JP7440087B2 - 神経内分泌腫瘍の治療における二重標的化のための合成物および方法 - Google Patents
神経内分泌腫瘍の治療における二重標的化のための合成物および方法 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
さらに前記合成物は、a)前記ノルエピネフリントランスポーターおよびb)前記インテグリンαvβ3受容体との反応とを介して腫瘍細胞を二重に標的とするように構成される。
概説
ヘテロ二官能性リンカーは市販されているが、この例の目的のために、調製のための以下の合成経路が使用される。
使用方法
以下に、本発明の実施態様を列挙する。
1.
一般式:
式中、R1、R2、R3、およびR4は、それぞれ独立して、水素、ヨウ素、フッ素、臭素、メトキシ基、ニトロ基、アミン基、およびニトリル基からなる群から選択され、
式中、R5、R6、R7、およびR8は、それぞれ独立して、水素、ヨウ素、およびアルカン基からなる群から選択され、そして
n1≧0;
n2≧1;そして
2.
前記R5、R6、R7、およびR8のうちの少なくとも1つは、イソプロピル基およびtert-ブチル基からなる群から選択される、前記1に記載の合成物。
3.
前記化合物は、以下:
4.
前記化合物は、
5.
前記化合物は、N-ベンジルグアニジンを含む、前記1に記載の合成物。
6.
前記化合物は、トリヨードチロ酢酸およびテトラヨードチロ酢酸からなる群から選択されるチロインテグリンαvβ3受容体拮抗薬を含む、前記1に記載の合成物。
7.
前記1に記載の合成物を含む、神経内分泌腫瘍の治療剤。
8.
前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、前記7に記載の治療剤。
9.
前記1に記載の合成物を含む、神経内分泌腫瘍を画像化するための薬剤。
10.
前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、前記9に記載の薬剤。
11.
前記1に記載の合成物を含む、神経内分泌腫瘍を標的とするための薬剤。
12.
前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、前記11に記載の薬剤。
13.
腫瘍細胞を標的とするための、腫瘍細胞を二重に標的とするための、神経内分泌腫瘍を画像化するための、神経内分泌腫瘍を治療するための、または神経内分泌腫瘍の画像化と治療を同時に行うための、前記1に記載の合成物の使用。
以下に、本発明のさらなる実施態様を列挙する。
A1-1.
一般式:
式中、R 1 、R 2 、R 3 、およびR 4 は、それぞれ独立して、水素、ヨウ素、フッ素、臭素、メトキシ基、ニトロ基、アミン基、およびニトリル基からなる群から選択され、
式中、R 5 、R 6 、R 7 、およびR 8 は、それぞれ独立して、水素、ヨウ素、およびアルキル基からなる群から選択され、そして
n1≧0;
n2≧1;そして
A1-2.
前記R 5 、R 6 、R 7 、およびR 8 のうちの少なくとも1つは、イソプロピル基およびtert-ブチル基からなる群から選択される、A1-1に記載の合成物。
A1-3.
前記化合物は、以下:
A1-4.
前記化合物は、
A1-5.
A1-1に記載の合成物を含む、神経内分泌腫瘍の治療剤。
A1-6.
前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、A1-5に記載の治療剤。
A1-7.
A1-1に記載の合成物を含む、神経内分泌腫瘍を画像化するための薬剤。
A1-8.
前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、A1-7に記載の薬剤。
A1-9.
前記A1-1に記載の合成物を含む、神経内分泌腫瘍を標的とするための薬剤。
A1-10.
