CN111558052B - 双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用 - Google Patents
双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用 Download PDFInfo
- Publication number
- CN111558052B CN111558052B CN202010632397.1A CN202010632397A CN111558052B CN 111558052 B CN111558052 B CN 111558052B CN 202010632397 A CN202010632397 A CN 202010632397A CN 111558052 B CN111558052 B CN 111558052B
- Authority
- CN
- China
- Prior art keywords
- contrast agent
- grpr
- nanoparticles
- nano
- imaging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000003384 imaging method Methods 0.000 title claims abstract description 69
- 239000002872 contrast media Substances 0.000 title claims abstract description 50
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 title claims abstract description 37
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 title claims abstract description 37
- 230000002902 bimodal effect Effects 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 title claims abstract 10
- 101150032569 Grpr gene Proteins 0.000 title claims abstract 8
- 239000002105 nanoparticle Substances 0.000 claims abstract description 72
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 34
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 34
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 30
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 29
- 229920001184 polypeptide Polymers 0.000 claims abstract description 28
- WXFBZGUXZMEPIR-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4,5,5-undecafluoropentane Chemical compound FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F WXFBZGUXZMEPIR-UHFFFAOYSA-N 0.000 claims abstract description 22
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229920006022 Poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) Polymers 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 210000000998 shell membrane Anatomy 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000000833 heterodimer Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- 239000008055 phosphate buffer solution Substances 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 229920001577 copolymer Polymers 0.000 claims description 7
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 6
