可分泌的螯合物，低聚物，单体或其组合。 这些图像增强剂可以进一步包含用于增强由感应磁共振信号引起的图像的顺磁金属离子。 当本发明的图像增强剂包含发射γ粒子的放射性同位素金属离子时，可以增强扫描γ粒子发射产生的图像。 这些图像增强剂到微球体的物理转化允许图像增强剂进一步内部定向具有吞噬能力的器官。 葡聚糖是优选的聚合物DTPA，钆是分别优选的螯合剂和顺磁金属离子。

公开(公告)号：US5707604A

公开(公告)日：1998-01-13

申请号：US472634

申请日：1995-06-07

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： C08B37/00 ,  A61B5/055

CPC分类号： B82Y5/00 ,  C08B37/0063 ,  Y10S514/836 ,  Y10T436/24

摘要： This application concerns novel agents comprising cationic or chemically basic metal chelators in association with hydrophilic carriers of anionic or chemically acidic saccharides, sulfatoids and glycosaminoglycans. In certain embodiments, the agents comprise metals and metal ions. Covalent and non-covalent chemical and physical means are described for stabilizing the binding of the metal chelators to the carriers. Novel non-covalently bound compositions are described which give uniquely high payloads and ratio of metal chelator to carrier, ranging from a low of about 15% metal chelator by weight, to a characteristic range of 70% to 90% metal chelator by weight. Specific embodiments are described comprising deferoxamine, ferrioxamine, iron-basic porphine, iron-triethylenetetraamine, gadolinium DTPA-lysine, gadolinium DOTA-lysine and gadolinium with basic derivatives of porphyrins, porphines, expanded porphyrins, Texaphyrins and sapphyrins as the basic or cationic metal chelators, which are in turn, bound to acidic or anionic carriers, including one or more of acidic or anionic saccharides, and including sulfated sucrose, pentosan polysulfate, dermatan sulfate, essentially purified dermatan sulfate with a sulfur content of up to 9% and with selective oligosaccharide oversulfation, chondroitin sulfate, oversulfated chondroitin sulfate, heparan sulfate, beef heparin, porcine heparin, non-anticoagulant heparins, and other native and modified acidic saccharides and glycosaminoglycans.

摘要翻译： 本申请涉及包含阳离子或化学碱性金属螯合剂与阴离子或化学酸性糖，硫酸酯和糖胺聚糖的亲水载体相关的新型试剂。 在某些实施方案中，试剂包含金属和金属离子。 描述了用于稳定金属螯合剂与载体的结合的共价和非共价化学和物理手段。 描述了新的非共价结合的组合物，其赋予独特的高有效载荷和金属螯合剂与载体的比例，范围从约15重量％的金属螯合剂的低至特征范围为70重量％至90重量％的金属螯合剂。 描述了具体的实施方案，其包括去铁胺，铁草胺，铁 - 碱性卟吩，铁三亚乙基四胺，钆DTPA-赖氨酸，钆DOTA-赖氨酸和钆与卟啉，卟吩，扩增的卟啉，Texaphyrins和sap with的碱性衍生物作为碱性或阳离子金属螯合剂 ，它们依次与酸性或阴离子载体结合，包括一种或多种酸性或阴离子糖，并且包括硫酸化蔗糖，戊聚糖多硫酸盐，硫酸皮肤素，硫酸含量高达9％的基本上纯化的硫酸皮肤素，并具有选择性 寡糖过硫酸盐，硫酸软骨素，硫酸硫酸软骨素，硫酸乙酰肝素，牛肝素，猪肝素，非抗凝血素肝素等天然和改性酸性糖和糖胺聚糖。

公开(公告)号：US5213788A

公开(公告)日：1993-05-25

申请号：US680675

申请日：1991-04-04

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K49/06 ,  A61K49/08 ,  A61K49/18 ,  G01R33/28

CPC分类号： G01R33/5601 ,  A61K47/4823 ,  A61K49/06 ,  A61K49/085 ,  A61K49/128 ,  A61K49/1836 ,  A61K49/1845 ,  A61K49/1863 ,  Y10S436/806 ,  Y10S514/836 ,  Y10T436/24