前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、A1-9に記載の薬剤。
Claims (10)
- 一般式:
式中、R1、R2、R3、およびR4は、それぞれ独立して、水素、ヨウ素、フッ素、臭素、メトキシ基、ニトロ基、アミン基、およびニトリル基からなる群から選択され、
式中、R5、R6、R7、およびR8は、それぞれ独立して、水素、ヨウ素、およびアルキル基からなる群から選択され、そして
n1≧0;
n2≧1;そして
- 前記R5、R6、R7、およびR8のうちの少なくとも1つは、イソプロピル基およびtert-ブチル基からなる群から選択される、請求項1に記載の合成物。
- 前記化合物は、以下:
- 前記化合物は、
- 請求項1に記載の合成物を含む、神経内分泌腫瘍の治療剤。
- 前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、請求項5に記載の治療剤。
- 請求項1に記載の合成物を含む、神経内分泌腫瘍を画像化するための薬剤。
- 前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、請求項7に記載の薬剤。
- 請求項1に記載の合成物を含む、神経内分泌腫瘍を標的とするための薬剤。
- 前記神経内分泌腫瘍は、神経芽細胞腫、褐色細胞腫、膵臓神経内分泌腫瘍、およびカルチノイド腫瘍のうちの1つである、請求項9に記載の薬剤。
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US11351137B2 (en) * | 2018-04-11 | 2022-06-07 | Nanopharmaceuticals Llc | Composition and method for dual targeting in treatment of neuroendocrine tumors |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100255108A1 (en) | 2009-03-31 | 2010-10-07 | Hung-Yun Lin | Combination Treatment of Cancer With Cetuximab and Tetrac |
US20130224115A1 (en) | 2010-04-01 | 2013-08-29 | Baylor College Of Medicine | Non-radioactive agents for neuroblastoma imaging |
US20170348425A1 (en) | 2016-06-07 | 2017-12-07 | Nanopharmaceuticals, Llc | Non-cleavable polymer conjugated with alpha v beta 3 integrin thyroid antagonists |
Family Cites Families (121)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3625214A (en) | 1970-05-18 | 1971-12-07 | Alza Corp | Drug-delivery device |
IL51354A (en) | 1977-01-28 | 1979-07-25 | Ames Yissum Ltd | Assay method for the quantitative determination of a hapten in aqueous solution |
US4208483A (en) | 1978-09-21 | 1980-06-17 | The University Of Toledo | Tissue culture system |
US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4650751A (en) | 1983-04-29 | 1987-03-17 | Technicon Instruments Corporation | Protected binding assay avoiding non-specific protein interference |
US4719182A (en) | 1985-03-18 | 1988-01-12 | Eastman Kodak Company | Fluorescent labels and labeled species and their use in analytical elements and determinations |
US4789734A (en) | 1985-08-06 | 1988-12-06 | La Jolla Cancer Research Foundation | Vitronectin specific cell receptor derived from mammalian mesenchymal tissue |
US5449665A (en) | 1985-09-24 | 1995-09-12 | Item Development Aktiebolag | Continuous intravenous infusion of adenosine to human patients undergoing percutaneous transluminal angioplasty |
US4801575A (en) | 1986-07-30 | 1989-01-31 | The Regents Of The University Of California | Chimeric peptides for neuropeptide delivery through the blood-brain barrier |
US4925673A (en) | 1986-08-18 | 1990-05-15 | Clinical Technologies Associates, Inc. | Delivery systems for pharmacological agents encapsulated with proteinoids |
US5091513A (en) | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5231000A (en) | 1987-10-08 | 1993-07-27 | The Mclean Hospital | Antibodies to A4 amyloid peptide |
IT1216687B (it) | 1988-04-01 | 1990-03-08 | Boehringer Biochemia Srl | Complessi di platino (ii), loro preparazione e impiego come antitumorali. |
US4968590A (en) | 1988-04-08 | 1990-11-06 | Stryker Corporation | Osteogenic proteins and polypeptides |
US5011486A (en) | 1988-11-18 | 1991-04-30 | Brown University Research Foundation | Composite nerve guidance channels |
US5635482A (en) | 1989-08-14 | 1997-06-03 | The Regents Of The University Of California | Synthetic compounds and compositions with enhanced cell binding |
US5438126A (en) | 1989-09-11 | 1995-08-01 | Arch Development Corporation | Human thyroid hormone receptor DNA |
US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5158978A (en) | 1990-02-05 | 1992-10-27 | British Technology Group (U.S.A.) | Thyroid hormone treatment of acute cardiovascular compromise |