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000005642 Oleic acid Substances 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 6
- 229920001427 mPEG Polymers 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 6
- 239000012498 ultrapure water Substances 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 230000001804 emulsifying effect Effects 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 2
- 238000002601 radiography Methods 0.000 claims 1
- 230000008685 targeting Effects 0.000 abstract description 19
- 230000008859 change Effects 0.000 abstract description 18
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 abstract description 13
- 230000008901 benefit Effects 0.000 abstract description 9
- 238000002595 magnetic resonance imaging Methods 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000002604 ultrasonography Methods 0.000 description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 8
- 238000009835 boiling Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 229910052742 iron Inorganic materials 0.000 description 5
- 239000007908 nanoemulsion Substances 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- ISEYJGQFXSTPMQ-UHFFFAOYSA-N 2-(phosphonomethyl)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CP(O)(O)=O ISEYJGQFXSTPMQ-UHFFFAOYSA-N 0.000 description 3
- 108010051479 Bombesin Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 208000023958 prostate neoplasm Diseases 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 125000003396 thiol group Chemical class [H]S* 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 102000013585 Bombesin Human genes 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 102100038358 Prostate-specific antigen Human genes 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 239000002088 nanocapsule Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102400000921 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000016983 Releasing hormones receptors Human genes 0.000 description 1
- 108070000025 Releasing hormones receptors Proteins 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229960004692 perflenapent Drugs 0.000 description 1
- 229960004624 perflexane Drugs 0.000 description 1
