JP6067225B2 - インビボでの酵素プロファイリングのための方法および生成物 - Google Patents
インビボでの酵素プロファイリングのための方法および生成物 Download PDFInfo
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
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- YIGWVOWKHUSYER-UHFFFAOYSA-F tetracalcium;hydrogen phosphate;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YIGWVOWKHUSYER-UHFFFAOYSA-F 0.000 description 1
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 1
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- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
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- 150000003573 thiols Chemical class 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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- 102000003601 transglutaminase Human genes 0.000 description 1
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- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6848—Methods of protein analysis involving mass spectrometry
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6842—Proteomic analysis of subsets of protein mixtures with reduced complexity, e.g. membrane proteins, phosphoproteins, organelle proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Analytical Chemistry (AREA)
- Bioinformatics & Computational Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Cell Biology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Neurosurgery (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
本出願は、米国仮出願連番第US 61/156,660号、題名「METHODS AND PRODUCTS FOR IN VIVO ENZYME PROFILING」、2009年3月2日出願の35 U.S.C. § 119(e)の下での利益を請求し、その開示は、その全体において本明細書中に参照によって組み込まれる。
政府支援
本発明は、NIHによって授与された認可番号第5−R01−CA124427−03号の下で、政府支援を伴ってなされた。政府は、本発明において特定の権利を有する。
本発明は、インビボでの酵素プロファイリングと関連する方法および生成物に関する。本発明のいくつかの側面は、酵素反応生成物をプロファイリングすることに関する。特に、本発明は、外因性分子のインビボ処理、続いて疾患または状態(condition)と関連する活性酵素の存在または不存在の代表としてのシグネチャー分子の検出の方法に関する。本発明はまた、本発明の方法において用いるための生成物、キットおよびデータベースに関する。
配列番号:1は、GGPQGIWGQCである。
配列番号:2は、GGPLGVRGKCである。
配列番号:3は、GGPLANvaDapARGCである。
配列番号:4は、GGPVGLIGLである。
配列番号:5は、GGPVPLSLVMCである。
配列番号:6は、GGSGGPLGLRSWCである。
配列番号:7は、GGGPWGIWGQGCである。
配列番号:8は、GGdFPipRSGGGCである。
配列番号:10は、GGPQGである。
配列番号:11は、GGPLGである。
配列番号:12は、GGPLAである。
配列番号:13は、GGPVGである。
配列番号:14は、GGPVPLSである。
配列番号:15は、GGSGGPLGである。
配列番号:16は、GGGPWGである。
配列番号:18は、GGLVPである。
配列番号:19は、GGVVVLSである。
配列番号:20は、Fl−dR−dS−dRである。
配列番号:21は、Fl−dR−G−dS−dRである。
配列番号:22は、Fl−dR−dS−dR−G−G−P−Q−G−I−W−G−Q−Cである。
配列番号:23は、Fl−dR−G−dS−dR−G−G−P−L−G−V−R−G−K−Cである。
配列番号:24は、Fl−dR−G−dS−dR−G−G−P−L−A−Nva−Dpa−A−R−G−Cである。
配列番号:26は、Fl−dR−dS−dR−G−G−P−V−P−L−S−L−V−M−Cである。
配列番号:27は、Fl−dR−G−dS−dR−G−G−V−V−V−L−S−M−T−A−Cである。
配列番号:28は、Fl−dR−G−dS−dR−G−G−S−G−G−P−L−G−L−R−S−W−Cである。
配列番号:29は、Fl−dR−G−dS−dR−G−G−G−P−W−G−I−W−G−Q−G−Cである。
配列番号:30は、Fl−dR−G−G−dS−G−G−dF−Pip−R−S−G−G−G−Cである。
配列番号:31は、Fl−dR−dS−dR−G−G−L−V−P−R−G−S−G−Cである。
配列番号:32は、Fl−dR−G−G−dS−G−G−F−P−R−S−G−G−G−Cである。
配列番号:34は、Fl−dR−G−G−dS−G−G−G−dF−P−K−S−G−G−G−Cである。
配列番号:35は、dR−dS−dRである。
配列番号:36は、dR−G−dS−dRである。
(Fl:フルオレセイン;Nva:ノルバリン;Dap=(N−β−(2,4−ジニトロフェニル))−L−α,β−ジアミノプロピオン酸);Pip:ピペコリン酸;d:D−異性体。)
対象の生理的状態の状況を、また「分子シグネチャー」と呼ばれる分子特性を特定することによって、本発明の方法を用いて評価することができる。そのような分子シグネチャーは、疾患、例えば癌、関節リウマチおよび動脈硬化を診断するために、ならびに予後の指標のために有用である。ほとんどの癌の医療介入に対する応答を、ここで物理的試験および多様な臨床的画像診断法によってモニタリングする。少数の癌、例えば前立腺癌および卵巣癌を、血液中の単一のバイオマーカーを用いることによってモニタリングする。そのような診断技術は、例えば特定の疾患状態において活性化される分子マーカーの蛍光検出を用いて達成される。
ポリビニルアルコール(PVA)は、酢酸基の水酸基での置き換えによってポリ酢酸ビニルから調製されるポリマーであり、式(CH2CHOH)[n]を有する。ほとんどのポリビニルアルコールは、水に可溶である。
特定の態様において、粒子は、ポリ(乳酸−コ−グリコール酸)(PLGA)を含んでいてもよい。
キャリアは、無機材料から構成され得る。無機材料は、例えば、磁性材料、導電性材料および半導体材料を含む。
本出願を通じて用いる「複数種」の要素は、2種または3種以上の要素を指す。
例1:方法
ナノ粒子プロ診断試薬の合成
40nmのデキストランで被覆した酸化鉄ナノ粒子(NP;鉄核あたり115,000g/mol)を、2mg/mLの濃度にて1×リン酸緩衝生理食塩水(PBS;137mMのNaCl、10mMのリン酸塩、2.7mMのKCl、pH7.4)に溶解した。Vivotag-750 フルオロフォアを、NPに対して標識して、各々のNPが約2個のVT−750フルオロフォアを有するようにした。リンカーN−スクシンイミジルヨードアセテート(SIA)を、DMSOに20mg/mLにて溶解した。2種の溶液を混合して、酸化鉄NPとSIAとの間で1対7の質量比を得るために、室温にて2時間振盪した。ゲル濾過クロマトグラフィー(カラム直径×高さ=1cm×30cm;媒体:Sephadex G-50-coarse)を用いて、過剰のSIAを分離し、NPをホウ酸塩緩衝液(50mMのホウ酸ナトリウム、5mMのEDTA、pH8.3)中で交換した。
43種の正規化した(5μMのペプチド濃度を基準として)pP−NPを、透明な半96ウェルプレート上で等分した。等分した「保存」プレートから、20μLの各々の試料を取り出し、黒色の半領域96ウェルプレート中に投入した。MMP−2を、1xHEPES塩緩衝液(5mMのCaCl2を含む)に64nMにて溶解し、溶液を37℃にて15分間加熱して、酵素を活性化した。20μLのMMP−2溶液を、黒色半96ウェルプレート上のすべての43個のウェルの各々(それは既にpP−NP試料を含んでいた)中に投入して、各々のウェルが32nMのMMP−2および2.5μMのペプチド濃度を有するようにした。