US5410016A (en) | 1990-10-15 | 1995-04-25 | Board Of Regents, The University Of Texas System | Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers |
US5773574A (en) | 1990-12-03 | 1998-06-30 | The Scripps Research Institute | Polypeptides for promoting cell attachment |
JPH04356184A (ja) | 1991-05-31 | 1992-12-09 | Tabai Espec Corp | 培養カラム |
US5766635A (en) | 1991-06-28 | 1998-06-16 | Rhone-Poulenc Rorer S.A. | Process for preparing nanoparticles |
US5591709A (en) | 1991-08-30 | 1997-01-07 | Life Medical Sciences, Inc. | Compositions and methods for treating wounds |
US5225204A (en) | 1991-11-05 | 1993-07-06 | Chen Jivn Ren | Stable dosage of levothyroxine sodium and process of production |
AU3129793A (en) | 1991-11-08 | 1993-06-07 | General Hospital Corporation, The | Methods for the treatment of neuronal damage associated with ischemia, hypoxia or neurodegeneration |
AU4406793A (en) | 1992-06-04 | 1993-12-30 | Clover Consolidated, Limited | Water-soluble polymeric carriers for drug delivery |
US5482719A (en) | 1992-10-30 | 1996-01-09 | Guillet; James E. | Drug delivery systems |
US5571840A (en) | 1993-06-22 | 1996-11-05 | The Regents Of The University Of Michigan | Method for treating central nervous system ischemia |
US5593688A (en) | 1993-06-25 | 1997-01-14 | Nexstar Pharmaceuticals, Inc. | Liposomal targeting of ischemic tissue |
EP0831769B2 (en) | 1995-06-07 | 2008-07-23 | Lavin, Dr., Thomas N. | Novel uses for thyroid hormones or thyroid hormone-like compounds |
CN1126589A (zh) | 1995-06-09 | 1996-07-17 | 中国科学院成都有机化学研究所 | 一种激素缓释微囊注射剂及其制备方法 |
EP0852501B1 (en) | 1995-09-28 | 2004-12-01 | Sangstat Medical Corporation | Use of hyaluronic acid as an immunosuppressant |
FR2742357B1 (fr) | 1995-12-19 | 1998-01-09 | Rhone Poulenc Rorer Sa | Nanoparticules stabilisees et filtrables dans des conditions steriles |
US6596712B2 (en) | 1996-04-26 | 2003-07-22 | Genaera Corporation | Treatment of carcinomas using squalamine in combination with other anti-cancer agents or modalities |
US6214966B1 (en) | 1996-09-26 | 2001-04-10 | Shearwater Corporation | Soluble, degradable poly(ethylene glycol) derivatives for controllable release of bound molecules into solution |
DE69837968D1 (de) | 1997-01-30 | 2007-08-02 | Univ Technology Corp | Diagnose und behandlung myocardieller fehler |
US6207665B1 (en) | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
US5994309A (en) | 1997-07-25 | 1999-11-30 | Angstrom Pharmaceuticals, Inc. | Anti-invasive and anti-angiogenic compositions and methods |
US6414037B1 (en) | 1998-01-09 | 2002-07-02 | Pharmascience | Pharmaceutical formulations of resveratrol and methods of use thereof |
US6482406B1 (en) | 1999-03-26 | 2002-11-19 | Duncan J. Stewart | Cell-based gene therapy for the pulmonary system |
AU3545399A (en) | 1998-04-08 | 1999-10-25 | G.D. Searle & Co. | Dual avb3 and metastasis-associated receptor ligands |
US6022901A (en) | 1998-05-13 | 2000-02-08 | Pharmascience Inc. | Administration of resveratrol to prevent or treat restenosis following coronary intervention |
KR19990085365A (ko) | 1998-05-16 | 1999-12-06 | 허영섭 | 지속적으로 약물 조절방출이 가능한 생분해성 고분자 미립구 및그 제조방법 |
WO1999062549A1 (en) | 1998-06-04 | 1999-12-09 | Mount Sinai School Of Medicine Of New York University | Method of inhibiting angiogenesis and tumor growth and preventing tumor growth and metastases |
CA2246791A1 (en) | 1998-09-01 | 2000-03-01 | Alison Buchan | Treatment of endothelium with somatostatin analogues |
US6521593B1 (en) | 1999-02-01 | 2003-02-18 | Childrens Hospital Los Angeles | Methods for inhibiting brain tumor growth |
ATE294577T1 (de) | 1999-02-24 | 2005-05-15 | Univ Cincinnati | Verwendung von sulfamat derivaten zur behandlung von impulsiven störungen |