摘要： Improved compositions and methods for selective access to tumor regions (or other regions of abnormal endothelial properties). This capability provides powerful contrast-enhancement agents for nuclear magnetic resonance imaging. A polyatomic complex which includes intramolecular ferromagnetic coupling between metal atoms is associated with a polymer or microsphere carrier matrix which will bind to endothelial determinants. A solution containing this carrier complex is injected into a human (or other) body to be imaged. The carrier complex will preferentially extravasate at locations where the blood vessel walls have increased porosity or microvascular surface changes, and especially at tumor sites. Thus, the changes in relaxation time induced by the presence of the carrier complex will provide a high-gain marker for magnetic resonance imaging.Multiple superparamagnetic polyatomic complexes are described, including novel complexes which include acetate and glycinate bridging ligands with a polyatomic metal-atom-complex core.

摘要翻译： 用于选择性进入肿瘤区域（或其他异常内皮特性区域）的组合物和方法的改进。 该功能为核磁共振成像提供了强大的对比度增强剂。 包含金属原子之间的分子内铁磁耦合的多原子络合物与将与内皮决定簇结合的聚合物或微球载体基质相关联。 将含有该载体复合物的溶液注入待成像的人体（或其他）体内。 载体复合物优先在血管壁增加孔隙度或微血管表面变化的位置，特别是在肿瘤部位外渗。 因此，由载体复合物的存在引起的弛豫时间的变化将为磁共振成像提供高增益标记。 描述了多个超顺磁性多原子复合物，包括新型配合物，其包括具有多原子金属 - 原子 - 复合核心的乙酸盐和甘氨酸桥连配体。

公开(公告)号：US06790607B1

公开(公告)日：2004-09-14

申请号：US09680738

申请日：2000-10-06

申请人： David N. Edwards ,  Arlene Leon ,  David F. Ranney

发明人： David N. Edwards ,  Arlene Leon ,  David F. Ranney

IPC分类号： C12Q100

CPC分类号： C12N15/1055 ,  C12Q1/02 ,  G01N33/743

摘要： A method for detecting interactions between first and second interacting molecules at variable sensitivity. This variable sensitivity may be obtained by providing for the overexpression of either a bait hybrid protein containing a DNA binding domain (desensitization) or a prey hybrid protein containing the DNA activation domain for a reporter gene (enhanced sensitivity). The use of exogenous activators of one or the other according to the needs of a particular system is readily accomplished.

摘要翻译： 一种以可变灵敏度检测第一和第二相互作用分子之间的相互作用的方法。 可以通过提供含有DNA结合结构域（脱敏）的诱饵杂交蛋白或含有报告基因的DNA活化域的猎物杂交蛋白（增强的灵敏度）来过表达。 可以容易地实现根据特定系统的需要使用一种或另一种外源活化剂。

公开(公告)号：US6106866A

公开(公告)日：2000-08-22

申请号：US509338

申请日：1995-07-31

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K47/48 ,  A61K49/12 ,  A61K31/726

CPC分类号： A61K49/189 ,  A61K47/4823 ,  A61K49/12 ,  B82Y5/00

摘要： A drug carrier composition comprising a drug complexed with dermatan sulfate is disclosed. The drug is preferably an anti tumor drug and may be taxol, a peptide onco-agent or vincristine. The most preferred antitumor drug is doxorubicin. The dermatan sulfate is essentially purified dermatan sulfate with a sulfur content of up to 9% (w/w) and with selective oligosaccharide oversulfation. The compositions are administered in a fashion that allows efficient vascular access and induces the following in vivo effects: 1) rapid, partial or total endothelial envelopment of the drug (diagnostic) carrier; 2) sequestration of the carrier and protection of the entrapped agent from blood vascular clearance at an early time (2 minutes) when the endothelial pocket which envelops the carrier still invaginates into the vascular compartment; 3) acceleration of the carrier's transport across and/or through the vascular endothelium or subendothelial structures into the tissue compartment (interstitium); and 4) improvement of the efficiency with which the drug migrates across the endothelium, or epi-endothelial or subendothelial barriers, such that a lower total drug dose is required to obtain the desired effect relative to that required for standard agents. Analogous tissue uptake is described for transepithelial migration into the lungs, bladder and bowel.