HT−1080ヒト線維肉腫細胞(American Type Culture Collection;ATCC)を、DMEM(89%)、胎児ウシ血清(10%;Invitrogen)およびペニシリン/ストレプトマイシン(1%)からなる細胞培地溶液を用いることによって、組織培養フラスコ(150cm2)中で培養した。細胞を、数世代にわたって成長させ(n=4〜5)、次に血清を含まない溶液(66%のDMEM、33%のマトリクスゲルおよび1%のペニシリン/ストレプトマイシン)中で約2×106百万個の細胞/mLに濃縮した。
トロンビンに特異的なpP−NP試料(ペプチド濃度を基準として2nmol)を、各々の4匹の1月齢の成体雌白色マウス(Swiss Webster;系統コード:024;Charles River Laboratories, Inc., Wilmington, MA) 中に注射した。試薬(また本明細書中でNPシャペロンと呼ぶ)を、血流中で5分間(その終点を0時間と定義した)循環させた。15μLの血液試料を、ヘパリン処置した毛細管で以下の時点にてレトロオービタリーに(retro-orbitally)採取した:0時間、1時間、3時間、6時間、8時間および12時間。10μLの血液試料を、10mMのEDTAを含む40μLの1×PBSと温和に混合して、血中カルシウムをキレートし、凝固を防止した;混合物をボルテックスし、遠心分離して、赤血球を沈渣させ、それを次に廃棄した。30μLの上清(血漿)を、24×36マイクロアレイプレート上のウェル中に投入した。
9種の選択されたペプチド−PEG−NP(pP−NP)から、最初の7種のペプチドを、腫瘍モニタリングのための標的とし、一方最後の2種のペプチドを、内部の血管傷害評価のために選択した。これらの9種のpP−NPを、大量に(ペプチド濃度を基準として少なくとも100nmol)再び合成した。各々の9種のpP−NP(約5nmol)を、VT−750フルオロフォア(NPについてのペプチド濃度に対して5倍モル過剰にて)と2時間反応させ、過剰の未反応のVT−750を、100kフィルターカラム上で沈降させることによって<0.01%に濾過して除去した。VT−750をここで、pP−NP上でペプチドの末端に共有結合させ、本発明者らは、これらの生成物を750−pP−NPと略す。
ヌードマウスおよび白色マウスの両方についての試料の大きさが極めて小さく、正規分布を推測することができないため、スチューデント両側t−検定を、この研究におけるすべての統計的試験について行った。帰無仮説は、2つの群(例えば腫瘍対非腫瘍;傷害対非傷害)が排出されたペプチドの量において異ならず、<0.05のp値が帰無仮説を拒絶するであろう。
ペプチド−PEG−ナノ粒子(pP−NP)で構成された43種のプロ診断試薬を調製し、分光計で分析して、各々のナノ粒子に結合したペプチドの数を評価した。試薬を、迅速な高処理量選別法を可能にするように設計した。図1は、プロ診断試薬に基づく質量コード化ナノ粒子の多重化されたインビボの酵素プロファイリングのための本発明の方法を示す概略図である。
最初に、本発明者らは、プロ診断試薬が腫瘍または傷害を標的とすることができることを確立した。本発明者らは次に、43種のプロ診断試薬の選別を行って、腫瘍および傷害プロテアーゼの検出のための最適な順序を蛍光的に見出した。特定のペプチド基質についてのプロテアーゼ活性を、フルオロフォア強度レベルによって時間経過と共に測定した。ペプチド−フルオロフォア(シグネチャー分子)がナノ粒子鉄核(キャリア)に付着した際に、フルオロフォアの蛍光は、隣接する吸収鉄核によってクエンチされた。しかし、ペプチドを切断した際に、フルオロフォアはもはやクエンチされず、蛍光の増大が検出された。
プロ診断試薬での腫瘍および創傷の標的化は、いかにしてキャリアがペプチド(それはさもなければ数分以内にクリアランスされる)の循環時間を増大させ、腫瘍または傷害のいずれかに対する標的を可能にするかを示す。図2は、プロ診断試薬での腫瘍および創傷の標的化のプロセスを描写するデータを示す。図2Aは、プロ診断試薬の概略図であり、円はキャリアを指し、星印は蛍光分子であり、ジグザグ線は酵素感受性ドメインおよびシグネチャー分子を指す(より暗い末端領域)。図2Bは、プロ診断試薬の電子顕微鏡写真である。図2Cは、静脈内注射の後の時間に関する血液中のキャリアの検出をプロットすることによる、プロ診断試薬の循環時間を描写するグラフである。図2Dは、プロ診断試薬を投与した、腫瘍または傷害のいずれかを有するマウスの写真である(それぞれ左側および右側のパネル)。図2Eは、腫瘍または傷害の領域に誘導されるキャリアの組織病理学的分析である。
インビボでのプロ診断試薬の循環時間を、評価した。最適化したプロ診断試薬を、マウス中に静脈内に注射し、切断したペプチド(シグネチャー構成要素)を、注射後に尿中に蛍光的に追跡した。血漿試料における蛍光の強度を、Odyssey画像化システムで検出した。図5は、インビボでの腫瘍および傷害による尿レポーター活性化の蛍光検出の結果を描写する。図5Aは、腎クリアランスを受ける分子の部分およびRESクリアランスを受ける部分をさらに描写する、図3Aに示すプロ診断試薬の概略図である。
図7は、注入可能な診断カプセルの例示的な態様を示す。図7Aは、例えばDaniel, K.D., et al., Implantable diagnostic device for cancer monitoring. Biosensors and Bioelectronics 24 (2009) 3252-3257に記載されている典型的な埋め込み型カプセルの写真を示し、それを、本発明においてナノ粒子を負荷させるために用いることができる。ナノ粒子を、ウェル形状の容器中に負荷させ、半透性ポリカーボネート膜によって密封し、酵素および他の分子の自由な輸送を可能にするが、ナノ粒子のカプセル外(extracapsule)拡散を制限することができる。
多様な配列の一連のペプチド(A1〜A14)を調査して、LC/MSによる容易な検出を可能にする最適な配列の長さおよび荷電密度を決定した。3種の代表的なタンパク質分解生成物、即ち配列GGVVVLS(配列番号:19)、GGPVG(配列番号:13)およびGGdFPipR(配列番号:17)を選択し、それに多様な長さおよび荷電密度のペプチドキャップを付加した(図8A)。次に、配列を、LC/MSによって検出した。図8Bは、ペプチドレポーターの正規化された相対的強度を示す。図8Bの挿入図は、LC/MSによって測定した、ペプチド配列A1〜A6の正規化された相対的強度の拡大を示す。一般的に、より短いキャップを付加した親水性配列は、より容易に検出された。
A Fl−dR−dS−dR−G−G−P−Q−G−I−W−G−Q−C(配列番号:22)
B Fl−dR−G−dS−dR−G−G−P−L−G−V−R−G−K−C(配列番号:23)
C Fl−dR−G−dS−dR−G−G−P−L−A−Nva−Dpa−A−R−G−C(配列番号:24)
D Fl−dR−G−dS−dR−G−G−P−V−G−L−I−G−C(配列番号:25)
E Fl−dR−dS−dR−G−G−P−V−P−L−S−L−V−M−C(配列番号:26)
G Fl−dR−G−dS−dR−G−G−S−G−G−P−L−G−L−R−S−W−C(配列番号:28)
H Fl−dR−G−dS−dR−G−G−G−P−W−G−I−W−G−Q−G−C(配列番号:29)
I Fl−dR−G−G−dS−G−G−dF−Pip−R−S−G−G−G−C(配列番号:30)
J Fl−dR−dS−dR−G−G−L−V−P−R−G−S−G−C(配列番号:31)
Ia Fl−dR−G−G−dS−G−G−F−P−R−S−G−G−G−C(配列番号:32)
Ib Fl−dR−G−G−dS−G−G−G−dF−Pip−K−S−G−G−G−C(配列番号:33)
Ic Fl−dR−G−G−dS−G−G−G−dF−P−K−S−G−G−G−C(配列番号:34)
各々が異なるペプチドで官能化された12種のプロ診断ナノ粒子の2つの同一の混合物(図9A)を、トロンビンまたはコラゲナーゼに曝露し、タンパク質分解的に放出されたレポーターを、LC/MSによって分析した。6つのペプチドは、トロンビンのための標的ペプチド配列を含んでおり、一方他の6つのペプチドは、コラゲナーゼのための標的ペプチド配列を含んでいた。第1の多重化混合物のトロンビンへの曝露の後および第2の多重化混合物のコラゲナーゼへの曝露の後のすべての12個のペプチドのLC/MSピーク面積測定を、それぞれ図9Bおよび図9Cに示す。
本出願中で列挙したすべての参考文献、特許および特許公報は、その全体において本明細書中に参照によって組み込まれる。
Claims (9)
- 診断方法に使用するためのプロ診断試薬であって、酵素によって切断される部分と、キャリア部分と、前記キャリア部分から前記酵素の切断によって産生されるシグネチャー分子とを含み、
前記シグネチャー分子が産生される部位とは異なる部位にある生体試料を同定して;