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 description 1
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012782 phase change material Substances 0.000 description 1
- KFDKNTQGTAEZGC-UHFFFAOYSA-N phenanthrene-1-carboxylic acid Chemical compound C1=CC2=CC=CC=C2C2=C1C(C(=O)O)=CC=C2 KFDKNTQGTAEZGC-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000005267 prostate cell Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Nanotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Radiology & Medical Imaging (AREA)
- Acoustics & Sound (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明属于造影剂领域,提供了一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂,以PLGA‑PEG为壳膜,内部包裹液态氟碳1H‑全氟戊烷和Fe3O4纳米粒,外壳连接异二聚体多肽。本发明还提供了上述造影剂在制备诊断或者治疗前列腺癌的药物中的应用。本发明还提供了上述造影剂的制备方法。所制备纳米造影剂的平均粒径为213.7±65.27nm,Fe3O4纳米粒发挥磁共振成像作用,1H‑全氟戊烷具备液‑气相变的特性,兼具稳定性和相变所需能量较低的优势,发挥超声、光声显像及可控释药等作用,所设计的多肽可高效特异靶向前列腺癌细胞。本发明中的纳米造影剂能同时靶向前列腺癌两个重要靶点PSMA和GRPr。
Description
技术领域
本发明属于生物医学领域,涉及一种造影剂,具体来说是一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用。
背景技术
前列腺癌病灶具有散发、多灶、不易被影像学技术精准检出的特点,目前,影像学技术在前列腺癌诊断、分期方面的价值仍不令人满意,其敏感性及特异性仍不能排除随机穿刺。寻找一种能精准检测前列腺癌的影像学方法是目前临床上亟待解决的难题。纳米医学的快速发展为解决上述问题提供了新手段,构建能穿过前列腺肿瘤微血管,进入组织间隙,可与前列腺癌细胞特异性结合、在肿瘤组织中具有良好增强显像效果的靶向分子探针,有望实现前列腺癌病灶的精准检出、诊断。前列腺癌的检出主要采用经直肠超声(US)和磁共振(MR)成像技术。经直肠US成像便捷、经济、时间分辨率好,是初次前列腺穿刺中的首要影像学成像模式,并可实时引导穿刺活检,但空间分辨率差;MR成像空间分辨率好,被认为是前列腺癌检出及诊断中最准确的影像学技术,但时间分辨率差。若综合两者的成像优势,弥补单一成像的不足,将获得更加丰富的影像信息,从而更有效的检出、诊断前列腺癌。
Fe3O4纳米粒毒性低、灵敏度高、具有超顺磁性,可以使T2弛豫时间缩短,从而产生负性增强效果,故其常被作为MR成像造影剂。包裹液态氟碳的纳米粒,具有在升温、光热、超声辐照下发生液-气相变的特性,发生相变前其粒径小可以穿过肿瘤组织血管内皮间隙到特定的靶组织,发生相变后产生微气泡增强US回声信号,具有良好的血池外US、光声成像能力,同时具备相变后释药、栓塞血管、增效HIFU等治疗效果,因而在分子影像学研究中引人瞩目。
在目前常用氟碳中,全氟戊烷的沸点较低(29℃),稳定性差,制成纳米颗粒后较难保存;全氟己烷沸点较高(56℃),相变所需能量较大,易损伤周围组织,实际应用中难以精确掌控其相变条件。而1H-全氟戊烷(1H-PFP),常温下沸点42℃,性质稳定,兼具稳定性和相变所需能量较低的优势,是一较理想的液态氟碳。高分子聚合物聚乳酸羟基乙酸(PLGA)是经美国食品药品监督管理局(FDA)批准的医用辅料,具有良好的生物相容性、可降解性以及表面易修饰性,是最常用的纳米载体之一。
配体能增强纳米颗粒的主动靶向性,在常用配体中,抗体具有高度特异性和亲和力,但分子量大,组织渗透性差,免疫原性和生产成本高,影响了其临床应用前景;多肽分子量小且水溶性好,显示出优异的组织穿透性和低免疫原性,并且成本低廉,可大规模生产,但多肽从目标受体解离快,存在结合时间较短的不足;研究表明多价相互作用可显著降低多肽的解离速率,实现其与靶受体的长效结合。肿瘤细胞的表面受体具有异质性和不均一性,即使在同一患者肿瘤组织中,受体的表达类型、水平,或治疗前后的受体表达也存在差异。异二聚体多肽,靶向不同受体的两种多肽通过共价连接,可同时与两种受体结合,并延长纳米粒与靶部位的结合时间,显著增强纳米粒的主动靶向性,已成为有前景的重要分子靶向配体。