US6740680B1 (en) | 1999-04-26 | 2004-05-25 | Becton Pharma, Inc. | Pharmaceutical compositions to tetrac and methods of use thereof |
JP2002542284A (ja) | 1999-04-26 | 2002-12-10 | ダンフォース,エリオット,ジュニア | テトラックの薬学組成物およびその使用方法 |
US6776984B1 (en) | 1999-08-20 | 2004-08-17 | George R. Schwartz | Induced regeneration and repair of damaged neurons and nerve axon myelin |
US6531580B1 (en) | 1999-06-24 | 2003-03-11 | Ixsys, Inc. | Anti-αvβ3 recombinant human antibodies and nucleic acids encoding same |
AU6634400A (en) | 1999-08-13 | 2001-03-13 | Chiron Corporation | Dose of an angiogenic factor and method of administering to improve myocardial blood flow |
US6677473B1 (en) | 1999-11-19 | 2004-01-13 | Corvas International Inc | Plasminogen activator inhibitor antagonists |
CA2395567A1 (en) | 2000-01-12 | 2001-07-19 | Light Sciences Corporation | Novel treatment for eye disease |
FI107018B (fi) | 2000-04-06 | 2001-05-31 | Ipsat Therapies Oy | Dermatologinen käyttö ja valmiste |
ATE465756T1 (de) | 2000-06-23 | 2010-05-15 | Mitsubishi Tanabe Pharma Corp | Antitumoreffekt-verstärker |
CA2415080A1 (en) | 2000-07-06 | 2002-01-17 | Delsys Pharmaceutical Corporation | Improved thyroid hormone formulations |
FR2811936B1 (fr) | 2000-07-24 | 2003-01-03 | Esatec Etudes Services Automat | Equipement pour l'assemblage de produits tels que des emballages de disques compacts |
CA2432797C (en) | 2000-12-18 | 2014-02-04 | David J. Yang | Local regional chemotherapy and radiotherapy using in situ hydrogel |
US6534676B2 (en) | 2001-01-31 | 2003-03-18 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Method to treat chronic heart failure and/or elevated cholesterol levels using 3,5-diiodothyropropionic acid and method to prepare same |
US20020132205A1 (en) | 2001-03-15 | 2002-09-19 | Gore Hardial S. | Gas burner |
ATE366270T1 (de) | 2001-05-07 | 2007-07-15 | Cornell Res Foundation Inc | Biologisch abbaubare copolymere, die an ein segment mit mehreren funktionellen gruppen gebunden sind |
EP1420792A4 (en) | 2001-08-01 | 2007-10-10 | Smithkline Beecham Corp | PRODUCTS AND EXCIPIENTS FOR THE ADMINISTRATION OF MEDICAMENTS |
CA2458941A1 (en) | 2001-08-30 | 2003-03-13 | Arbomedics Gmbh | Method and device for the in vitro cultivation of cells |
US6645526B2 (en) | 2001-11-13 | 2003-11-11 | Mylan Pharmaceuticals, Inc. | Storage stable thyroxine active drug formulations and methods for their production |
US6821947B2 (en) | 2001-12-04 | 2004-11-23 | Thomas Jefferson University | Endorepellin: methods and compositions for inhibiting angiogenesis |
AU2002360489A1 (en) | 2001-12-07 | 2003-06-23 | The Regents Of The University Of California | Treatment for age-related macular degeneration |
US6720008B2 (en) | 2002-01-22 | 2004-04-13 | Pr Pharmaceuticals, Inc. | Composition and method for the encapsulation of water-soluble molecules into nanoparticles |
US7033823B2 (en) | 2002-01-31 | 2006-04-25 | Cesco Bioengineering, Inc. | Cell-cultivating device |
AU2003213682C1 (en) | 2002-03-04 | 2008-06-12 | Medimmune, Inc. | Methods of preventing or treating disorders by administering an integrin alphavbeta3 antagonist in combination with an HMG-CoA reductase inhibitor or a bisphosphonate |
WO2003084470A2 (en) | 2002-04-02 | 2003-10-16 | Arizeke Pharmaceuticals, Inc. | Compositions and methods for targeted biological delivery of molecular carriers |
EP1354953A1 (en) | 2002-04-17 | 2003-10-22 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Smac-peptides as therapeutics against cancer and autoimmune diseases |
US20040024749A1 (en) | 2002-08-01 | 2004-02-05 | Omega Systems, Inc. | Automated system and method for reviewing medical and financial claim records and for identifying missing devices and/or services associated with medical and financial procedures |