質量分析法または液体クロマトグラフィー−質量分析法を含む群から選択される分析法により、前記シグネチャー分子の存在を検出する、前記プロ診断試薬。 - 酵素が、癌、心血管疾患、関節炎、ウィルス性、細菌性、寄生虫もしくは真菌感染症、アルツハイマー病、気腫、血栓症、血友病、脳卒中、臓器障害、すべての炎症状態、または血管疾患によって分泌されるものである、請求項1に記載のプロ診断試薬。
- 酵素によって切断される部分がペプチドであり、ここで前記ペプチドは、MMPによって切断される部分、カリクレインによって切断される部分、カテプシンによって切断される部分、プラスミノーゲン活性化因子によって切断される部分またはADAMによって切断される部分を含む、請求項1または2に記載のプロ診断試薬。
- 酵素が、プロテアーゼ、グリコシダーゼ、リパーゼ、ヘパリナーゼ、ホスファターゼおよびコラーゲナーゼを含む群から選択される酵素である、請求項1〜3のいずれか一項に記載のプロ診断試薬。
- 酵素によって切断される部分が、ペプチドであり、前記ペプチドがGGPQGIWGQC(配列番号:1)、GGPLGVRGKC(配列番号:2)、GGPLANvaDapARGC(配列番号:3)、GGPVGLIGL(配列番号:4)、GGPVPLSLVMC(配列番号:5)、GGSGGPLGLRSWC(配列番号:6)、GGGPWGIWGQGC(配列番号:7)、GGdFPipRSGGGC(配列番号:8)またはGGLVPRGSGC(配列番号:9)を含む、請求項1〜4のいずれか一項に記載のプロ診断試薬。
- 生体試料が尿である、請求項1〜5のいずれか一項に記載のプロ診断試薬。
- 質量分析法または液体クロマトグラフィー−質量分析法を含む群から選択される分析法により、請求項1〜6のいずれか一項に記載のプロ診断試薬を用いて同定された生体試料におけるシグネチャー分子の存在を検出する方法。
- 請求項1〜6のいずれか一項に記載のプロ診断試薬を収納している容器とプロ診断試薬を対象に投与することおよび、対象から生体試料を同定するための指示を含む、キット。
- 対象に試薬を投与し、前記対象から非蛍光性シグネチャー分子が産生される部位とは異なる部位にある生体試料を同定し、質量分析法または液体クロマトグラフィー−質量分析法を含む群から選択される分析法により、前記非蛍光性シグネチャー分子の存在を検出するための前記試薬であって、
複数の酵素によって切断される部分と、キャリア部分と、前記キャリア部分から前記酵素の切断によって生産される前記非蛍光性シグネチャー分子を含む、前記試薬。
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EP2686000B1 (en) | 2011-03-15 | 2021-05-05 | Massachusetts Institute of Technology | Multiplexed detection with isotope-coded reporters |
US8663912B2 (en) | 2011-07-18 | 2014-03-04 | Washington University | Fluorogenic substrate for ADAMTS13 |
WO2013043812A1 (en) * | 2011-09-22 | 2013-03-28 | Board Of Regents Of The University Of Texas System | Logical enzyme triggered (let) layer-by-layer nanocapsules for drug delivery system |
DE102012213465A1 (de) | 2012-07-31 | 2014-02-06 | Brose Fahrzeugteile GmbH & Co. Kommanditgesellschaft, Würzburg | Permanentmagnet-Synchronmotor und Servolenkungsanordnung |
NL2010040C2 (en) * | 2012-12-21 | 2014-06-24 | Internat Inst For Diagnostic And Analitical Affairs B V | Cleavable coating material having microbial functionality. |
WO2014197840A1 (en) * | 2013-06-07 | 2014-12-11 | Massachusetts Institute Of Technology | Affinity-based detection of ligand-encoded synthetic biomarkers |
US9145581B1 (en) * | 2014-10-17 | 2015-09-29 | Daniel Lai | Rapid nucleic acid extraction method and apparatus |
US11448643B2 (en) | 2016-04-08 | 2022-09-20 | Massachusetts Institute Of Technology | Methods to specifically profile protease activity at lymph nodes |
US11428689B2 (en) | 2016-05-05 | 2022-08-30 | Massachusetts Institute Of Technology | Methods and uses for remotely triggered protease activity measurements |
CN106526041A (zh) * | 2016-12-05 | 2017-03-22 | 百奥森(江苏)食品安全科技有限公司 | 一种多种霉菌毒素同时检测方法 |
EP3607085A1 (en) * | 2017-04-07 | 2020-02-12 | Massachusetts Institute Of Technology | Methods to spatially profile protease activity in tissue and sections |
WO2019173332A1 (en) | 2018-03-05 | 2019-09-12 | Massachusetts Institute Of Technology | Inhalable nanosensors with volatile reporters and uses thereof |
US11732009B2 (en) | 2018-06-08 | 2023-08-22 | Glympse Bio, Inc. | Activity sensor with tunable analyte |
US11028425B2 (en) | 2018-06-08 | 2021-06-08 | Glympse Bio, Inc. | Diagnosis and monitoring of liver disease |
WO2020081635A2 (en) | 2018-10-16 | 2020-04-23 | Massachusetts Institute Of Technology | Renal clearable nanocatalysts for disease monitoring |
EP3911753A1 (en) | 2019-01-17 | 2021-11-24 | Massachusetts Institute of Technology | Sensors for detecting and imaging of cancer metastasis |
CA3128722A1 (en) * | 2019-02-01 | 2020-08-06 | Glympse Bio, Inc. | Bodily processing of activity sensors |
US20210262025A1 (en) | 2020-02-18 | 2021-08-26 | Massachusetts Institute Of Technology | Multiplexed in vivo disease sensing with nucleic acid-barcoded reporters |
WO2024081646A1 (en) | 2022-10-11 | 2024-04-18 | Massachusetts Institute Of Technology | Reagents and methods for the conditional delivery of cargo |
Family Cites Families (152)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4217344A (en) | 1976-06-23 | 1980-08-12 | L'oreal | Compositions containing aqueous dispersions of lipid spheres |