前列腺特异性膜抗原(PSMA)是位于前列腺细胞膜上的一种糖蛋白,具有很高的组织特异性,表达与肿瘤侵袭性、分期成正相关,在细胞膜上表达的特性使其成为一重要的靶点,被认为是用于前列腺癌特异性定位显像诊断和治疗的最有意义的靶蛋白。胃泌素释放激素受体(GRPr)是糖基化的七跨膜G蛋白偶联受体,在正常人前列腺组织中表达极低,但高表达于前列腺癌组织中,特别是较低等级和较小体积的病灶,GRPr表达和Gleason评分、PSA值及肿瘤大小有显著的负相关性,是前列腺癌发生中早期分子事件的标志物。因此,如能同时靶向两者,将对前列腺癌组织产生更为高效、敏感、特异的靶向分子显像作用。
聚乳酸-羟基乙酸-聚乙二醇-单甲氧基共聚物(PLGA-mPEG,分子量36000/3000,聚合比例50:50),来自美国PolyScitech公司。
聚乳酸-羟基乙酸-聚乙二醇-马来酰亚胺共聚物(PLGA-PEG-MAL,分子量30000/5000,聚合比例50:50),来自美国PolyScitech公司。
发明内容
针对现有技术中的上述技术问题,本发明提供了一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用,所述的这种双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用要解决现有技术对于诊断前列腺癌的效果不佳的技术问题。
本发明提供一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂,以PLGA-PEG为壳膜,内部包裹液态1H-全氟戊烷和Fe3O4纳米粒,外壳连接异二聚体多肽。
进一步的,所述的异二聚体多肽含Glu-urea-Lys及BZH3(DTyr-Gln-Trp-Ala-Val-betaAla-His-Thi-Nle-NH2)氨基酸结构,其分子式为C147H196N28O35S3,分子量为3011.491道尔顿,同位素质量为3009.358,其结构式如下所示,
进一步的,所述的双特异性PSMA/GRPr靶向双模态显像纳米造影剂呈球形,平均粒径为213.7±65.27nm,zeta电位为-33.60±5.34mV。
进一步的,Fe3O4纳米粒的负载率为15.7%。
本发明还提供了上述双特异性PSMA/GRPr靶向双模态显像纳米造影剂在制备诊断或者治疗前列腺癌的药物中的应用。
本发明还提供了上述双特异性PSMA/GRPr靶向双模态显像纳米造影剂的制备方法,包括如下步骤:
1)准确称取PLGA-mPEG共聚物、PLGA-PEG-MAL共聚物、油酸修饰的Fe3O4纳米颗粒和1H-全氟戊烷,将上述物料溶解在二氯甲烷中;PLGA-mPEG共聚物、PLGA-PEG-MAL共聚物、油酸修饰的Fe3O4纳米颗粒,1H-全氟戊烷和二氯甲烷的物料比为15mg:5mg:4mg:40uL:1ml;
2)将上述溶液加入到质量百分比浓度为4%的聚乙烯醇溶液中;聚乙烯醇溶液和二氯甲烷的体积比为8~10:1;
3)冰水浴条件下使用超声波细胞粉碎机将上述混合物乳化成球;
4)磁力搅拌混合物使二氯甲烷充分挥发;
5)将步骤4)的纳米粒离心并洗涤至少3次,重悬于超纯水中并于4℃储存;
6)将上一步所得的纳米粒分散到PH=7.2的PBS溶液中,纳米粒与PBS溶液的物料比为2mg:1ml;
7)溶解含巯基的异二聚体多肽,将其加入步骤6)的含纳米粒的PBS溶液中,其中异二聚体多肽和纳米粒的质量比为1:60~80,搅拌1-4小时;
8)离心收集纳米颗粒,洗涤至少3次并重悬于超纯水中,得最终产物双特异性PSMA/GRPr靶向双模态显像纳米造影剂。
具体的,在步骤7)中,可以采用二甲基甲酰胺溶液溶解含巯基的异二聚体多肽。
本发明综合材料学、肿瘤生物学、分子生物学、影像学等多学科的交叉知识及技术,设计并制备具有双靶向、双模态成像功能的前列腺癌靶向分子探针。该靶向纳米探针主要包括以下几部分:①选用经FDA批准可用于人体的高分子聚合物材料PLGA-PEG为外壳,安全无毒,生物相容性好,PEG增加其亲水性,延长纳米颗粒的体循环时间;②内包裹Fe3O4纳米颗粒和液态氟碳化合物1H-全氟戊烷,1H-全氟戊烷具有在升温、光热及超声辐照下发生液-气相转变的特性,并且常温下沸点42℃,兼具稳定性和所需相变能量较低的优势;Fe3O4纳米颗粒具有负性MR增强显像和光热效果,当接收808nm激光照射时,Fe3O4纳米颗粒可吸收红外光并将该光能转化为热能,促使1H-全氟戊烷发生液气相变,产生大量微米尺寸的气泡,用于增强US成像;③通过马来酰亚胺与巯基的迈克尔加成反应,外修饰异二聚体多肽,异二聚体多肽包括Glu-urea-Lys及BZH3结构,能同时靶向前列腺癌两个重要靶点PSMA和GRPr,增强纳米探针的前列腺癌主动靶向效果。
马来酰亚胺与巯基的迈克尔加成反应制备双特异性PSMA/GRPr靶向双模态显像纳米造影剂的反应方程式如下所示:
本发明提供了一种价格低廉,具有US/MR双模态成像能力的前列腺癌诊疗一体化的靶向纳米粒,能同时靶向前列腺癌两个重要靶点PSMA和GRPr;所制备纳米造影剂中,Fe3O4纳米粒发挥磁共振成像作用,1H-全氟戊烷具备液-气相变的特性,兼具稳定性和相变所需能量较低的优势,发挥超声、光声显像及可控释药等作用,所设计的多肽可高效特异靶向前列腺癌细胞。
本发明的优点在于:
(1)本发明所制备的相变型纳米粒,所用液态氟碳为1H-全氟戊烷,常温下沸点42℃,性质稳定,能在4℃条件下长期保存,适宜的相变温度为42-45℃,较容易达到,可减少对周围组织的损伤,兼具稳定性和相变所需能量较低的优势,是一较理想的液态氟碳。
(2)本发明所设计的异二聚体多肽可靶向前列腺癌最重要的两个分子靶点,即更高表达于中后期/低分化病灶的PSMA,及更高表达于中早期/高分化病灶的GRPr,两者优势互补,可显著提高前列腺癌靶向的敏感性及特异性。
(3)本发明所制备的纳米粒,可用于制备治疗前列腺癌的药物制剂,高效靶向前列腺癌病灶,并通过氟碳的相变特性定向释药,有效杀伤肿瘤细胞,同时,其具备的双模态成像能力还能实时动态监测治疗效果。
附图说明
图1为本发明双特异性PSMA/GRPr靶向双模态显像纳米造影剂的示意图。
图2为本发明纳米造影剂的粒径分布(a)和Zeta电位图(b)。
图3为本发明纳米造影剂的透射电镜及元素mapping图。
图4为本发明纳米造影剂的体外T2加权MR成像图。
图5为本发明纳米造影剂在808nm激光照射下相变光镜图(a)及超声成像图(b)。
图6为不同浓度本发明纳米造影剂对前列腺癌C4-2和PC3细胞的毒性实验结果。
图7为激光共聚焦显微镜检测本发明纳米造影剂对前列腺癌C4-2和PC3细胞靶向性实验结果。
图8为本发明纳米造影剂体内MR成像图。
图9为本发明纳米造影剂体内US成像图。
具体实施方式
下面结合实施例并附图对本发明做进一步详细说明。
原料:1H-全氟戊烷(1H-PFP),来自北京百灵威科技有限公司。
油酸修饰的Fe3O4纳米颗粒(7-10nm),来自上海羧菲生物医药科技有限公司。
实施例1:双特异性PSMA/GRPr靶向双模态显像纳米造影剂的制备
双模态显像纳米造影剂的制备方法,步骤如下:
①准确称取15mgPLGA-mPEG共聚物、5mg PLGA-PEG-MAL共聚物、4mg油酸修饰的Fe3O4纳米颗粒和移取40uL 1H-全氟戊烷溶解在1mL二氯甲烷中;
②将上述溶液滴加到质量百分比浓度为4%的聚乙烯醇溶液中;
③冰水浴条件下使用超声波细胞粉碎机将上述混合物乳化成球;
④磁力搅拌混合物使二氯甲烷充分挥发;
⑤将纳米粒离心并洗涤3次重悬于超纯水中并于4℃储存。、
⑥将上一步所得的纳米粒分散到PH=7.2的PBS溶液中,纳米粒与PBS溶液的物料比为2mg:1ml;
⑦溶解含巯基的异二聚体多肽,将其加入上述含纳米粒的PBS溶液中,其中异二聚体多肽和纳米粒的质量比为1:60~80,搅拌2小时;
所述的异二聚体多肽其结构式如下所示,
⑧离心收集纳米颗粒,洗涤3次并重悬于超纯水中,得最终产物双特异性PSMA/GRPr靶向双模态显像纳米造影剂,于4℃储存(如图1所示)。
如图2所示,马尔文纳米粒度电位分析仪结果显示连接异二聚体多肽前纳米颗粒(MP-PS)的平均粒径为190.9±57.83nm(PDI=0.085),zeta电位为-29.50±5.25mV;连接异二聚体多肽后的靶向纳米颗粒(GBP-PS)的平均粒径为213.7±65.27nm(PDI=0.139),zeta电位为-33.60±5.34mV。与MP-PS纳米颗粒相比,GBP-PS纳米颗粒的平均粒径更大,GBP-PS纳米颗粒的zeta电位降低,这表明含Glu-urea-Lys-BZH3异二聚体肽的成功连接。
透射电镜图像(图3a、b)显示,GBP-PS纳米颗粒为形态规则的球形,分散性好,无明显聚集,大小均匀,粒径大多在200nm以下,与纳米粒度电位分析仪测得结果相符;在纳米微囊内部可以观察到大量的深灰色斑点和一不规则的暗区,表明Fe3O4纳米颗粒和液性1H-全氟戊烷的存在。元素mapping检测同样表明纳米微囊中碳、氧、氟、铁元素的存在,同样说明Fe3O4纳米颗粒和1H-全氟戊烷的成功包封。
体外T2加权MR成像图显示GBP-PS纳米乳液呈负性增强显像,如图4所示,随着铁浓度的增加,GBP-PS纳米乳液的T2加权MR信号强度逐渐降低,当铁浓度达0.018mg/ml时,样品管中信号强度较难与背景区分,显示良好的MR负性增强效果。
纳米颗粒内所包裹的液性氟碳1H-全氟戊烷沸点为42℃,在升温条件下可转化为气体,纳米颗粒转变为微泡。我们首先通过光学显微镜观察GBP-PS纳米颗粒的相变情况。如图5a所示,在37℃时没有观察到气泡的出现,表明GBP-PS纳米颗粒在生理温度下较稳定,没有发生相变。40℃时可见大量气泡出现,随着温度升高,气泡明显变大。据光学显微镜下观察到的结果,显示42-45℃是诱导GBP-PS纳米颗粒相变的适宜温度。然后,分别在37,40,42和45℃以超声常规灰阶和造影双辐成像模式扫描样品管中的GBP-PS纳米乳液。如图5b所示,在37℃时,GBP-PS纳米乳液在灰阶和造影成像模式均未显示回声或增强信号。随着温度升高,灰阶和造影图像上逐渐出现回声和增强信号,在45℃时,灰阶和造影图像上显示出明显的回声和增强信号。
实施例2:双特异性PSMA/GRPr靶向双模态显像纳米造影剂的安全性评估
如图6所示,GBP-PS纳米颗粒与前列腺癌C4-2和PC3细胞孵育24小时后,即使铁浓度高达200μg/mL,细胞存活率仍保持在90%以上,这表明GBP-PS纳米颗粒的细胞毒性低。