ATE355395T1 (de) | 2002-11-19 | 2006-03-15 | Hitachi Tool Eng | Hartstoffschicht und damit beschichtetes werkzeug |
US20070037739A1 (en) | 2003-02-03 | 2007-02-15 | Medlogics Device Corporation | Compounds useful in coating stents to prevent and treat stenosis and restenosis |
CA2515603C (en) | 2003-02-10 | 2016-06-07 | To-Bbb Holding B.V. | Differentially expressed nucleic acids in the blood-brain barrier under inflammatory conditions |
WO2005020933A2 (en) | 2003-09-02 | 2005-03-10 | University Of South Florida | Nanoparticles for drug-delivery |
US8668926B1 (en) | 2003-09-15 | 2014-03-11 | Shaker A. Mousa | Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations thereof |
US8071134B2 (en) | 2003-09-15 | 2011-12-06 | Ordway Research Institute, Inc. | Thyroid hormone analogs and methods of use |
AU2004273986B2 (en) | 2003-09-15 | 2010-04-22 | Nanopharmaceuticals Llc | Thyroid hormone analogs and methods of use in angiogenesis |
US9198887B2 (en) | 2003-09-15 | 2015-12-01 | Nanopharmaceuticals Llc | Thyroid hormone analogs and methods of use |
WO2005033263A1 (en) | 2003-10-01 | 2005-04-14 | Athena Capital Partners, Llc | Circulating flow device for assays of cell cultures, cellular components and cell products |
US20050158376A1 (en) | 2003-10-23 | 2005-07-21 | Sardi William F. | Dietary supplement and method of processing same |
WO2005040758A2 (en) | 2003-10-24 | 2005-05-06 | Intermune, Inc. | Use of pirfenidone in therapeutic regimens |
CA2548671C (en) | 2003-12-29 | 2015-02-24 | President And Fellows Of Harvard College | Compositions for treating or preventing obesity and insulin resistance disorders |
US20080193377A1 (en) | 2004-06-28 | 2008-08-14 | University Of Maryland, Baltimore | Radiolabeled Nanohybrids Targeting Solid Tumor Neovasculature and Method of Using Same |
US7968085B2 (en) | 2004-07-05 | 2011-06-28 | Ascendis Pharma A/S | Hydrogel formulations |
EP1793814B1 (en) | 2004-09-15 | 2015-01-21 | NanoPharmaceuticals LLC | Thyroid hormone analogs for inhibiting angiogenesis |
US20060166303A1 (en) | 2005-01-24 | 2006-07-27 | Eberhard Spanuth | Use of cardiac hormones for assessing a cardiovascular risk with respect to the administration of anti-inflammatory drugs |
EP2314614B1 (en) | 2005-02-28 | 2015-11-25 | Sangamo BioSciences, Inc. | Anti-angiogenic methods and compositions |
US7776915B2 (en) | 2005-03-24 | 2010-08-17 | Tracie Martyn International, Llc | Topical formulations and methods of use |
MX2007012157A (es) | 2005-04-01 | 2008-03-14 | Intezyne Technologies Llc | Micelas polimericas para suministro de farmacos. |
US20090022806A1 (en) | 2006-12-22 | 2009-01-22 | Mousa Shaker A | Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists and formulations and uses thereof |
US9498536B2 (en) | 2005-09-15 | 2016-11-22 | Nanopharmaceuticals Llc | Method and composition of thyroid hormone analogues and nanoformulations thereof for treating anti-inflammatory disorders |
US10130686B2 (en) | 2005-09-15 | 2018-11-20 | Nanopharmaceuticals Llc | Method and composition of thyroid hormone analogues and nanoformulations thereof for treating inflammatory disorders |
WO2007035612A2 (en) | 2005-09-16 | 2007-03-29 | Ordway Research Institute, Inc. | Polyphenol conjugates as rgd-binding compounds and methods of use |
EP1934599A1 (en) | 2005-10-11 | 2008-06-25 | Merck Patent GmbH | Egfr dependent modulation of chemokine expression and influence on therapy and diagnosis of tumors and side effects thereof |
EP2018186A2 (en) | 2006-04-11 | 2009-01-28 | Ordway Research Institute, Inc. | Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations thereof |
JP5630998B2 (ja) | 2006-05-15 | 2014-11-26 | マサチューセッツ インスティテュート オブ テクノロジー | 機能的粒子のためのポリマー |