US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4186183A (en) | 1978-03-29 | 1980-01-29 | The United States Of America As Represented By The Secretary Of The Army | Liposome carriers in chemotherapy of leishmaniasis |
US4261975A (en) | 1979-09-19 | 1981-04-14 | Merck & Co., Inc. | Viral liposome particle |
US4485054A (en) | 1982-10-04 | 1984-11-27 | Lipoderm Pharmaceuticals Limited | Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV) |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US4946929A (en) | 1983-03-22 | 1990-08-07 | Massachusetts Institute Of Technology | Bioerodible articles useful as implants and prostheses having predictable degradation rates |
US4946787A (en) | 1985-01-07 | 1990-08-07 | Syntex (U.S.A.) Inc. | N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US4638045A (en) | 1985-02-19 | 1987-01-20 | Massachusetts Institute Of Technology | Non-peptide polyamino acid bioerodible polymers |
US5333675C1 (en) | 1986-02-25 | 2001-05-01 | Perkin Elmer Corp | Apparatus and method for performing automated amplification of nucleic acid sequences and assays using heating and cooling steps |
US4774085A (en) | 1985-07-09 | 1988-09-27 | 501 Board of Regents, Univ. of Texas | Pharmaceutical administration systems containing a mixture of immunomodulators |
US4806621A (en) | 1986-01-21 | 1989-02-21 | Massachusetts Institute Of Technology | Biocompatible, bioerodible, hydrophobic, implantable polyimino carbonate article |
US4889818A (en) | 1986-08-22 | 1989-12-26 | Cetus Corporation | Purified thermostable enzyme |
CA1340581C (en) | 1986-11-20 | 1999-06-08 | Joseph P. Vacanti | Chimeric neomorphogenesis of organs by controlled cellular implantation using artificial matrices |
US5804178A (en) | 1986-11-20 | 1998-09-08 | Massachusetts Institute Of Technology | Implantation of cell-matrix structure adjacent mesentery, omentum or peritoneum tissue |
US5736372A (en) | 1986-11-20 | 1998-04-07 | Massachusetts Institute Of Technology | Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5019379A (en) | 1987-07-31 | 1991-05-28 | Massachusetts Institute Of Technology | Unsaturated polyanhydrides |
US5211657A (en) | 1988-11-07 | 1993-05-18 | The United States Government As Represented By The Secretary Of The Department Of Health And Human Services | Laminin a chain deduced amino acid sequence, expression vectors and active synthetic peptides |
US5010167A (en) | 1989-03-31 | 1991-04-23 | Massachusetts Institute Of Technology | Poly(amide-and imide-co-anhydride) for biological application |
WO1991017424A1 (en) | 1990-05-03 | 1991-11-14 | Vical, Inc. | Intracellular delivery of biologically active substances by means of self-assembling lipid complexes |
JPH07507394A (ja) | 1992-05-29 | 1995-08-10 | ザ ロックフェラー ユニバーシティ | 質量スペクトロメータを用いてペプチドの配列決定を行う為の方法及び物質 |
US5399665A (en) | 1992-11-05 | 1995-03-21 | Massachusetts Institute Of Technology | Biodegradable polymers for cell transplantation |
US5512600A (en) | 1993-01-15 | 1996-04-30 | Massachusetts Institute Of Technology | Preparation of bonded fiber structures for cell implantation |
US5514378A (en) | 1993-02-01 | 1996-05-07 | Massachusetts Institute Of Technology | Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures |
US5500161A (en) * | 1993-09-21 | 1996-03-19 | Massachusetts Institute Of Technology And Virus Research Institute | Method for making hydrophobic polymeric microparticles |
ATE226642T1 (de) * | 1994-07-07 | 2002-11-15 | Tno | Modifizierte proenzyme als substrate für proteolische enzyme |
US5716404A (en) | 1994-12-16 | 1998-02-10 | Massachusetts Institute Of Technology | Breast tissue engineering |
US6123727A (en) | 1995-05-01 | 2000-09-26 | Massachusetts Institute Of Technology | Tissue engineered tendons and ligaments |
JP2001500606A (ja) | 1995-05-19 | 2001-01-16 | パーセプティブ バイオシステムズ,インコーポレーテッド | 質量スペクトル分析を用いた統計的に確実性のあるポリマー配列決定のための方法および装置 |
US6095148A (en) | 1995-11-03 | 2000-08-01 | Children's Medical Center Corporation | Neuronal stimulation using electrically conducting polymers |
US5902599A (en) | 1996-02-20 | 1999-05-11 | Massachusetts Institute Of Technology | Biodegradable polymer networks for use in orthopedic and dental applications |