摘要翻译： 公开了包含与硫酸皮肤素复合的药物的药物载体组合物。 药物优选为抗肿瘤药物，并且可以是紫杉醇，肽原剂或长春新碱。 最优选的抗肿瘤药物是多柔比星。 硫酸皮肤素基本上是硫酸含量高达9％（w / w）和选择性寡糖过硫酸盐的硫酸皮肤素。 组合物以允许有效血管通路并诱导以下体内效应的方式施用：1）药物（诊断）载体的快速，部分或全部内皮包膜; 2）当包围载体的内皮袋仍然陷入血管隔室时，早期（2分钟），载体的螯合和夹带的药物保护被血管清除; 3）加速载体穿过和/或通过血管内皮或内皮下结构进入组织隔室（间质）; 和4）提高药物通过内皮或外膜 - 内皮或内皮下屏障迁移的效率，使得需要较低的总药物剂量以获得相对于标准试剂所需的效果。 描述类似组织摄取用于跨上皮移植到肺，膀胱和肠中。

公开(公告)号：US5260050A

公开(公告)日：1993-11-09

申请号：US463692

申请日：1990-01-11

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K49/06 ,  A61K49/08 ,  G01R33/28 ,  G01N24/08 ,  A61K33/24 ,  C07F19/00 ,  C07H23/00

CPC分类号： G01R33/5601 ,  A61K47/4823 ,  A61K47/48923 ,  A61K49/085 ,  A61K49/128 ,  A61K49/1863 ,  Y10S436/806 ,  Y10S977/705 ,  Y10T436/24

摘要： Improved compositions and methods for selective access to tumor regions (or other regions of abnormal endothelial properties). This capability provides powerful contrast-enhancement agents for nuclear magnetic resonance imaging. A polyatomic complex which includes intramolecular ferromagnetic coupling between metal atoms is associated with a polymer or microsphere carrier matrix which will bind to endothelial determinants. A solution containing this carrier complex is injected into a human (or other) body to be imaged. The carrier complex will preferentially extravasate at locations where the blood vessel walls have increased porosity or microvascular surface changes, and especially at tumor sites. Thus, the changes in relaxation time induced by the presence of the carrier complex will provide a high-gain marker for magnetic resonance imaging.Multiple superparamagnetic polyatomic complexes are described, including novel complexes which include acetate and glycinate bridging ligands with a polyatomic metal-atom-complex core.

摘要翻译： 用于选择性进入肿瘤区域（或其他异常内皮特性区域）的组合物和方法的改进。 该功能为核磁共振成像提供了强大的对比度增强剂。 包含金属原子之间的分子内铁磁耦合的多原子络合物与将与内皮决定簇结合的聚合物或微球载体基质相关联。 将含有该载体复合物的溶液注入待成像的人体（或其他）体内。 载体复合物优先在血管壁增加孔隙度或微血管表面变化的位置，特别是在肿瘤部位外渗。 因此，由载体复合物的存在引起的弛豫时间的变化将为磁共振成像提供高增益标记。 描述了多个超顺磁性多原子复合物，包括新型配合物，其包括具有多原子金属 - 原子 - 复合核心的乙酸盐和甘氨酸桥连配体。

公开(公告)号：US5108759A

公开(公告)日：1992-04-28

申请号：US448121

申请日：1989-12-08

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K9/16 ,  A61K9/50 ,  A61K9/51 ,  A61K47/48

CPC分类号： A61K9/5146 ,  A61K47/4823 ,  A61K47/48769 ,  A61K9/1652 ,  A61K9/167 ,  A61K9/5036 ,  A61K9/5161 ,  Y10S436/829 ,  Y10S514/963 ,  Y10S514/965 ,  Y10T428/2984 ,  Y10T428/2989