取GBP-PS纳米乳液200ul从尾静脉注入小鼠体内(铁剂量16mg kg-1),对照组小鼠尾静脉注射200ul生理盐水,观察14天后,取血行全血分析及血生化检测,对心脏,肝脏,脾脏,肺,肾脏行HE染色,结果表明实验组和对照组的各项血液检测指标及各脏器的切片无明显差异,说明GBP-PS纳米颗粒的体内安全性高。
实施例3:双特异性PSMA/GRPr靶向双模态显像纳米造影剂的细胞靶向性评估
将GBP-PS纳米颗粒与前列腺癌C4-2(PSMA高表达及GRPr低表达)和PC3(GRPr高表达及PSMA低表达)细胞孵育6小时后,激光共聚焦显微镜图像显示,C4-2(图7a)和PC3(图7b)细胞的细胞质内见大量GBP-PS所带的FITC绿色荧光,表明该两种细胞对GBP-PS纳米颗粒的大量摄取,PSMA拮抗剂2-PMPA或GRPr结合肽Bombesin可明显竞争性抑制相应细胞对其的摄取,而C4-2和PC3细胞对未接靶向肽的纳米颗粒(FP-PS)均只有少量摄取。结果证明了GBP-PS纳米颗粒对C4-2和PC3细胞的特异靶向性。
实施例4:双特异性PSMA/GRPr靶向双模态显像纳米造影剂的体内靶向性及成像性能评估
使用7T小动物MR成像仪分别在纳米造影剂注射前,注射后1小时,3小时和6小时获得T2加权MR图像。如图8所示,在前列腺癌C4-2和PC3皮下移植瘤病灶中,GBP-PS纳米造影剂随着在体内循环时间的增加在肿瘤部位逐渐聚集,T2加权MR信号强度逐渐下降,注射6h后肿瘤部位明显变黑,表明GBP-PS纳米造影剂具有良好的体内靶向性和MR负性增强效果。2-PMPA(图8a)或Bombesin(图8b)可竞争性抑制GBP-PS纳米造影剂在肿瘤部位的聚集,其T2加权MR信号强度在3小时及6小时成像时下降幅度小于GBP-PS纳米造影剂组,进一步证明了GBP-PS纳米造影剂在体内对PSMA及GRPr高表达肿瘤细胞有着特异靶向性。在未接靶向肽的纳米造影剂(PP-PS)组中,肿瘤部位的T2加权MR信号强度下降幅度即使在注射后6h也很小。
如图9所示,在注射纳米造影剂前,所有组别肿瘤部位在超声灰阶成像模式下均为低回声,且超声造影成像模式下均无增强信号。尾静脉注射纳米造影剂6小时并用808nm激光照射后,在GBP-PS纳米造影剂组中,C4-2及PC3皮下移植瘤模型肿瘤部位超声造影声像图上出现肉眼可见的增强信号,竞争组(分别以2-PMPA(图9a),Bombesin(图9b)竞争抑制)仅见极少量增强信号,而PP-PS纳米造影剂组未见明显增强信号。
上述结果表明GBP-PS纳米造影剂可用于PSMA和GRPr表达前列腺肿瘤病灶的MR及US靶向分子成像。
本发明成功制备了以PLGA-PEG为外壳、内包裹液态氟碳1H-全氟戊烷和Fe3O4纳米颗粒、外修饰能同时靶向PSMA和GRPr的异二聚体多肽、具有MR/US双模态成像功能的相变型纳米造影剂;其形态规则,稳定性好,大小均匀,粒径满足穿过肿瘤毛细血管内皮间隙的实验要求;其内包裹的氟碳1H-全氟戊烷常温下性质稳定,兼具稳定性和所需相变能量较低的优势;Fe3O4纳米颗粒不仅能用于MR显像,其光热效果可促使1H-全氟戊烷发生液-气相变,增强US显像;在体外及体内实验中,该纳米造影剂生物安全性高,也显示出对C4-2和PC3前列腺癌细胞及肿瘤模型良好的靶向性和MR/US双模态成像效果,是一种新型的双靶向相变型多功能造影剂,为下一步临床前列腺肿瘤的诊断及治疗奠定了研究基础。
Claims (5)
2.根据权利要求1所述的一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂,其特征在于:所述的双特异性PSMA/GRPr靶向双模态显像纳米造影剂呈球形,平均粒径为213.7±65.27nm,zeta电位为-33.60±5.34mV。
3.根据权利要求1所述的一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂,其特征在于:Fe3O4纳米粒的负载率为15.7%。
4.权利要求1所述的一种双特异性PSMA/GRPr靶向双模态显像纳米造影剂在制备诊断或者治疗前列腺癌的药物中的应用。
5.权利要求1所述的一种双特异性PSMA/GRPr靶向双模态显像纳米造影的制备方法,其特征在于包括如下步骤:
1)准确称取PLGA-mPEG共聚物、PLGA-PEG-MAL共聚物、油酸修饰的Fe3O4纳米颗粒和1H-全氟戊烷,将上述物料溶解在二氯甲烷中;PLGA-mPEG共聚物、PLGA-PEG-MAL共聚物、油酸修饰的Fe3O4纳米颗粒,1H-全氟戊烷和二氯甲烷的物料比为15mg∶5mg∶4mg∶40uL∶1ml;
2)将上述溶液加入到质量百分比浓度为4%的聚乙烯醇溶液中;聚乙烯醇溶液和二氯甲烷的体积比为8~10∶1;
3)冰水浴条件下使用超声波细胞粉碎机将上述混合物乳化成球;
4)磁力搅拌混合物使二氯甲烷充分挥发;
5)将步骤4)的纳米粒离心并洗涤至少3次,重悬于超纯水中,并于4℃储存;
6)将步骤5)的所得的纳米粒分散到PH=7.2的PBS溶液中,纳米粒与PBS溶液的物料比为2mg∶1ml;
7)溶解含巯基的异二聚体多肽,将其加入步骤6)的含纳米粒的PBS溶液中,其中异二聚体多肽和纳米粒的质量比为1∶60~80,搅拌1-4小时;