US5885775A (en) | 1996-10-04 | 1999-03-23 | Perseptive Biosystems, Inc. | Methods for determining sequences information in polynucleotides using mass spectrometry |
US6037137A (en) | 1997-02-20 | 2000-03-14 | Oncoimmunin, Inc. | Fluorogenic peptides for the detection of protease activity |
US5996586A (en) | 1997-03-26 | 1999-12-07 | Phillips; Michael | Breath test for detection of lung cancer |
US5837752A (en) | 1997-07-17 | 1998-11-17 | Massachusetts Institute Of Technology | Semi-interpenetrating polymer networks |
US6342611B1 (en) | 1997-10-10 | 2002-01-29 | Cytovia, Inc. | Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for capsases and other enzymes and the use thereof |
US6592847B1 (en) * | 1998-05-14 | 2003-07-15 | The General Hospital Corporation | Intramolecularly-quenched near infrared flourescent probes |
EP1329513B1 (en) * | 1998-08-25 | 2011-12-07 | University of Washington | Rapid quantitative analysis of proteins or protein function in complex mixtures |
US6844148B1 (en) * | 1998-09-24 | 2005-01-18 | Pharmacia & Upjohn Company | Alzheimer's disease secretase, APP substrates therefor, and uses therefor |
US6629040B1 (en) * | 1999-03-19 | 2003-09-30 | University Of Washington | Isotope distribution encoded tags for protein identification |
US6764817B1 (en) | 1999-04-20 | 2004-07-20 | Target Discovery, Inc. | Methods for conducting metabolic analyses |
EP1190364A2 (en) | 1999-04-23 | 2002-03-27 | Massachusetts Institute Of Technology | System and method for polymer notation |
US20040014652A1 (en) | 2000-06-01 | 2004-01-22 | Andre Trouet | Tumor activated prodrug compounds and methods of making and using the same |
AU8356201A (en) * | 2000-08-11 | 2002-02-25 | Agilix Corp | Ultra-sensitive detection systems |
WO2002042427A2 (en) * | 2000-10-25 | 2002-05-30 | Surromed, Inc. | Mass tags for quantitative analysis |
US20020119490A1 (en) * | 2000-12-26 | 2002-08-29 | Aebersold Ruedi H. | Methods for rapid and quantitative proteome analysis |
EP1370867B1 (en) | 2001-03-02 | 2010-08-04 | Activx Biosciences, Inc. | Protein profiling platform |
CA2477163C (en) | 2002-02-21 | 2010-07-27 | Institute Of Virology | Soluble form of carbonic anhydrase ix (s-ca-ix), assays to detect s-ca ix, and ca ix's coexpression with her-2/neu/c-erbb-2, and ca ix-specific monoclonal antibodies to non-immunodominant epitopes |
WO2004006898A2 (en) * | 2002-07-11 | 2004-01-22 | Sema Aps | Use of compounds capable of inhibiting the proteolytic processing of semaphorins for prevention, treatment, diagnosis and prognosis of an invasive disease |
US7041453B2 (en) | 2002-08-22 | 2006-05-09 | Bioarray Solutions Ltd. | Molecular constructs and methods of use for detection of biochemical reactions |
US7169892B2 (en) | 2003-01-10 | 2007-01-30 | Astellas Pharma Inc. | Lipid-peptide-polymer conjugates for long blood circulation and tumor specific drug delivery systems |
US20050260695A1 (en) | 2003-09-23 | 2005-11-24 | Genprime, Inc. | Methods, compositions, devices, and kits for detecting mastitis |
SE0302559D0 (sv) * | 2003-09-25 | 2003-09-25 | Astrazeneca Ab | Method |
US7431915B2 (en) | 2003-10-31 | 2008-10-07 | The Regents Of The University Of California | Peptides whose uptake by cells is controllable |
US9695251B2 (en) | 2003-10-31 | 2017-07-04 | The Regents Of The University Of California | Activatable cell penetrating peptides with quenched fluorophores |
US7985401B2 (en) | 2003-10-31 | 2011-07-26 | The Regents Of The University Of California | Peptides whose uptake by cells is controllable |
JP4575394B2 (ja) * | 2004-02-27 | 2010-11-04 | ヒタチ ケミカル リサーチ センター インコーポレイテッド | 多重検出プローブ |
WO2006073419A2 (en) | 2004-04-01 | 2006-07-13 | Gang Zheng | Lipoprotein nanoplatforms |
US20070054345A1 (en) | 2004-05-19 | 2007-03-08 | Hunter Christie L | Expression quantification using mass spectrometry |
WO2005113804A1 (en) * | 2004-05-20 | 2005-12-01 | Trillion Genomics Limited | Use of mass labelled probes to detect target nucleic acids using mass spectrometry |
US20070048752A1 (en) * | 2004-07-12 | 2007-03-01 | Applera Corporation | Mass tags for quantitative analyses |