摘要： This application describes the preparation and in vivo testing of surface coatings and matrix materials, which when applied to or caused to comprise the carriers for drugs and diagnostic agents, and administered in a fashion that allows efficient vascular access, causes the carriers to recognize determinants present or normal or focally diseased endothelium, and induces the following in vivo effects: 1) rapid, partial or total endothelial envelopment of the drug (diagnostic) carrier; 2) sequestration of the carrier and protecting entrapped agent from blood vascular clearance at an early time (2 minutes) when the endothelial pocket which envelops the carrier still invaginates into the vascular compartment; 3) acceleration of the carrier's transport across or through the vascular endothelium and/or subendothelial structures into the tissue compartment (interstitium); and 4) improvement of the efficiency with which the drug (or diagnostic) carrier migrates across the endothelium, or epi-endothelial or subendothelial barriers, such that a lower total drug dose is required to obtain the desired effect relative to that required for standard agents.

摘要翻译： 本申请描述了表面涂层和基质材料的制备和体内测试，当其应用于或引起包含用于药物和诊断剂的载体并且以允许有效血管通路的方式施用时，导致载体识别存在的决定簇 或正常或焦点病变的内皮，并诱导以下体内效应：1）药物（诊断）载体的快速，部分或全部内皮包膜; 2）当包围载体的内皮袋仍然陷入血管隔室时，早期（2分钟），将载体螯合并保护被包裹的药物免于血管清除; 3）载体穿过或穿过血管内皮和/或内皮下结构进入组织隔室（间质）的加速; 和4）提高药物（或诊断）载体迁移穿过内皮或外膜内皮或内皮下屏障的效率，使得需要更低的总药物剂量以获得相对于标准试剂所需的效果 。

公开(公告)号：US4925678A

公开(公告)日：1990-05-15

申请号：US33432

申请日：1987-04-01

申请人： David F. Ranney

发明人： David F. Ranney

IPC分类号： A61K9/127 ,  A61K9/16 ,  A61K9/50 ,  A61K9/51 ,  A61K31/70 ,  A61K47/36 ,  A61K47/40 ,  A61K47/42 ,  A61K47/48 ,  A61K49/00

CPC分类号： A61K9/5146 ,  A61K47/4823 ,  A61K47/48769 ,  A61K9/1652 ,  A61K9/167 ,  A61K9/5036 ,  A61K9/5115 ,  A61K9/5161 ,  A61K9/5169 ,  Y10S436/829 ,  Y10S514/963 ,  Y10S514/965 ,  Y10T428/2984 ,  Y10T428/2989

摘要： This application describes the preparation and in vivo testing of surface coatings and matrix materials, which when applied to or caused to comprise the carriers for drugs and diagnostic agents, and administered in a fashion that allows efficient vascular access, causes the carriers to recognize determinants present or normal or focally diseased endothelium, and induces the following in vivo effects: (1) rapid, partial or total endothelial envelopment of the drug (diagnostic) carrier; (2) sequestration of the carrier and protecting entrapped agent from blood vascular clearance at an early time (2 minutes) when the endothelial pocket which envelops the carrier still invaginates into the vascular compartment; (3) acceleration of the carrier's transport across or through the vascular endothelium and/or subendothelial structures into the tissue compartment (interstitium); and (4) improvement of the efficiency with which the drug (or diagnostic) carrier migrates across the endothelium, or epi-endothelial or subendothelial barriers, such that a lower total drug dose is required to obtain the desired effect relative to that required for standard agents.

摘要翻译： 本申请描述了表面涂层和基质材料的制备和体内测试，当将其应用于或引起包含用于药物和诊断剂的载体并且以允许有效血管通路的方式施用时，导致载体识别存在的决定簇 或正常或焦点病变的内皮，并诱导以下体内作用：（1）药物（诊断）载体的快速，部分或全部内皮包膜; （2）当包围载体的内皮口袋仍然陷入血管室时，早期（2分钟），载体的螯合和保护被包裹的药物免于血管清除; （3）载体穿过或通过血管内皮和/或内皮下结构加速进入组织隔室（间质）中; 和（4）提高药物（或诊断）载体迁移穿过内皮或外膜内皮或内皮下屏障的效率，使得需要更低的总药物剂量以获得相对于标准所需的效果 代理商