EP2040751A2 (en) | 2006-06-15 | 2009-04-01 | Biogen Idec MA Inc. | Combination therapy employing lymphotoxin beta receptor binding molecules in combination with second agents |
KR100830889B1 (ko) | 2006-12-18 | 2008-05-21 | 주식회사 케이티 | 세툭시맵이 결합된 나노 입자 및 이의 제조 방법 |
EP2120913B1 (en) | 2006-12-22 | 2015-01-21 | NanoPharmaceuticals LLC | Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations and uses thereof |
US20110112079A1 (en) | 2008-01-09 | 2011-05-12 | Thomas Craig J | Phosphodiesterase inhibitors |
US8420380B2 (en) | 2008-01-31 | 2013-04-16 | Transmedics, Inc. | Systems and methods for ex vivo lung care |
CN104225613A (zh) | 2008-03-14 | 2014-12-24 | Visen医药公司 | 整联蛋白靶向试剂及使用其的体内和体外成像方法 |
US20100159021A1 (en) | 2008-12-23 | 2010-06-24 | Paul Davis | Small Molecule Ligands of the Integrin RGD Recognition Site and Methods of Use |
US20160348052A1 (en) | 2009-03-31 | 2016-12-01 | Hung-Yun Lin | In Vitro Pharmacokinetics/Pharmacodynamics Bellows Perfusion System for Enhancing Effectiveness of Cancer Chemotherapy |
WO2010148007A2 (en) | 2009-06-17 | 2010-12-23 | Ordway Research Institute, Inc. | Nanoparticle and polymer formulations for thyroid hormone, analogs, antagonists, and formulations and uses thereof |
EP2575816B1 (en) | 2010-05-28 | 2019-01-02 | Nexgen Dermatologics, Inc. | Combination therapy for skin disorders |
EP3155087A4 (en) | 2010-07-13 | 2018-01-24 | NanoPharmaceuticals LLC | In vitro pharmacokinetics/pharmacodynamics bellows perfusion system for enhancing effectiveness of cancer chemotherapy |
US8802240B2 (en) | 2011-01-06 | 2014-08-12 | Nanopharmaceuticals Llc | Uses of formulations of thyroid hormone analogs and nanoparticulate forms thereof to increase chemosensitivity and radiosensitivity in tumor or cancer cells |
WO2012103328A1 (en) | 2011-01-26 | 2012-08-02 | The Methodist Hospital Research Institute | Labeled, non- peptidic multivalent integrin alpha -v - beta - 3 antagonists, compositions containing them and their use |
ES2741308T3 (es) | 2013-10-15 | 2020-02-10 | Scripps Research Inst | Interruptores de células T con receptores de antígenos quiméricos y usos de los mismos |
US10060934B2 (en) | 2013-11-18 | 2018-08-28 | Nanopharmaceuticals Llc | Methods for screening patients for resistance to angioinhibition, treatment and prophylaxis thereof |
KR101566345B1 (ko) | 2014-03-21 | 2015-11-23 | 한국생명공학연구원 | 다가성 리간드의 내부 표면작용기와 암 표적 리간드 단위의 비율을 조절하여 암 진단 효율을 향상시키는 방법 |
EP2954933A1 (en) | 2014-06-10 | 2015-12-16 | 3B Pharmaceuticals GmbH | Conjugate comprising a neurotensin receptor ligand |
WO2016004043A1 (en) | 2014-06-30 | 2016-01-07 | Blend Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
JP2017526682A (ja) | 2014-09-02 | 2017-09-14 | イミュノジェン, インコーポレイテッド | 抗体薬物複合体組成物の製剤化方法 |
CN104530417B (zh) | 2014-10-01 | 2017-09-08 | 厦门赛诺邦格生物科技股份有限公司 | 一种多官能化h型聚乙二醇衍生物及其制备方法 |
US10328043B1 (en) * | 2018-04-11 | 2019-06-25 | Nanopharmaceuticals, Llc. | Composition and method for dual targeting in treatment of neuroendocrine tumors |
-
2018
- 2018-04-11 US US15/950,870 patent/US10328043B1/en active Active
-
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- 2019-04-03 CA CA3095074A patent/CA3095074A1/en active Pending
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100255108A1 (en) | 2009-03-31 | 2010-10-07 | Hung-Yun Lin | Combination Treatment of Cancer With Cetuximab and Tetrac |
US20130224115A1 (en) | 2010-04-01 | 2013-08-29 | Baylor College Of Medicine | Non-radioactive agents for neuroblastoma imaging |
US20170348425A1 (en) | 2016-06-07 | 2017-12-07 | Nanopharmaceuticals, Llc | Non-cleavable polymer conjugated with alpha v beta 3 integrin thyroid antagonists |
Non-Patent Citations (1)
Title |
---|
Bioorganic & Medicinal Chemistry Letters,2018年,28(7),pp.1223-1227 |
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