EP1805323B1 (en) | 2004-09-20 | 2010-02-24 | University Of Florida Research Foundation, Inc. | Systems and methods for evaluating enzyme competency |
US7329506B2 (en) | 2004-12-03 | 2008-02-12 | Rutgers, The State University | Apparatuses and methods for determining protease activity |
MX2007007732A (es) * | 2004-12-22 | 2007-10-08 | Kuros Biosurgery Ag | Hidrogeles peg con grupos funcionales para la reaccion de adicion tipo michael con biofactores incorporados con el factor xiiia. |
EP1851551A2 (en) * | 2005-02-03 | 2007-11-07 | Perkinelmer Las, Inc. | Ultra-sensitive detection systems using multidimension signals |
US20060257883A1 (en) | 2005-05-10 | 2006-11-16 | Bjoraker David G | Detection and measurement of hematological parameters characterizing cellular blood components |
JP2007024631A (ja) | 2005-07-14 | 2007-02-01 | Human Science Shinko Zaidan | 同位体標識法 |
EP1999150A1 (en) | 2005-11-08 | 2008-12-10 | Oxford Genome Sciences (UK) Limited | New protein isoforms and uses thereof |
US20090088332A1 (en) * | 2005-11-21 | 2009-04-02 | Jingyue Ju | Multiplex Digital Immuno-Sensing Using a Library of Photocleavable Mass Tags |
US20090016988A1 (en) * | 2005-11-21 | 2009-01-15 | Buckley J Thomas | Modified Pore-Forming Protein Toxins and Use Thereof |
JP4124226B2 (ja) | 2005-11-25 | 2008-07-23 | ダイキン工業株式会社 | 空気調和装置 |
GB0524313D0 (en) * | 2005-11-29 | 2006-01-04 | Imp College Innovations Ltd | Particles |
WO2007136413A2 (en) * | 2005-12-22 | 2007-11-29 | Visen Medical, Inc. | Biocompatible fluorescent metal oxide nanoparticles |
EP1808187A1 (en) * | 2006-01-11 | 2007-07-18 | Straumann Holding AG | Cell selective implant surface with controlled release of bioactive agents |
US8975404B2 (en) | 2006-01-24 | 2015-03-10 | Dh Technologies Development Pte. Ltd. | Labeling reagents for analyte determination and methods and compounds used in making the same |
WO2008048345A2 (en) | 2006-02-14 | 2008-04-24 | Perkinelmer Las, Inc. | Detection systems for mass labels |
US7468258B2 (en) * | 2006-03-07 | 2008-12-23 | Wake Forest University Health Sciences | Self-quenching homofluorophore compositions for detecting enzyme activity |
CA2644694C (en) | 2006-03-10 | 2014-05-13 | Sangeeta N. Bhatia | Triggered self-assembly conjugates and nanosystems |
US7906341B2 (en) * | 2006-06-30 | 2011-03-15 | Dh Technologies Development Pte, Ltd. | Methods, mixtures, kits and compositions pertaining to analyte determination |
US20080113875A1 (en) * | 2006-09-08 | 2008-05-15 | Pierre Chaurand | Molecular detection by matrix free desorption ionization mass spectrometry |
US7696309B2 (en) * | 2006-10-23 | 2010-04-13 | The Brigham And Women's Hospital, Inc. | Protease resistant mutants of stromal cell derived factor-1 in the repair of tissue damage |
US20080213377A1 (en) * | 2006-12-08 | 2008-09-04 | Bhatia Sangeeta N | Delivery of Nanoparticles and/or Agents to Cells |
WO2008072676A1 (ja) | 2006-12-12 | 2008-06-19 | Kagoshima University | 新規疾患マーカーおよびそれを用いた診断 |
GB0701821D0 (en) * | 2007-02-01 | 2007-03-14 | Pentapharm Ag | Diagnostic composition and its use in the determination of coagulation characteristics of a test liquid |
JP2008189773A (ja) | 2007-02-02 | 2008-08-21 | Soken Chem & Eng Co Ltd | 架橋性高分子化合物およびこれを含有する感光性樹脂組成物 |
US8324355B2 (en) * | 2007-02-23 | 2012-12-04 | Yeda Reearch and Development Co. Ltd | Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins |
KR100857770B1 (ko) | 2007-04-11 | 2008-09-09 | 한국과학기술연구원 | 단백질 분해효소 검출 및 생체 내 영상화를 위한 금속 나노입자 및 그것의 용도 |
US8278057B2 (en) * | 2007-09-14 | 2012-10-02 | Nestec S.A. | Addressable antibody arrays and methods of use |
JP5604782B2 (ja) | 2007-09-28 | 2014-10-15 | 独立行政法人農業・食品産業技術総合研究機構 | 受容体再構築物、ならびにこれを用いる疾病検査法 |
US20090239252A1 (en) | 2007-10-19 | 2009-09-24 | Trevejo Jose M | Rapid detection of volatile organic compounds for identification of bacteria in a sample |
US20090286286A1 (en) * | 2007-11-06 | 2009-11-19 | Ambergen , Inc. | Methods for controlling amplification |
EP2229147A2 (en) | 2007-12-03 | 2010-09-22 | The Johns Hopkins University | Methods of synthesis and use of chemospheres |