8)离心收集纳米颗粒,洗涤至少3次并重悬于超纯水中,得最终产物双特异性PSMA/GRPr靶向双模态显像纳米造影剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010632397.1A CN111558052B (zh) | 2020-07-02 | 2020-07-02 | 双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010632397.1A CN111558052B (zh) | 2020-07-02 | 2020-07-02 | 双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111558052A CN111558052A (zh) | 2020-08-21 |
CN111558052B true CN111558052B (zh) | 2022-03-25 |
Family
ID=72073953
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010632397.1A Active CN111558052B (zh) | 2020-07-02 | 2020-07-02 | 双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111558052B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113616816B (zh) * | 2021-08-19 | 2022-08-05 | 中国科学院精密测量科学与技术创新研究院 | 一种基于全氟戊烷的激光响应型分子探针的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110404082A (zh) * | 2019-09-02 | 2019-11-05 | 上海市肿瘤研究所 | 一种靶向超声相变型双模态显像纳米造影剂及其制备方法和应用 |
CN111344021A (zh) * | 2017-11-13 | 2020-06-26 | 德国癌症研究中心 | 用于分子成像的双标记的探针及其用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015119763A1 (en) * | 2014-02-06 | 2015-08-13 | Immunomedics, Inc. | Al-f-18-labeled, al-f-19-labeled and ga-68-labeled gastrin-releasing peptide receptor (grpr)-antagonists for imaging of prostate cancer |
EP3474879A4 (en) * | 2016-06-24 | 2020-05-06 | University of Iowa Research Foundation | COMPOSITIONS AND METHODS FOR TREATING MELANOMAS |
-
2020
- 2020-07-02 CN CN202010632397.1A patent/CN111558052B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111344021A (zh) * | 2017-11-13 | 2020-06-26 | 德国癌症研究中心 | 用于分子成像的双标记的探针及其用途 |
CN110404082A (zh) * | 2019-09-02 | 2019-11-05 | 上海市肿瘤研究所 | 一种靶向超声相变型双模态显像纳米造影剂及其制备方法和应用 |
Non-Patent Citations (4)
Title |
---|
Bispecific radioligands targeting prostate-specific membrane antigen and gastrin-releasing peptide receptors on the surface of prostate cancer cells;Christos Liolios et al;《J Label Compd Radiopharm.》;20191231;第62卷;第510-522页 * |
Novel DiR and SPIO nanoparticles embedded PEG-PLGA nanobubbles as a multimodal imaging contrast agent;Binhua Luo et al;《Bio-Medical Materials and Engineering》;20151231;第26卷;第S911-S916页 * |
On-demand drug release nanoplatform based on fluorinated aza-BODIPY for imaging-guided chemo-phototherapy;Jiaojiao Zhang et al;《Biomaterials》;20200701;第256卷;第1-10页 * |