MX2010009766A (es) | 2008-03-03 | 2010-09-28 | Univ Kansas State | Ensayo de proteasa. |
WO2009124265A1 (en) | 2008-04-03 | 2009-10-08 | The Board Of Trustees Of The Leland Stanford Junior University | Probes for in vivo targeting of active cysteine proteases |
KR101103548B1 (ko) | 2008-08-29 | 2012-01-09 | 한국과학기술연구원 | 단백질분해효소 활성 측정용 나노입자 센서 및 그 제조방법 |
CA3026701C (en) | 2009-03-02 | 2023-04-18 | Massachusetts Institute Of Technology | Methods and products for in vivo enzyme profiling |
US20110021908A1 (en) | 2009-05-27 | 2011-01-27 | Lumicell Diagnostics, Inc. | Methods and systems for spatially identifying abnormal cells |
US9155471B2 (en) | 2009-05-27 | 2015-10-13 | Lumicell, Inc'. | Methods and systems for spatially identifying abnormal cells |
AU2010273321A1 (en) | 2009-07-15 | 2012-03-08 | The Regents Of The University Of California | Peptides whose uptake in cells is controllable |
US9006415B2 (en) | 2010-04-06 | 2015-04-14 | Massachusetts Institute Of Technology | Targeted delivery of nucleic acids |
EP4098272A3 (en) | 2010-07-13 | 2023-03-08 | University of Rhode Island Board of Trustees | Compositions comprising a ph-sensitive membrane insertion polipeptide |
WO2012021790A1 (en) | 2010-08-13 | 2012-02-16 | Rhode Island Board Of Governors For Higher Education | Liposome compositions and methods of use thereof |
US20120055055A1 (en) | 2010-09-02 | 2012-03-08 | Illumin8 Outdoor Media, LLC | Systems and Method for Outdoor Media Signage |
US9314304B2 (en) | 2010-12-08 | 2016-04-19 | Lumicell, Inc. | Methods and system for image guided cell ablation with microscopic resolution |
IT1403720B1 (it) | 2010-12-22 | 2013-10-31 | Univ Padova | Metodo di rilevamento di un enzima proteolitico mediante amplificazione di un segnale catalizzata da nanoparticelle di oro |
EP2686000B1 (en) | 2011-03-15 | 2021-05-05 | Massachusetts Institute of Technology | Multiplexed detection with isotope-coded reporters |
US10449260B2 (en) | 2011-07-08 | 2019-10-22 | Theodosia Maina-Nock | Enhanced in vivo targeting of radiolabelled peptides with the means of enzyme inhibitors |
CA2841249C (en) | 2011-07-29 | 2023-09-26 | Avelas Biosciences, Inc. | Selective delivery molecules and methods of use |
WO2013083518A1 (en) | 2011-12-06 | 2013-06-13 | Meon Medical Solutions Gmbh & Cokg | Method of diagnosing pneumonia by detecting a volatile organic compound |
CN102558362A (zh) | 2012-02-17 | 2012-07-11 | 东莞金朗生物科技有限公司 | 一种用于治疗糖尿病的融合蛋白及其制备方法 |
EP3563872A1 (en) | 2012-04-05 | 2019-11-06 | Massachusetts Institute Of Technology | Immunostimulatory compositions and methods of use thereof |
JP2015516813A (ja) | 2012-04-27 | 2015-06-18 | シトムクス セラピューティクス,インコーポレイティド | 上皮成長因子受容体を結合する活性化可能抗体及びその使用方法 |
WO2013177231A1 (en) | 2012-05-21 | 2013-11-28 | Massachusetts Institute Of Technology | Translocation of non-natural chemical entities through anthrax protective antigen pore |
CN103012595B (zh) | 2012-12-17 | 2014-05-21 | 同昕生物技术(北京)有限公司 | 稳定的NT-proBNP校准品及应用 |
CN105008918A (zh) | 2013-01-04 | 2015-10-28 | 西托姆克斯治疗公司 | 用于检测生物***中的蛋白酶活性的组合物和方法 |
BR112015018104A2 (pt) | 2013-01-30 | 2017-11-21 | Ngm Biopharmaceuticals Inc | polipeptídeos de gdf15 modificados, seu uso, composições compreendendo os mesmos e recipiente estéril compreendendo as referidas composições |
AU2014212308B2 (en) | 2013-01-30 | 2018-08-09 | Avelas Biosciences, Inc. | Selective delivery molecules and methods of use |
US9763577B2 (en) | 2013-03-14 | 2017-09-19 | Lumicell, Inc. | Imaging agent for detection of diseased cells |
EP2988786A4 (en) | 2013-04-22 | 2016-12-21 | Avelas Biosciences Inc | COMPOSITIONS AND METHODS OF USE FOR SELECTIVE DRUG DELIVERY |
WO2014197816A1 (en) | 2013-06-06 | 2014-12-11 | Massachusetts Institute Of Technology | Stimulus responsive nanocomplexes and methods of use thereof |
WO2014197840A1 (en) | 2013-06-07 | 2014-12-11 | Massachusetts Institute Of Technology | Affinity-based detection of ligand-encoded synthetic biomarkers |
US20160184459A1 (en) | 2013-08-09 | 2016-06-30 | The Research Foundation For The State University Of New York | Cancer cell specific imaging probes and methods of use |
US20150080721A1 (en) | 2013-09-17 | 2015-03-19 | Blaze Bioscience, Inc. | Detection of tumor microenvironment with chlorotoxin conjugates |
EP3046572A4 (en) | 2013-09-17 | 2017-06-28 | Blaze Bioscience, Inc. | Chlorotoxin conjugates and methods of use thereof |
WO2015171543A1 (en) | 2014-05-05 | 2015-11-12 | California Institute Of Technology | Mutant akt-specific capture agents, compositions, and methods of using and making |
MA41374A (fr) | 2015-01-20 | 2017-11-28 | Cytomx Therapeutics Inc | Substrats clivables par métalloprotéase matricielle et clivables par sérine protéase et procédés d'utilisation de ceux-ci |
EP3347035A4 (en) | 2015-09-09 | 2019-05-01 | Fred Hutchinson Cancer Research Center | CARTON PEPTIDES |
EP3400299B1 (en) | 2016-01-08 | 2020-11-11 | University of Georgia Research Foundation, Inc. | Methods for cleaving dna and rna molecules |
US20170267727A1 (en) | 2016-03-04 | 2017-09-21 | Lehigh University | Conjugates of pH Low Insertion Peptide and Monomethyl Auristatins in the Treatment of Solid Tumors |
US11448643B2 (en) | 2016-04-08 | 2022-09-20 | Massachusetts Institute Of Technology | Methods to specifically profile protease activity at lymph nodes |
EP3442996A4 (en) | 2016-04-12 | 2019-11-27 | Blaze Bioscience, Inc. | METHODS OF TREATMENT INVOLVING CHLOROTOXIN CONJUGATES |
AU2017250359B2 (en) | 2016-04-15 | 2022-06-16 | Blaze Bioscience, Inc. | Methods of treating breast cancer |
US11428689B2 (en) | 2016-05-05 | 2022-08-30 | Massachusetts Institute Of Technology | Methods and uses for remotely triggered protease activity measurements |
US20190375786A1 (en) | 2016-09-09 | 2019-12-12 | Fred Hutchinson Cancer Research Center | Stable peptides and methods of use thereof |
CA3037767A1 (en) | 2016-09-28 | 2018-04-05 | Georgia Tech Research Corporation | Methods and compositions for noninvasive detection of organ transplant rejection |
EP3607085A1 (en) * | 2017-04-07 | 2020-02-12 | Massachusetts Institute Of Technology | Methods to spatially profile protease activity in tissue and sections |
CA3066384A1 (en) | 2017-06-09 | 2018-12-13 | Rhode Island Council On Postsecondary Education | Linked and other ph-triggered compounds |
US20190076081A1 (en) | 2017-09-12 | 2019-03-14 | Elwha Llc | Systems, compositions, and methods for targeted challenge and identification of gut microbiota |
CN111630162A (zh) | 2017-10-04 | 2020-09-04 | 博德研究所 | 基于crispr效应***的诊断 |
WO2019075292A1 (en) | 2017-10-12 | 2019-04-18 | Massachusetts Institute Of Technology | PROSTATE CANCER PROTEIN NANOCATORS AND USES THEREOF |
SG11202003863VA (en) | 2017-11-01 | 2020-05-28 | Univ California | Casz compositions and methods of use |
WO2019089804A1 (en) | 2017-11-01 | 2019-05-09 | The Regents Of The University Of California | Casy compositions and methods of use |
WO2019126716A1 (en) | 2017-12-22 | 2019-06-27 | The Broad Institute, Inc. | Cas12b systems, methods, and compositions for targeted rna base editing |
US20210108267A1 (en) | 2017-12-22 | 2021-04-15 | The Broad Institute, Inc. | Crispr effector system based multiplex diagnostics |
US20210079366A1 (en) | 2017-12-22 | 2021-03-18 | The Broad Institute, Inc. | Cas12a systems, methods, and compositions for targeted rna base editing |
AU2019213047A1 (en) | 2018-01-29 | 2020-07-16 | Massachusetts Institute Of Technology | CRISPR effector system based diagnostics |
CN108484847A (zh) | 2018-02-27 | 2018-09-04 | 同济大学 | 一种含金纳米粒子的多重响应性嵌段共聚物纳米材料的制备方法 |
WO2019173332A1 (en) | 2018-03-05 | 2019-09-12 | Massachusetts Institute Of Technology | Inhalable nanosensors with volatile reporters and uses thereof |
US11732009B2 (en) | 2018-06-08 | 2023-08-22 | Glympse Bio, Inc. | Activity sensor with tunable analyte |
EP3856921A2 (en) | 2018-09-25 | 2021-08-04 | Massachusetts Institute Of Technology | Lung protease nanosensors and uses thereof |
US20210262025A1 (en) | 2020-02-18 | 2021-08-26 | Massachusetts Institute Of Technology | Multiplexed in vivo disease sensing with nucleic acid-barcoded reporters |
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