携抗PSMA多肽的超声—磁共振双模态靶向造影剂诊断前列腺癌的实验研究;朱云开;《中国优秀博硕士学位论文全文数据库(博士) 医药卫生科技辑》;20200315(第3期);E060-20 * |
Also Published As
Publication number | Publication date |
---|---|
CN111558052A (zh) | 2020-08-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8940277B2 (en) | Intracellular microbubble for imaging an anatomical site | |
CN106267241B (zh) | 一种多功能多模态肿瘤特异性靶向相变型纳米微球光声造影剂及其应用 | |
Ao et al. | Gd‐DTPA‐loaded PLGA microbubbles as both ultrasound contrast agent and MRI contrast agent—A feasibility research | |
CN108704134A (zh) | 一种包载ir780的靶向多功能纳米粒、应用及其制备方法 | |
Li et al. | Neuropeptide Y Y1 receptor-mediated biodegradable photoluminescent nanobubbles as ultrasound contrast agents for targeted breast cancer imaging | |
US20120323112A1 (en) | Nanoparticles for accoustic imaging, methods of making, and methods of accoustic imaging | |
Li et al. | A preliminary study of photoacoustic/ultrasound dual-mode imaging in melanoma using MAGE-targeted gold nanoparticles | |
Cheng et al. | Ultrasound-triggered phase transition sensitive magnetic fluorescent nanodroplets as a multimodal imaging contrast agent in rat and mouse model | |
CN106581698A (zh) | 用于动脉粥样硬化不稳定斑块识别的超声荧光双模态纳米探针的制备方法 | |
CN103055329A (zh) | 用于动脉粥样硬化易损斑块早期诊断的靶向磁性纳米探针的制备方法 | |
CN109420177A (zh) | 用于有效体内递送dna纳米结构至动脉粥样硬化斑块的材料和方法 | |
Zhang et al. | PEGylated PLGA-based phase shift nanodroplets combined with focused ultrasound for blood brain barrier opening in rats | |
CN111558052B (zh) | 双特异性PSMA/GRPr靶向双模态显像纳米造影剂及其制备方法和应用 | |
CN112587677A (zh) | 一种iRGD磁性靶向微泡造影剂及其应用 | |
CN111450269A (zh) | 一种多功能超声造影剂及其制备方法 | |
CN113398286B (zh) | 一种靶向载铁氧体多功能纳米粒及其制备方法和应用 | |
CN103638534A (zh) | 一种纳米脂质超声造影剂及制备方法 | |
CN109481700A (zh) | 一种用于肝癌早期诊断的分子探针及其制备方法 | |
Lin et al. | Ultrasound-based multimodal molecular imaging and functional ultrasound contrast agents | |
CN102772808B (zh) | 一种多模态成像微气泡构造、制备方法及用途 | |
CN111110657A (zh) | 可双模成像及靶向治疗乳腺癌的纳米微球及其制备方法 | |
CN112870387B (zh) | 一种磁性纳米药物载体及其制备方法和应用 | |
Ding et al. | Lactoferrin-Conjugated Polylactic Acid Nanobubbles Encapsulated Perfluoropentane as a Contrast Agent for Ultrasound/Magnetic Resonance Dual-Modality Imaging | |
JP6997717B2 (ja) | イメージングのためのビーズの調製のための方法 | |
CN101780285B (zh) | 一种热增强型负载液态氟碳的聚合物纳米超声显像胶束及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |