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WO2018085050A1 - Compositions et procédés pour l'imagerie de tissus et de tumeurs - Google Patents

Compositions et procédés pour l'imagerie de tissus et de tumeurs Download PDF

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Publication number
WO2018085050A1
WO2018085050A1 PCT/US2017/057357 US2017057357W WO2018085050A1 WO 2018085050 A1 WO2018085050 A1 WO 2018085050A1 US 2017057357 W US2017057357 W US 2017057357W WO 2018085050 A1 WO2018085050 A1 WO 2018085050A1
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Prior art keywords
tumor
subject
tracer
tissue
seq
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Inventor
Gary Braun
Xiangyou LIU
Kazuki Sugahara
Erkki Ruoslahti
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Sanford Burnham Prebys Medical Discovery Institute
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Sanford Burnham Prebys Medical Discovery Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • 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
    • A61K49/1884—Nanotubes, nanorods or nanowires
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors

Definitions

  • the present invention relates generally to compositions and methods for in vivo imaging of tissues and tumors with etchable tracers.
  • Tissue and tumor imaging suffers from poor specificity (Yu et al., ACSNano 9:6655-6674 (2015)).
  • the design of nanoprobes for in vivo imaging has traditionally focused on optimization of probe properties such as size, surface coating, and signal intensity to maximize target sensitivity and specificity (Choi et al., Nat Nanotechnol 5 :42-47 (2010); Barreto et al, Adv Mater 23 :H18-H40 (201 1); Chen et al, Nat Mater 12:445-451 (2013)).
  • Nanoparticles that are larger than the renal filtration threshold ( ⁇ 6-8 nm) have been used in efforts to promote longer circulation and more accumulation of the nanoparticles in tumors (Yu et al, ACSNano 9:6655-6674 (2015)). Nonetheless, long washout periods increase background signals, especially in the mononuclear phagocyte system (MPS), e.g., liver and spleen.
  • MPS mononuclear phagocyte system
  • the present invention is based, in part, on the discovery of compositions and methods for imaging tissues and tumors in vivo with a tracer that can be dissolved or made inactive by an etchant.
  • the etchant is able to increase the difference in the concentration of the tracer in a tissue/tumor of interest and the concentration in other tissues/tumors and the blood, leading to an increased contrast index of at least five, e.g., at least six, seven, eight, nine, 10, 12, 15, 18, 20, 25, 50, or at least 100.
  • the present specification provides methods of imaging a tissue or tumor in a subject.
  • the methods can include administering a tissue- or tumor-targeted tracer to the subject; administering an etchant to the subject; and performing a first imaging of the subject, wherein the methods capture an image of the tissue or tumor at a contrast index of at least five.
  • the methods can include a second administration of the tissue- or tumor-targeted tracer to the subject; a second administration of the etchant to the subject; and performing a second imaging of the subject, wherein the second administration of the tissue- or tumor-targeted tracer to the subject is performed about 10 to 30 minutes after performing the first imaging of the subject, and wherein the second imaging captures an image of the tissue or tumor at a contrast index of at least five.
  • the present disclosure features methods of selectively delivering a therapeutic agent to a tissue or tumor in a subject.
  • the methods can include administering a tissue- or tumor-targeted tracer to the subject, wherein the tracer is conjugated to the therapeutic agent; and administering an etchant to the subject.
  • the methods can include performing an imaging of the subject, wherein the methods capture an image of the tissue or tumor at a contrast index of at least five.
  • methods of removing a tumor from a subject having or suspected of having a tumor are provided.
  • the methods can include administering a tumor-targeted tracer to the subject; administering an etchant to the subject;
  • the method performs an imaging of the subject to identify a tumor, wherein the method captures an image of the tissue or tumor at a contrast index of at least five; and removing the tumor.
  • the present specification provides methods of detecting peritoneal carcinoma in a subject, wherein the methods can include administering a tumor-targeted tracer to the subject; administering an etchant intraperitoneally to the subject; and performing an imaging the subject, wherein the method captures an image of the tissue or tumor at a contrast index of at least five.
  • the methods can include administering a tumor-targeted tracer to the subject;
  • methods of selectively administering a therapy e.g., radiotherapy and/or chemotherapy, to a desired location in a tissue or tumor of a subject in need thereof are featured.
  • the methods can include administering a tissue- or tumor-targeted tracer to the subject; administering an etchant to the subject;
  • the method captures an image of the tissue or tumor at a contrast index of at least five; and based on the imaging, administering the therapy to the desired location in the tissue or tumor of the subject.
  • the present disclosure also provides a nanosystem, wherein the nanosystem has a targeting agent; a photoluminescent, magnetic, or radiochemical tracer, wherein the tracer does not comprise silver; and a membrane-impermeable etchant.
  • the tracer can contain zinc (Zn 2+ ), mercury (Hg 2+ ), and selenium (Se 2" ), e.g., Zn x Hgi- x Se.
  • the tracer has zinc (Zn 2+ ), silver (Ag + ), and selenium (Se 2" ).
  • the tracer has manganese zinc sulfide (Mn x Zni- x S), manganese zinc selenide (Mn x Zni- x Se), cadmium selenide (CdSe), indium phosphide (InP), copper indium sulfide (CuInS), and/or copper indium selenide (CuInSe).
  • the tracer has a magnetic ion or radioisotope.
  • the tracer is a quantum dot.
  • the quantum dot can have a core size of about 1 nm to about 50 nm, e.g., about 1 nm to about 40 nm, about 1 nm to about 30 nm, about 1 nm to about 20 nm, about 1 nm to about 10 nm, about 1 nm to about 5 nm, about 5 nm to about 40 nm, about 10 nm to about 40 nm, about 20 nm to about 40 nm, about 30 nm to about 40 nm, or about 5 nm, 10 nm, 20 nm, 30 nm, 40 nm, or about 50 nm.
  • mercury Hg 2+
  • the quantum dot has a zinc sulfide (ZnS) shell.
  • the tracer has or is coated with polyethylene glycol, dextran, L-cysteine, albumin, and/or a high molecular weight peptide polymer.
  • the polyethylene glycol has an average molecular weight of about 100 daltons to about 80000 daltons, e.g., PEG2000, which has an average molecular weight of about 1900 daltons to about 2200 daltons, or an average molecular weight of about 500 daltons to about 10000 daltons, e.g., about 1000 daltons to about 3000 daltons, or about 1500 daltons to about 2500 daltons.
  • the tracer is administered intravenously, intraperitoneally, subcutaneously, intrathecally, intrathoracically, intratracheally, intratumorally, and/or intracranially.
  • the tracer is targeted to a tissue by administering prior to administering the tracer, and/or co-administering with the tracer, a tissue-targeting agent.
  • the tissue-targeting agent comprises a peptide, an antibody or antigen-binding fragment thereof, an aptamer, or an enzyme.
  • the tissue-targeting agent comprises a peptide comprising an amino acid sequence of CGFECVRQCPERC (SEQ ID NO: 9), CAGALCY (SEQ ID NO: 10), CGNKRTRGC (SEQ ID NO:4), CAQK, VHPKQHRGGSKGC (SEQ ID NO: 11), or CDAGRKQKC (SEQ ID NO: 12).
  • the tissue-targeting agent is administered intravenously, intraperitoneally, subcutaneously, intrathecally, intrathoracically, intratracheally, intratumorally, and/or intracranially.
  • the tracer is targeted to a tumor by administering prior to administering the tracer, and/or co-administering with the tracer, a tumor-targeting agent.
  • the tumor-targeting agent comprises a peptide, an antibody or antigen-binding fragment thereof, an aptamer, or an enzyme.
  • the tumor-targeting agent comprises a peptide comprising an amino acid sequence of CRGDKGPDC (SEQ ID NO: l), CRGDRGPDC (SEQ ID NO:2), CGNKRTR (SEQ ID NO:3), CGNKRTRGC (SEQ ID NO:4), CRNGRGPDC (SEQ ID NO:5), CKRGARSTC (SEQ ID NO:6), AKRGARSTA (SEQ ID NO:7), a CendR peptide, or a uPARCendR peptide.
  • the tumor-targeting agent is administered intravenously, intraperitoneally, subcutaneously, intrathecally, intrathoracically, intratracheally, intratumorally, and/or intracranially.
  • the etchant comprises a metal chelator.
  • the etchant comprises silver, copper, bismuth, manganese, indium, gold, tin, nickel, iron, cobalt, and/or zinc.
  • the etchant comprises Ag(S203)2 " (Ag-TS), penicillamine with CuS04 (Cu-Pen), copper thiosulfate (Cu- TS), iron desferoxamine, AgNCb, K3Fe(CN)6, and/or Hg(C104)2.
  • the etchant is administered intravenously, intraperitoneally, subcutaneously, intrathecally, intrathoracically, intratracheally, intratumorally, and/or intracranially.
  • the subject is imaged by optical excitation and emission detection.
  • the subject can be imaged at a wavelength of about 550 nm to about 850 nm.
  • the subject is imaged by positron emission tomography.
  • the subject is imaged by magnetic resonance imaging.
  • adenocarcinoma adenocarcinoma, peritoneal carcinoma, or pancreatic intraepithelial neoplasia.
  • FIG. 1A is a TEM image of ZHS-QDs. Scale bar, 20 nm.
  • FIG. 1C is a line graph showing PL spectra of ZHS-QDs under excitation at 450 nm before and after etching.
  • FIG. ID depicts PL spectra of ZHS-QDs with excitation at 785 nm.
  • the inset shows ZHS-QDs with and without etching with Ag-TS imaged under an 800 nm channel (which uses an excitation of 785 nm) and white light with Li-Cor Pearl Impulse small animal imager.
  • FIG. IF is a photomicrograph showing vasculature of a mouse intravenously injected with ZHS-QDs imaged under an 800 nm channel.
  • FIG. 1G depicts a mechanism of ZHS-QD etching.
  • Ag-TS provides Ag + to ZHS-QDs in exchange with Zn 2+ and Hg 2+ , which abolishes PL of the QDs.
  • FIG. II is a panel of nine NIR images of mice after multiple intravenous injections of ZHS-QDs and etchant.
  • H heart; Li, liver; Sp, spleen; Lu, lung; K, kidney; B, brain.
  • Statistics Student's /-test; error bars, mean + SEM; ns, not significant; ***P ⁇ 0.001.
  • FIG. 2A is a panel of raw images at indicated time points. Arrows indicate tumor locations. Note the tumor specific signals in mice that received iRGD, ZHS- QDs, and etchant.
  • FIG. 2B is a line graph showing fluorescent signals in a tumor per unit area plotted against time. iRGD pre-injection significantly increased tumor signals.
  • Etching decreased tumor signals to a similar degree in each group indicating passive entry of etchant into the tumor regardless of peptide pre-injection.
  • FIG. 2C is a line graph showing an exponential increase in CI in the iRGD group after etching was performed in the tumor area.
  • FIG. 2D is a panel of two whole body images of breast tumor mice performed 40 minutes post-etching with the Pearl imager. Arrows indicate tumor locations.
  • FIG. 2F shows tumors and organs that were collected from the mice and imaged with a Pearl imager.
  • FIG. 2G is a panel of bar graphs showing fluorescent signals per unit area in collected tissues (left panel) and T/Li ratio (right panel) based on ex vivo imaging.
  • B brain; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney; T, tumor.
  • FIG. 2H is a panel of confocal micrographs of tumor sections. Scale bars, 50 ⁇ . The inset is a magnified view of a tumor blood vessel. Note that QDs are widely distributed in the extravascular tumor space with minimal co-localization with the vasculature. Statistics, ANOVA (b and c) or Student's /-test (g); error bars, mean + SEM; ns, not significant; *P ⁇ 0.05; ***P ⁇ 0.001.
  • FIG. 3A shows in vivo whole body images of mice that were anesthetized and imaged with a Li-Cor Pearl Impulse imager under white light and an 800 nm channel. Arrows indicate tumor locations. The mice were sacrificed under deep anesthesia and tumors and organs were collected for ex vivo imaging with the Pearl imager.
  • FIG. 4A is a TEM image of PL spectra under excitation at 460 nm.
  • FIG. 4B is a TEM image obtained with a Li-Cor Pearl Impulse imager under 800 nm channel and white light.
  • FIG. 4C is a TEM image ZAS-QDs before and after etching with lx Ag-TS. Scale bars, 20 nm.
  • FIG. 4D shows in vivo whole body images of mice that were anesthetized and imaged with a Xenogen IVIS for luminescence (Lum), and a Li-Cor Pearl imager under an 800 nm channel.
  • FIG. 4E shows images of mice that were sacrificed under deep anesthesia, necropsied, and imaged again to study QD biodistribution in more detail.
  • FIG. 4F shows tumors and organs that were collected from the mice and imaged ex vivo.
  • FIG. 4G is a bar graph showing fluorescent signals per unit area in peritoneal tumors and non-tumor tissues.
  • Statistics ANOVA; error bars, SEM; ns, not significant; *P ⁇ 0.05; ***P ⁇ 0.001.
  • B brain; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney.
  • FIG. 4H is a bar graph showing fluorescent signals per unit area in subcutaneous tumor versus peritoneal tumors in the iRGD group based on the ex vivo imaging results.
  • Statistics Student's /-test; error bars, mean + SEM; ns, not significant; *P ⁇ 0.05; ***P ⁇ 0.001.
  • B brain; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney.
  • FIG. 41 is a panel of three confocal micrographs of peritoneal tumor sections. Scale bars, 50 ⁇ . The dotted lines show the subcutaneous tumor.
  • FIG. 4 J shows panels of confocal micrographs of peritoneal tumor sections. Scale bars, 50 ⁇ .
  • FIG. 4K is a schematic diagram of peritoneal tumor imaging with
  • intraperitoneally delivered etchable ZHS-QDs left panel: intraperitoneal ZHS-QDs attach to the tumor and peritoneal surfaces. Middle panel: iRGD facilitates local penetration of ZHS-QDs specifically into peritoneal tumors. Right panel:
  • Intraperitoneal etching differentially quenches the non-targeted counterparts of the QDs leading to highly tumor-specific signals.
  • FIG. 5A shows in vitro etching of ZHS-QDs by various chemicals.
  • the chemicals were added to ZHS-QDs in vitro and imaged under an 800 nm channel with a Li-Cor Pearl imaging system. Each column corresponds to the tube above.
  • a number of chemicals including Ag(S2Cb)2 3" (Ag-TS) and CuSC effectively quenched ZHS-QDs in vitro.
  • ⁇ ( ⁇ enhanced the fluorescence intensity.
  • FIG. 5B is a TEM image of ZHS-QDs after etching with Ag-TS. Scale bar, 20 nm. Note that the particles sizes are similar to the QDs before etching shown in FIG. 1A
  • FIG. 5C shows in vitro etching of various QDs with Ag-TS.
  • PL spectra of the QDs before and after etching are shown.
  • the emission peaks of the QDs are also listed.
  • the insets show fluorescence images taken with or without etching.
  • FIG. 5D are micrographs of cultured PC-3 human prostate cancer cells treated with cell-penetrating QDs followed by etching with Ag-TS. PPC1 cells were incubated with CdSe/ZnS QDs coated with a cell-penetrating peptide
  • KCDGRPARPAR which has affinity to a cell penetration receptor neuropilin-1. Epifluorescence images were taken before and after etching with Ag-TS. Note that only speckled peri-nuclear signals remain after etching. The inset shows a magnified view of the boxed area. Scale bars, 50 ⁇ .
  • FIG. 5E shows confocal micrographs of cultured MCFlOCAla human breast cancer cells treated with ZHS-QDs with or without free iRGD followed by etching with Ag-TS. Note that the QDs were taken up into the cells in the presence of iRGD, and that only the extracellular QDs were etched. The inset shows a magnified view of the boxed area. Scale bars, 20 ⁇ .
  • FIG. 6A shows NIR images of serum collected from normal mice that received an intravenous injection of PBS or ZHS-QDs followed 30 minutes later by intraperitoneal PBS or lx Ag-TS injection.
  • FIG. 6B shows in vivo etching of intravenously injected ZHS-QDs with subcutaneous injections of penicillamine/CuSC as the etchant.
  • ZHS-QDs normal mice injected five minutes earlier with ZHS-QDs received PBS or three consecutive injections of a mixture of penicillamine and CuS04 at a molar ratio of 2: 1. Note that near complete etching was achieved within approximately 20 minutes from the first etchant injection.
  • FIG. 7A is a panel of two bar graphs showing an analysis of renal and liver functions as performed with plasma biochemical assays performed in mice 24 hours (upper panel) and one week (lower panel) after injection of PBS alone, PBS followed by etchant (lx Ag-TS), or ZHS-QDs followed by PBS or an etchant (lx Ag-TS).
  • n 6 per group.
  • ALB albumin (g/L); ALP, alkaline phosphatase (units/L); ALT, alanine transaminase (units/L); AMY, amylase (units/L); TBIL, total bilirubin ( ⁇ ); BUN, blood urea nitrogen (mM); CA, calcium (mM); PHOS, phosphorus (mM); CRE, creatinine ( ⁇ ); GLU, glucose (mM); TP, total protein (g/L); GLOB, globulin (g/L).
  • Statistics ANOVA; error bars, SEM; none of the comparisons between the four groups were statistically significant.
  • FIG. 7B shows no pathological changes to major organs from H&E staining results from mice one week after the indicated treatments. Scale bars, 100 ⁇ .
  • FIG. 8B shows H&E staining of KRAS-Ink tumor tissue.
  • FIG. 9B shows the mice sacrificed under deep anesthesia, necropsied, and imaged again to study QD biodistribution in more detail.
  • FIG. 9C shows tissues collected from the mice and imaged with the Xenogen IVIS and Pearl imager.
  • FIG. 9D shows fluorescent signal per unit area in collected tissues. Statistics, ANOVA; error bars, SEM; ns, not significant; ***P ⁇ 0.001.
  • B brain; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney.
  • FIG. 9E show confocal micrographs of tumors. Scale bars, 50 ⁇ . The dotted lines indicate PT surface.
  • FIG. 9F show confocal micrographs of non-tumor tissues. Scale bars, 50 ⁇ . The dotted lines indicate PT surface.
  • etchant lx Ag-TS
  • SCT extraperitoneal MK 45P-luc subcutaneous tumor
  • FIG. IOC shows fluorescent signal per unit area in SCTs and PTs calculated based on ex vivo imaging results. Statistics, Student's /-test; error bars, SEM; **P ⁇ 0.01.
  • FIG. 10D shows confocal micrographs of SCT. Scale bar, 50 ⁇ . Arrows point to blood vessels positive for ZHS-QDs.
  • FIG. 11A is a cartoon showing iron oxide nanoworms that before and after etching.
  • FIG. 1 IB is a line graph showing that etching of NWs dampening MRI decay.
  • FIG. llC is a bar graph comparing the NW and etched NW T2 values.
  • the present disclosure provides a nanosystem that probes tissues and tumors with high specificity and a low background in other tissues, even in the MPS, to produce detailed in vivo images of the tissues and tumors of interest.
  • the nanosystem is based at least in part on a tracer combined with a quenching agent, an "etchant.”
  • the etchant rapidly eliminates signal from the tracer through cationic exchange and facilitates renal clearance of heavy metal ions released from the tracers, leaving tissue- or tumor-specific signals provided by the intact tracers remaining in tissue or tumor.
  • the nanosystem can also include a targeting agent that helps to more specifically target a tracer to particular tissues and/or tumors of interest.
  • the present disclosure provides a unique approach to achieve exceptionally specific imaging that utilizes biocompatible in vivo chemical reactions.
  • the signal-to-noise ratio (SNR) of an image is usually defined as the ratio of the mean voxel value to the standard deviation of the voxel values.
  • SNR increases as the square root of the signal, and increasing the concentration of tracer within reasonable limits is beneficial to the SNR.
  • SNR increases as the square root of the signal, and increasing the concentration of tracer within reasonable limits is beneficial to the SNR.
  • Even a very high SNR is not useful if there is no contrast between the regions of the subject.
  • the contrast index (CI), defined as [(fluorescence intensity of tumor area - autofluorescence) / (fluorescence intensity of normal contralateral region - autofluorescence)], is a parameter for tumor-specific image quality (Yu et al., ACS Nano 9:6655-6674 (2015); Jiang et al, Proc Natl Acad Sci USA 101 : 17867-17872 (2004)).
  • a CI of 2.5 is a general cut-off for substantial tumor-specific detection with optical imaging (Yu et al., ACS Nano 9:6655-6674 (2015)).
  • a high CI is a desired aspect of an imaging system and of the probes used; however, the CI depends, at least in part, on the tracer distribution.
  • the CI is defined as the ratio of a higher to a lower value, where the higher value is that coming from a certain area of interest (e.g., tissue or tumor) and the lower value coming from a separate reference region located outside the area of interest.
  • a certain area of interest e.g., tissue or tumor
  • compositions can be used to capture an image of the area of interest at a CI of at least five, e.g., at least six, seven, eight, nine, 10, 12, 15, 18, 20, 25, 50, or at least 100.
  • nanoparticle tracers were designed that can be quenched in the circulation after the tracer is targeted to particular tissues and/or tumors.
  • the system and processes can employ a
  • PL photoluminescent
  • NIR near-infrared
  • QD quantum dot
  • QDs have high quantum yield (QY), resistance to photo-bleaching, and tunable PL (Altinoglu et al., Wiley Interdiscip Rev Nanomed Nanobiotech 2:461-477 (2010); Zrazhevskiy et al, Nat Commun 4: 1619 (2013); Wegner et al, Chem Soc Rev 44:4792-4834 (2015)).
  • Ion exchange chemistry was exploited to create a platform of quenchable (ionically etchable) tracers with a heavy metal ion that undergoes cation exchange when exposed to a metal chelator to abolish the PL.
  • the tracers have zinc (Zn 2+ ), mercury (Hg 2+ ), and selenium (Se 2" ).
  • the tracer may be a QD with Zn x Hgi- x Se (ZHS-QDs).
  • the tracer comprises zinc (Zn 2+ ), silver (Ag + ), and selenium (Se 2" ), e.g., ZAS-QDs.
  • the tracer may also have manganese zinc sulfide (Mn x Zni- x S), manganese zinc selenide (Mn x Zm- x Se), cadmium selenide (CdSe), indium phosphide (InP), copper indium sulfide (CuInS), and/or copper indium selenide (CuInSe).
  • Ions relevant to positron emission tomography (PET) imaging could include Zn, Mn, Cd, Cu, In, Zr, Mo, Fe, Eu, Pt, Pd, Au, Sb, Bi, Co, Ge, Sr, Sn, Tb, Zr, Pb, Ni, and many others.
  • the quantum dot comprises a zinc sulfide (ZnS) shell, e.g., Mn x Zni- x S/ZnS, Mn x Zm -x Se/ZnS,
  • the tracer has a formula of "ABZ,” where "A” is any metal ion, “B” is any metal ion, and “Z” is sulfur (S), selenium (Se), tellurium (Te), phosphorus (P), iodine (I), bromine (Br), fluorine (F), oxygen (O), or boron (B).
  • A is any metal ion
  • B is any metal ion
  • Z is sulfur (S), selenium (Se), tellurium (Te), phosphorus (P), iodine (I), bromine (Br), fluorine (F), oxygen (O), or boron (B).
  • Hg 2+ can be doped inside the quantum dot core.
  • the QDs have a core size of about 1 nm to about 50 nm, e.g., about 1 nm to about 40 nm, about 1 nm to about 30 nm, about 1 nm to about 20 nm, about 1 nm to about 10 nm, about 1 nm to about 5 nm, about 5 nm to about 40 nm, about 10 nm to about 40 nm, about 20 nm to about 40 nm, about 30 nm to about 40 nm, or about 5 nm, 10 nm, 20 nm, 30 nm, 40 nm, or about 50 nm.
  • magnetic ions can also be used as tracers in the present methods.
  • a nanoparticle e.g., a QD
  • a magnetic ion can be utilized and etched to provide in vivo images with a high CI, e.g., a CI of at least five.
  • FIG. 11 A shows a cartoon of iron oxide nano worms (NW) with a core chemistry of iron (Fe) and oxygen (O) atoms in a lattice.
  • Etching of the magnetic ions with a magnetic ion chelator releases the magnetic ions from the NW structure, leaving a less-magnetic structure.
  • Paramagnetic metal ions can be used as magnetic tracers, including iron oxide, iron platinum, gadolinium ions (Gd + ), manganese ions (Mn 2+ ), and copper ions (Cu 2+ ).
  • radiochemical tracers include nanoparticles with gamma-emitting radionuclides that can include 67 Ga, 99m Tc, m In, 123 I, 125 I, 1 1 ⁇ , and 201 T1.
  • Radionuclides used in PET scanning are typically isotopes with short half-lives such as n C (-20 minutes), 1 N (-10 minutes), 15 0 (-2 minutes), 18 F (-110 minutes), 68 Ga (-67 minutes), 89 Zr (-78.41 hours), and 82 Rb (-1.27 minutes) (Tavitian et al, Textbook of in vivo Imaging in Vertebrates, ed. Ntziachristos et al, John Wiley & Sons, Ltd., 2007)). These radionuclides can be incorporated into nanoparticle tracers for use in the present methods.
  • the tracer can be coated with polyethylene glycol, dextran, L-cysteine, albumin, and/or a high molecular weight peptide polymer.
  • the tracer e.g., the QD
  • the tracer can be coated with polyethylene glycol that has an average molecular weight of about 100 daltons to about 80000 daltons, e.g., PEG2000, which has an average molecular weight of about 1900 daltons to about 2200 daltons.
  • the tracer could also be coated with
  • polyethylene glycol that has an average molecular weight of about 500 daltons to about 10000 daltons, e.g., about 1000 daltons to about 3000 daltons, or about 1500 daltons to about 2500 daltons.
  • etchants Biocompatible quenching agents
  • Etchants may bind metal ions through one or more bonds, and the bonds need not be covalent.
  • thiosulfate and penicillamine have one sulfur atom to bind metal ions, while desferoxamine can bind iron through several of its atoms.
  • the etchants can be membrane-impermeable. The etchants can have a different metal ion or isotope than that found in the tracer to allow for cation exchange between the tracer and the etchant.
  • the etchant may be a chelator that is used without a metal ion, where the chelator binds onto the tracer, or binds to and causes release of metal ions from the tracer.
  • etchants that have a high affinity for the tracer's metal ion can be used.
  • magnetic tracers it was found that chelators can be used directly as etchants, i.e., no additional metal ions need to be mixed into the etchant to help with tracer ion release.
  • iron oxide was etched by mimosine in Example 2 (FIGs. 11A to 11C).
  • Other chelators include Deferiprone (FERRIPROX ® is a close analog of mimosine), Deferoxamine,
  • etchants with a metal ion that have a high affinity for the tracer's anion component can be used, e.g., sulfur, selenium, tellurium, phosphorus, oxygen, iodine, bromine, or boron.
  • the etchant has a combination of metal ion and chelator, then that metal ion must be capable of binding the non-metal ion in the tracer, to allow for cation exchange.
  • the metal ion in the etchant is stable in plasma, blood, and saline so that the ion can contact the circulating metal ion in the tracer.
  • Suitable etchants can have metal ions such as silver, copper, bismuth, manganese, indium, gold, tin, nickel, iron, cobalt, and/or zinc.
  • the etchants can also have hydrophilic agents to bind and solubilize the preferred metal ions while maintaining the membrane-impermeable character of the etchant.
  • the agent can be in large molar excess over the metal ion, e.g., about 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 15: 1, 20: 1, 30: 1, 50: 1, or about 100: 1.
  • the agent could be a molecule, protein, or polymer, e.g., thiosulfate (S2O3 2" ; "TS").
  • Some exemplary etchants include Ag(S203)2 " (Ag-TS), penicillamine with CuS04 (Cu-Pen), copper thiosulfate (Cu-TS), iron desferoxamine, AgNC , K 3 Fe(CN)e, and Hg(C10 4 ) 2 .
  • Accumulation of a tracer in a specific tissue, tumor, atherosclerotic plaque, tissue injury site, inflammation site, tissue degeneration site, or infectious agent can be achieved by selectively delivering the tracer using a targeting agent, e.g., a targeting agent that directs the tracer to penetrate a tissue, tumor, atherosclerotic plaque, tissue injury site, inflammation site, tissue degeneration site, or infectious agent.
  • a targeting agent e.g., a targeting agent that directs the tracer to penetrate a tissue, tumor, atherosclerotic plaque, tissue injury site, inflammation site, tissue degeneration site, or infectious agent.
  • the targeting agent can include a peptide, an antibody or antigen-binding fragment thereof, an aptamer, or an enzyme.
  • iRGD peptides comprising an amino acid sequence of CRGDKGPDC (SEQ ID NO: l) or CRGDRGPDC (SEQ ID NO:2) (Sugahara et al, Cancer Cell 16:510-520 (2009); Sugahara et al., Science 328: 1031-1035 (2010)) can be used to increase tumor uptake of a tracer that is administered at the same time or at about the same time as the targeting agent.
  • the targeting agent is administered before the tracer, e.g., about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes before the tracer is administered.
  • the targeting agent is administered to a subject at substantially the same time as the tracer is administered, e.g., co-administering the targeting agent with the tracer, i.e., at or at about the same time as the tracer is administered.
  • the targeting agent can also comprise a tLyP-1 peptide (CGNKRTR; SEQ ID NO:3), LyP-1 (CGNKRTRGC; SEQ ID NO:4), iNGR peptide
  • CRNGRGPDC SEQ ID NO:5
  • CKRGARSTC cyclo-TTl
  • AKRGARSTA Linear- TT1
  • CendR peptide CendR peptide
  • uPAR urokinase plasminogen activator receptor
  • the CendR peptide motif (R/KXXR/K-COOH, wherein X can be any amino acid, e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartate, and glutamate) binds to neuropilin-1 and cause vascular leakage and tissue penetration (Teesalu et al. Front Oncol 3:216 (2013)).
  • An example of a CendR peptide is RPARPAR (SEQ ID NO: 8).
  • Other details of a suitable targeting agents are described in US 2010/0322862 and US 2011/0262347, the entire contents of which are hereby incorporated by reference.
  • tissue e.g., the lungs, GFE-1, sequence CGFECVRQCPERC (SEQ ID NO:9), Rajotte et al, J Clin Invest 102:430-437 (1998); or brain, CAGALCY (SEQ ID NO: 10), Fan et al, Pharm Res 24:868-879 (2007)), atherosclerotic plaque (e.g., LyP-1, CGNKRTRGC (SEQ ID NO:4), Hamzah et al, Proc Natl Acad Sci USA 108: 7154-7159 (2011)), tissue injury site (e.g., brain injury, tetrapeptide CAQK, Mann et al., Nature Comm. 2016; 7: 11980. doi:
  • inflammation site e.g., V- CAM-binding peptide VHPKQHRGGS KGC (SEQ ID NO: 11) (Chen et al, PLoS
  • tissue degeneration site e.g., Alzheimer's disease brain, CDAGRKQKC (SEQ ID NO: 12), Mann et al, submitted
  • infectious agent e.g.
  • the tracers can also be modified on their surface with tissue- or tumor-targeting agents or other disease/organ-targeting agents.
  • tissue- or tumor-targeting agents or other disease/organ-targeting agents.
  • a targeting agent described herein may be coupled to the tracer to direct the tracer to a particular tissue, tumor, atherosclerotic plaque, tissue injury site, inflammation site, tissue degeneration site, or infectious agent.
  • a "targeted tracer” means a tracer that is targeted to a specific tissue, tumor, atherosclerotic plaque, tissue injury site, inflammation site, tissue degeneration site, or infectious agent by, for example, administering a targeting agent prior to administering the tracer, or co-administering the targeting agent with the tracer, i.e., at or at about the same time as the tracer is administered, e.g., the targeting agent can be administered about five minutes before the tracer is administered, e.g., about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes before the tracer is administered.
  • the "targeted tracer” can be “targeted” to a particular tissue, tumor, atherosclerotic plaque, tissue injury site, inflammation site, tissue degeneration site, or infectious agent by modifying the tracer with a targeting agent, e.g., by conjugating or otherwise linking a targeting agent to a tracer.
  • Tissues, tumors, atherosclerotic plaques, tissue injury sites, inflammation sites, tissue degeneration sites, or infectious agents can be imaged in vivo by administering a targeted tracer to a subject; administering an etchant to the subject; and performing an imaging of the subject to capture an image of the area of interest at a CI of at least five, e.g., at least six, seven, eight, nine, 10, 12, 15, 18, 20, 25, 50, or at least 100.
  • it is beneficial to perform a second imaging of the subject for example, to monitor disease progression or to monitor the subject's response to a certain treatment.
  • the methods can include a second imaging of the subject, for example, to monitor disease progression or to monitor the subject's response to a certain treatment.
  • the methods can include a second imaging of the subject, for example, to monitor disease progression or to monitor the subject's response to a certain treatment.
  • the methods can include a second imaging of the subject, for example, to monitor disease progression or to monitor the subject's response to
  • administration of the targeted tracer to the subject a second administration of the etchant to the subject; and performing a second imaging of the subject, wherein the second administration of the targeted tracer to the subject is performed at least about 10 to 30 minutes after performing the first imaging of the subject, e.g., about 15 to 45 minutes, about 30 to 60 minutes, about 60 to 90 minutes, about 120 to 180 minutes, about 240 to 480 minutes, about one day to two days, or about two days to seven days after performing the first imaging of the subject.
  • the tracer can be administered intravenously, intraperitoneally,
  • dosages for any one subject depend on many factors, including the sex, weight, body surface area, and age of the subject, as well as the particular composition to be administered, and the route of administration.
  • Dosages for the targeted tracer will vary, but can, when administered intravenously, be given in doses on the order of magnitude of about 1 ng/kg to about 100 mg/kg body weight, e.g., about 10 ng/kg to about 90 mg/kg, about 20 ng/kg to about 70 mg/kg, about 30 ng/kg to about 50 mg/kg, about 50 ng/kg to about 45 mg/kg, about 100 ng/kg to about 40 mg/kg, about 1 ⁇ g/kg to about 30 mg/kg, about 10 ⁇ g/kg to about 20 mg/kg, about 100 ⁇ g/kg to about 10 mg/kg, or about 1 mg/kg to about 10 mg/kg body weight, or on the order of magnitude of about 15 ng/L to about 1.5 g/L of blood volume, e.g., about 150 ng/L to about 1.35 g/L, about 300 ng/L to about 1.05 g/L, about 450 ng/L to about 750 mg/L, about 750 ng
  • the etchant can be administered intravenously, intraperitoneally, subcutaneously, intrathecally, intrathoracically, intratracheally, intratumorally, or intracranially to quench non-specific tracer.
  • the etchant is administered about five minutes after the targeted tracer has been administered, e.g., about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes after the targeted tracer has been administered.
  • dosages for the etchant will vary, but can, when administered intravenously, be given in doses on the order of magnitude of 1 ng/kg to about 1 g/kg body weight, e.g., about 10 ng/kg to about 900 mg/kg, about 20 ng/kg to about 700 mg/kg, about 30 ng/kg to about 500 mg/kg, about 50 ng/kg to about 450 mg/kg, about 100 ng/kg to about 400 mg/kg, about 1 ⁇ g/kg to about 300 mg/kg, about 10 ⁇ g/kg to about 200 mg/kg, about 100 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 10 mg/kg body weight, or on the order of magnitude of about 15 ng/L to about 15 g/L of blood volume, e.g., about 150 ng/L to about 13.5 g/L, about 300 ng/L to about 10.5 g/L, about 450 ng/L to about
  • the present methods include performing an imaging of the subject by any means to capture the signal of the tracer used.
  • the imaging can include optical excitation and emission detection.
  • One of ordinary skill in the art will be able to determine the appropriate wavelengths to excite and detect PL depending on the particular tracer used.
  • the tracer can be excited at a wavelength of about 400 nm to about 800 nm, e.g., about 450 nm to about 785 nm, about 460 nm to about 785 nm, about 450 nm to about 460 nm, or about 450 nm, 460 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 785 nm, or about 800 nm.
  • the subject can be imaged at a wavelength of about 550 nm to about 850 nm, e.g., about 600 nm to about 800 nm, about 650 nm to about 750 nm, or about 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, or about 850 nm.
  • an excitation wavelength greater than 300 nm can be used, e.g., about 300 nm to about 1000 nm, about 350 nm to about 950 nm, about 400 nm to about 900 nm, about 450 nm to about 850 nm, about 500 nm to about 800 nm, about 550 nm to about 750 nm, about 600 nm to about 700 nm, or about 300 nm, 350 nm, 400 nm, 450 nm, 460 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 785 nm, 800 nm, 850 nm, 900 nm, 950 nm, or about 1000 nm.
  • an excitation wavelength less than 400 nm can be used, e.g., about 10 nm to about 400 nm, about 50 nm to about 385 nm, about 100 nm to about 350 nm, about 150 nm to about 300 nm, about 200 nm to about 250 nm, or about 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, or about 400 nm.
  • an excitation wavelength across the visible (e.g., about 400 nm to about 700 nm) and infrared (e.g., about 700 nm to about 1 mm) wavelengths can be utilized depending on material and core size.
  • the subj ect can be imaged by magnetic resonance imaging (MRI), and if a radiochemical tracer is used, the subject can be imaged by single photon emission computerized tomography or positron emission tomography.
  • MRI magnetic resonance imaging
  • the tracer is targeted to a tissue by administering a tissue-targeting agent intravenously, intraperitoneally, subcutaneously, intrathecally, intrathoracically, intratracheally, intratumorally, or intracranially.
  • tissue-targeting agent can be administered prior to administering the tracer, or coadministering with the tracer.
  • the tissue-targeting agent can be administered about five minutes before the tracer is administered, e.g., about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes before the tracer is administered.
  • tumor-targeting agent can be administered prior to administering the tracer, or coadministering with the tracer.
  • the tumor-targeting agent can be administered about five minutes before the tracer is administered, e.g., about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes before the tracer is administered.
  • Routes of administration are also well known to skilled practitioners and include intravenous, intraperitoneal, subcutaneous, intrathecal, intrathoracic, intratracheal, intratumoral, or intracranial administration. It is expected that the intravenous, intraperitoneal, or subcutaneous routes will be preferred for the administration of the present compositions.
  • the present disclosure also features methods of selectively delivering a therapeutic agent to a tissue or tumor in a subject.
  • the methods can include administering a tissue- or tumor-targeted tracer to the subject, wherein the tracer is conjugated to the therapeutic agent.
  • therapeutic agent means a moiety that inhibits cell growth or promotes cell death when proximate to or absorbed by the cell. Suitable therapeutic agents in this regard include radioactive isotopes (radionuclides), chemotoxic agents such as differentiation inducers, and small chemotoxic drugs, toxin proteins, and derivatives thereof.
  • Non-limiting examples of therapeutic agents include cytotoxic agents such as alkylating agents, xorubicin, calicheamicin, maytansinoid derivatives (e.g., DM1, DM4), a toxin (e.g., truncated Pseudomonas endotoxin A, Pseudomonas exotoxin 38 (PE38), diphtheria toxin), auristatin, anthracycline, calicheamycin, combretastatin, doxorubicin, duocarmycin, CC-1065 anti-tumor antibiotic (Li et al., Cancer Res 42:999-1004 (1982)), ecteinsascidin, geldanamycin, maytansinoid, methotrexate, mycotoxin, taxol, ricin, bouganin, gelonin, and other toxin proteins known in the medical arts.
  • the methods can also include administering an e
  • Also provided are methods of selectively administering a therapy to a desired location in a tissue or tumor of a subject wherein the method includes administering a tissue-or tumor-targeted tracer to the subject; administering an etchant to the subject; performing an imaging the subject, wherein the method captures an image of the tissue or tumor at a CI of at least five, e.g., at least six, seven, eight, nine, 10, 12, 15, 18, 20, 25, 50, or at least 100.
  • suitable therapies e.g., radiotherapy and chemotherapy, may be administered to the desired location in the tissue or tumor of the subject.
  • the methods include administering a tumor-targeted tracer to the subject; administering an etchant to the subject; performing an imaging of the subject to identify a tumor, wherein the method captures an image of the tissue or tumor at a CI of at least five, e.g., at least six, seven, eight, nine, 10, 12, 15, 18, 20, 25, 50, or at least 100. Based on the images received from the imaging, any tumors detected in the images can be removed, for example, by surgery. Skilled practitioners will appreciate that in some cases when it is not possible to remove all of a cancerous tumor, for example, because doing so may severely harm an organ, the tumor may be removed as much as possible (debulking) to make chemotherapy or radiation more effective.
  • tissue or tumor imaging can be applied to detect or monitor various medical conditions, e.g., peritoneal carcinoma and a premalignant lesion.
  • the methods include administering a tumor-targeted tracer to the subject; administering an etchant to the subject; and performing an imaging the subject, wherein the method captures an image of the tissue or tumor at a CI of at least five, e.g., at least six, seven, eight, nine, 10, 12, 15, 18, 20, 25, 50, or at least 100. If a tumor is detected, or if tumor growth is observed, the methods can include removing the tumor, for example, by surgery.
  • compositions and methods are clearly contemplated for use in human subjects, the invention is not so limited.
  • the compositions and methods can be used to image any mammal or domesticated animal such as a dog, cat, horse, lion, bear, koala, monkey, giraffe, and tiger.
  • the subject has or is suspected of having a tumor, e.g., tumors of the breast, pancreas, lung, liver, stomach, intestine, prostate, or brain, pancreatic ductal adenocarcinoma, peritoneal carcinoma, or pancreatic intraepithelial neoplasia.
  • a subject suspected of having one of these conditions is one having one or more symptoms of the condition.
  • Symptoms of these conditions vary greatly depending on the particular condition and are well-known to those of skill in the art, and can include, without limitation, breast lumps, nipple changes, breast cysts, breast pain, weight loss, weakness, excessive fatigue, difficulty eating, loss of appetite, chronic cough, worsening breathlessness, coughing up blood, blood in the urine, blood in stool, nausea, vomiting, liver metastases, lung metastases, bone metastases, abdominal fullness, bloating, fluid in peritoneal cavity, vaginal bleeding, constipation, abdominal distension, perforation of colon, acute peritonitis (infection, fever, or pain), pain, vomiting blood, heavy sweating, fever, high blood pressure, anemia, diarrhea, jaundice, dizziness, chills, muscle spasms, colon metastases, lung metastases, bladder metastases, liver metastases, bone metastases, kidney metastases, pancreas metastases, difficulty swallowing, and the like.
  • an "effective amount” is an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.
  • Tumors were specifically visualized in mice bearing orthotopic breast tumors or desmoplastic pancreatic ductal adenocarcinomas (PDAC) with PL tracers.
  • the tumor-to-liver ratio (T/Li) was at least 10-fold higher than the typical ratio previously reported with nanoprobes.
  • Confocal microscopy revealed extensive tracer accumulation in tumor cells and tumor stroma. Importantly, no toxicity was noted in the mice.
  • the etchable tracer system was also applicable to peritoneal tumor imaging in which tracer were locally delivered to the tumors through the abdominal cavity.
  • MCFlOCAla human breast cancer cells (Santner et al, Breast Cancer Res Tr 65: 101-110 (2001)), KRAS-Ink mouse PDAC cells (Aguirre et al, Gene Dev 17:3112-3126 (2003)), PC-3 human prostate cancer cells (Teesalu et al, Proc Natl AcadSci USA 106: 16157-16162 (2009)), and MK 45P-luc luciferase-positive human gastric cancer cells (Sugahara et al, J Control Release 212:59-69 (2015)) were cultured in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin.
  • the human cell lines were authenticated by the DNA Analysis Core Facility at the Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA) and the KRAS-Ink cell line was authenticated by DDC Medical (Fairfield, OH). All the cells were tested negative for mycoplasma contamination.
  • Female BALB/c and athymic nude mice were both purchased from Harlan Laboratories (Indianapolis, IN).
  • Orthotopic breast tumors were generated by injecting 2 x 10 6 MCF IOC Ala cells into the mammary fat pad (Santner et al, Breast Cancer Res Tr 65: 101-110 (2001)), and orthotopic PDAC tumors were generated by injecting 2 x 10 6 KRAS-Ink cells into the pancreas (Sugahara et al, Cancer Cell 16:510-520 (2009)) of female nude mice at 10 weeks of age.
  • Peritoneal tumor mice were generated by injecting 10 7 MK 45P-luc cells into the peritoneal cavity of female nude mice at 10 weeks of age (Sugahara et al, J Control Release 212:59-69 (2015)). All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee at Sanford Burnham Prebys Medical Discovery Institute.
  • Manganese-doped zinc sulfide (Mn/ZnS) QDs were synthesized as previously reported (Yin et al, Chinese Phys B 21 : 116101 (2012)).
  • Cadmium selenide zinc sulfide (CdSe/ZnS) core/shell QDs were purchased from eBioscience (San Diego, CA).
  • Indium phosphide zinc sulfide (InP/ZnS) QDs and copper indium sulfide zinc sulfide (CIS/ZnS) QDs were both bought from NNCrystal US Corporation
  • CdSe/ZnS QDs coated with cell- penetrating KCDGRPARPAR peptides were prepared according to the manufacturer's instructions associated with the eFluor 605NC sulfhydryl-reactive conjugation kit (eBioscience).
  • TEM was performed with a JEM-1200EX II electron microscope (JEOL, Tokyo, Japan) operating at 80 kV.
  • PL spectra were measured with a FluoroMax-4 spectrofluorometer (Horiba, Kyoto, Japan).
  • ICP-OES measurement was performed with an Optima 3000 DV ICP-OES spectrometer (Perkin-Elmer, Waltham, MA).
  • Dynamic light scattering (DLS) was carried out with Malvern Zetasizer Nano ZS90
  • Ag-TS was synthesized as follows. AgN03 (0.08 mmol) was added into PBS (500 ⁇ ) and mixed for 30 seconds forming a precipitate. Na2S 2 03 in H2O (0.2 M, 1 mL) was then added to the solution and mixed for five minutes to allow the precipitate to dissolve. After filtration with a 0.22 ⁇ syringe filter, a clear colorless solution was obtained (0.05 M Ag-TS stock solution, designated as "lOx"). The solution was diluted 5 or 10 times with PBS to obtain a 2x or lx Ag-TS solution, which was used on the same day for in vivo etching studies.
  • ZHS-QDs or ZAS-QDs in PBS were mixed with either PBS (100 L) or lOx Ag-TS etchant (100 L) for one hour at room temperature, followed by ultrafiltration in ddfhO with Amicon Ultra-0.5 centrifugal filters (NMWL 10 KDa).
  • the filtrates and concentrates were collected separately for ICP-OES measurement (Liu et al, Adv Fund Mater 26:267-276 (2016)).
  • the collected concentrates were also subjected to TEM observation and PL spectra measurement.
  • Aqueous solutions of various chemicals were prepared to examine their etching capacity in vitro.
  • the concentration was 1 mM for all the chemicals except for Na 2 S 2 0 3 (Na-TS), which was 2.5 mM, and Ag-TS and Cu-TS, which were prepared by mixing AgNCb (2 mM) or CuS04 (2 mM) with an equal volume of Na- TS (5 mM).
  • Na-TS Na 2 S 2 0 3
  • Ag-TS and Cu-TS which were prepared by mixing AgNCb (2 mM) or CuS04 (2 mM) with an equal volume of Na- TS (5 mM).
  • Each chemical (400 ⁇ ) was mixed with ZHS-QDs (400 ⁇ , 0.5 mM of Zn 2+ ) at room temperature for one minute.
  • the mixtures were imaged with a Li-Cor Pearl imager under the 800 nm channel, and the PL spectra of the mixtures were also immediately measured with an excitation wavelength of 450 nm.
  • Emission peak intensity was used to calculate relative PL intensity.
  • aqueous solutions 400 ⁇ / ⁇ of Mn/ZnS (Zn concentration: 10 mM), InP/ZnS (0.25 mg/mL) and CIS/ZnS (0.5 mg/mL) QDs were added with an equal volume of lx Ag-TS or ddLhO, while CdSe/ZnS (QD concentration: 3.2 nM) in ddthO (400 ⁇ was added with an equal volume of lOx Ag-TS or ddLhO. After mixing at room temperature for five minutes, the mixtures were subjected to PL imaging and PL spectra measurement.
  • UVAVhite light transilluminator LMW-20 UVP, Upland, CA
  • Illumatool Bright Light System LT-9900 Li-Cor Pearl imager under a 700 nm channel for CIS/ZnS QDs.
  • PC-3 cells which express neuropilin-1, a cell surface receptor for the
  • KCDGRPARPAR peptide (Teesalu et al, Proc Natl Acad Sci USA 106: 16157-16162 (2009)), were incubated in 96 well plates with KCDGRPARPAR-coated CdSe/ZnS QDs (QD concentration: 25 nM) for 90 minutes at 37°C.
  • the cells were subjected to epifluorescence imaging with a Leica DMIRE2 microscope (Leica, Wetzlar,
  • MCFlOCAla cells were incubated with or without iRGD peptide (final concentration; 50 ⁇ ) in culture media in chambered coverglass (Nunc Lab-Tek II, Rochester, NY) for 30 minutes at 37°C, and ZHS-QDs were added to each chamber (final concentration; 1 mM Zn 2+ ). After incubation for 2.5 hours at 37°C, the cells were washed once with PBS, and cultured in fresh culture media containing Hoechst 33342 (10 ⁇ g/mL in 400 ⁇ , Molecular Probes, Eugene, OR) for 10 minutes at 37°C.
  • Hoechst 33342 10 ⁇ g/mL in 400 ⁇ , Molecular Probes, Eugene, OR
  • Etching was performed by adding lx Ag-TS (100 ⁇ ) to each chamber and incubating the cells for one minute at room temperature.
  • the cells were imaged with a Zeiss LSM 710 NLO confocal microscope (Carl Zeiss, Oberkochen, Germany) before and after etching.
  • mice 10-12 weeks of age were intravenously injected with 100 ⁇ , of PBS or ZHS-QDs in PBS (18 nmol Zn/g body weight) followed 30 minutes later with intraperitoneal injection of 300 ⁇ . of PBS or lx Ag-TS.
  • the mice were sacrificed under deep anesthesia one hour, 24 hours, and 10 days after Ag-TS injection.
  • Major tissues, serum, feces, and urine samples were collected for quantification of mercury with ICP-OES (Liu et a ⁇ ., Adv Fund Mater 26:267-276 (2016)).
  • Sectioned paraffin blocks were stained with hematoxylin and eosin (H&E), and whole slide scanning was performed with a Leica SCN 400 slide scanner. Imaging of Normal Mice
  • mice without tumors were anesthetized with isoflurane and imaged under an 800 nm channel with a Pearl Impulse small animal imaging system (Li-Cor, Lincoln, NE) before any injection. Then, the mice were intravenously injected with ZHS-QDs at a dose of 18 nmol Zn/g body weight per injection. Some mice received an intravenous dose of PBS (100 ⁇ ) or iRGD (100 ⁇ , 2.5 mM in PBS) 25 minutes before the QD injection.
  • PBS 100 ⁇
  • iRGD 100 ⁇ , 2.5 mM in PBS
  • Penicillamine/CuS04 was prepared by mixing stock solutions of CuS04 (20 mM) and an equal volume of D-penicillamine (40 mM) just prior to use and without filtration. In some cases, the mice were sacrificed under deep anesthesia for tissue collection.
  • mice bearing an orthotopic MCFlOCAla breast tumor or KRAS-Ink PDAC was performed under anesthesia with isoflurane using a Pearl Impulse imager equipped with an 800 nm channel.
  • the mice were
  • mice bearing MK 45P-luc peritoneal tumors were intraperitoneally injected with ZAS-QDs (30 nmol Zn/g body weight) or ZHS-QDs (45 nmol Zn/g body weight) in PBS (500 uL) with or without 450 ⁇ g of iRGD.
  • ZAS-QDs 30 nmol Zn/g body weight
  • ZHS-QDs 45 nmol Zn/g body weight
  • PBS 500 uL
  • iRGD 450 ⁇ g
  • the mice were intraperitoneally injected with luciferin (15 mg/mL in PBS, Biosynth International, Itasca, IL) at a dose of 0.28 mg/g body weight.
  • mice were then anesthetized with isoflurane, and imaged at different time points for luminescence with a Xenogen IVIS imager (Perkin-Elmer) and for NIR with a Li-Cor Pearl Impulse imager under an 800 nm channel. Some mice also had an extraperitoneal subcutaneous MK 45P-luc tumor in the presence of the peritoneal tumors.
  • lx Ag-TS 400 ⁇ was intraperitoneally injected. After five minutes, the mice were imaged with the Xenogen IVIS and Li-Cor Pearl Impulse imagers.
  • mice were then immediately sacrificed under deep anesthesia by cardiac perfusion with PBS, and the necropsied mice (in situ imaging) and resected tissues (ex vivo imaging) were imaged again.
  • the abdominal cavity of the necropsied mice was not washed before in situ imaging.
  • the tissues were processed for immunofluorescence as described elsewhere (Sugahara et al, J Control Release 212:59-69 (2015)). Fluorescence intensity quantification was performed with a Li-Cor Image Studio Lite 4.0 software.
  • Tissue sections were treated with 0.25% Triton X-100 for 10 minutes, washed with PBS three times, blocked with 1% bovine serum albumin for one hour, and incubated with a rat anti-mouse CD31 primary antibody (Catalog number: 553370, BD Biosciences, San Jose, CA), rabbit anti-mouse a-SMA antibody (Product code: ab5694, Abeam, Cambridge, MA), or a rat anti-mouse ER-TR7 antibody (Catalog number: sc-73355, Santa Cruz Biotechnology, Dallas, TX) at 4°C overnight.
  • a rat anti-mouse CD31 primary antibody Catalog number: 553370, BD Biosciences, San Jose, CA
  • rabbit anti-mouse a-SMA antibody Product code: ab5694, Abeam, Cambridge, MA
  • a rat anti-mouse ER-TR7 antibody Catalog number: sc-73355, Santa Cruz Biotechnology, Dallas,
  • ZHS-QDs Highly dispersed PEGylated Zn x Hgi- x Se QDs
  • ZHS-QDs were synthesized consisting of zinc (Zn 2+ ), mercury (Hg 2+ ), and Se 2" .
  • Hg 2+ was doped inside the core to improve NIR signals for enhanced light penetration through tissue.
  • Transmission electron microscopy (TEM) of the ZHS-QDs revealed an average core diameter of 6.6 ⁇ 2.3 nm (mean ⁇ standard deviation) (FIG. 1A).
  • Dynamic light scattering (DLS) showed a hydrodynamic diameter of approximately 12 nm (FIG. IB), a size above the renal filtration threshold (Choi et al, Nat Biotechnol 25: 1165-1170 (2007)).
  • the QDs had a 685 nm PL emission peak with a QY of 12% (FIG. 1C).
  • a strong PL signal at 800 nm was obtained using 785-nm excitation, which made the QDs detectable with a Li-Cor Pearl Impulse Small Animal Imaging System under an 800 nm channel (FIG. ID).
  • Approximately 90% of the PL intensity remained after the QDs were stored at 4°C for six months with no visible aggregation (FIG. IE).
  • Various chemicals with cation-exchange capacity quenched ZHS-QDs (FIG. 5A).
  • the etchant was quickly excreted or functionally consumed because a second dose of ZHS-QDs 10 minutes later produced strong signals.
  • a second dose of Ag-TS effectively eliminated the QD signal indicating that repetitive in vivo imaging can be performed over short intervals.
  • the mice tolerated the injections without noticeable behavioral changes.
  • Intraperitoneal injection of Ag- TS completely eliminated QD signals in about 30 minutes (FIG. 2A, second row). Serum collected one hour after intraperitoneal injection of Ag-TS showed complete absence of PL (FIG. 6A). Subcutaneous etchant injections were also effective.
  • Circulating nanoparticles can passively distribute into tumors by Enhanced Permeability and Retention (EPR) effect (Maeda et al, Int Immunopharmacol 3:319- 328 (2003)). However, this process can require several hours, and passive distribution may not be enough to deliver compounds in sufficient quantity against high interstitial fluid pressure in tumors (Maeda et al, Int Immunopharmacol 3:319- 328 (2003); Heldin et al, Nat Rev Cancer 4:806-813 (2004)).
  • EPR Enhanced Permeability and Retention
  • CRGDKGPDC CRGDKGPDC
  • iRGD carries a tumor-specific RGD motif and an RXXR/K motif (CendR motif).
  • the RGD motif initially targets the peptide to tumor vasculature by binding to av integrins, and after a proteolytic cleavage step, the CendR motif interacts with neuropilin-1.
  • background signals in non-tumor areas steeply decreased leaving a tumor- specific signal apparent. The background signals decreased to approximately 10% within 10 minutes from etching, while 75% of the tumor signal remained. After 30 minutes, almost no background was noted, while more than 50% of the tumor signal remained. The tumor-specific signal stayed apparent for at least 210 minutes after etching.
  • CRGDC a control RGD peptide without tissue-penetrating properties (Sugahara et al, Cancer Cell 16:510-520 (2009); Koivunen et al., J Biol Chem 268:20205-20210 (1993)), did not enhance tumor signals. Etching decreased tumor signals to a similar degree in each group indicating baseline passive entry of Ag-TS into the tumors regardless of peptide pre-injection. iRGD/ZHS-QDs/Ag-TS injections did not cause notable signals in normal mice.
  • CI reached 2.5 at 10 minutes post-etching, followed by an exponential increase to mark a CI of 10 after an additional 20 minutes (FIG. 2C).
  • Mice that received PBS or CRGDC pre- injection reached a CI of only about 2.5 after etching, representing the EPR effect.
  • the dim tumor signals were suboptimal for practical imaging.
  • Tumor targeting by the iRGD/ZHS-QD system was further assessed at 40 minutes post-etching, a time point that gave strong tumor-specific signals in vivo (FIG. 2D).
  • In situ imaging after necropsy and ex vivo imaging of resected tissues confirmed tumor-specific signals in the iRGD group, while minimal fluorescence was found in the non-iRGD group (FIG. 2E, F).
  • Quantitative analysis of ex vivo images revealed a 5-fold higher tumor signal in the iRGD group than that in the control group (FIG. 2G, left panel).
  • the T/Li ratio was 4.9 in the iRGD group, which is 17.5-fold higher than the average value (0.28) of previously reported inorganic nanoprobes in general, and 70-fold higher than the average value (0.07) of those with similar sizes (Yu et al., ACSNano 9:6655-6674 (2015); Gao et al, Bioconjugate Chem 21 :604-609 (2010)) (FIG. 2G, right panel).
  • the T/Li ratio in the non-iRGD group was 0.98 suggesting near-equal QD distributions in the tumor and the liver.
  • iRGD Confocal microscopy showed widespread distribution of ZHS-QDs in the extravascular tumor space in the iRGD group (FIG. 2H).
  • iRGD facilitates ZHS-QD entry into extravascular tumor tissue where the QDs are protected from intravascular etching.
  • mice bearing orthotopic tumors created with KRAS-Ink PDAC cells established from transgenic p48-CRE/LSL-KrasGl 2D/INK4af lox mice were prepared (Aguirre et al, Gene Dev 17:3112-3126 (2003); Mitchem et al, Cancer Res 73: 1128-1141 (2013)).
  • Orthotopic KRAS-Ink tumors develop a mixture of high-grade pancreatic intraepithelial neoplasia (PanIN) and desmoplastic PDAC (Mitchem et al, Cancer Res 73: 1128- 1141 (2013)) (FIG. 8B). Injection of ZHS-QDs and Ag-TS alone resulted in minimal signals (FIG. 3 A). In contrast, adding iRGD pre-injection led to a strong focal signal in the left flank where the tumor was located. Ex vivo imaging of resected tissues showed strong fluorescence only in the PDAC.
  • Intraperitoneally administered iRGD facilitates local penetration of coadministered compounds into peritoneal tumors in a tumor-specific and circulation- independent manner (Sugahara et al, J Control Release 212:59-69 (2015); Simon- Gracia et al, Biomaterials 104: 247-257 (2016)). Accordingly, intraperitoneal co- injection of etchable QDs and iRGD was tested to determine whether co-injection facilitates detection of peritoneal tumors.
  • the ZHS-QD system was improved by designing Hg-free PEGylated QDs consisting of Zn 2+ , Ag + , and Se 2" (ZAS-QDs) to avoid any concern for Hg exposure.
  • the ZAS-QDs were tested in mice bearing peritoneal tumors created with luciferase-positive MK 45P-luc human gastric cancer cells (Sugahara et al., J Control Release 212:59-69 (2015)). Intraperitoneal injection of ZAS-QDs into the mice resulted in a fluorescent abdomen (FIG. 4D). No obvious extraperitoneal signal was noted macroscopically, suggesting minimal QD entry into systemic circulation. Subsequent intraperitoneal Ag-TS injection abolished the fluorescence within five minutes. Intraperitoneal co-injection of the ZAS-QDs with iRGD followed by Ag-TS led to strong peritoneal tumor signals with minimal fluorescence in non-tumor tissues (FIGs.
  • This example introduces an important concept in imaging whereby probe brightness is controlled in vivo with a biocompatible chemical reaction.
  • Exceptionally tumor-specific imaging has been achieved by delivering etchable QDs specifically into tumor tissue through intravenous and intraperitoneal routes followed by preferential etching of excess counterparts in non-tumor tissues.
  • the differential etching is enabled by the contrast of QD dynamics between the rapid and active intratumoral spreading facilitated by iRGD, and the slow and passive accumulation into normal tissue such as the liver (Gao et al., Bioconjugate Chem 21 :604-609 (2010); Zhang et al, Biomaterials 34:3639-3646 (2013); Wu et al, Expert Opin Drug Met 9: 1265-1277 (2013)).
  • the lack of etching of intratumoral QDs can be attributed to endocytosis, which protects QDs from membrane-impermeable etchant, and the transient window for iRGD to enhance tumor entry of QDs more than the
  • MRI contrast from dextran-coated iron oxide nanoworms depends on the T2 relaxation rate, a property of the magnetic interaction between the magnetic lattice core and the surrounding water environment.
  • Etching of NWs dampened the MRI decay curve (FIG. 1 IB). This change is attributed to modification of the NW structure or iron content by the activity of the etchant, an iron chelator. Increased T2 was observed after etching consistent with removal of Fe from the oxide lattice.

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L'invention concerne des compositions et des procédés pour l'imagerie de tissus et de tumeurs in vivo avec un traceur qui peut être dissous ou rendu inactif par un agent d'attaque chimique pour augmenter la différence de concentration du traceur dans un tissu/tumeur d'intérêt et de concentration dans d'autres tissus/tumeurs et le sang.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114045168A (zh) * 2021-11-19 2022-02-15 复旦大学 一种水溶性合金量子点纳米酶及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074434A2 (fr) * 2003-01-31 2004-09-02 Immunomedics, Inc. Methodes et compositions permettant d'administrer des agents therapeutiques et diagnostiques
US20100322862A1 (en) 2009-06-22 2010-12-23 Burnham Institute For Medical Research Methods and compositions using peptides and proteins with c-terminal elements
US20110262347A1 (en) 2010-04-08 2011-10-27 The Salk Institute For Biological Studies Methods and compositions for enhanced delivery of compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074434A2 (fr) * 2003-01-31 2004-09-02 Immunomedics, Inc. Methodes et compositions permettant d'administrer des agents therapeutiques et diagnostiques
US20100322862A1 (en) 2009-06-22 2010-12-23 Burnham Institute For Medical Research Methods and compositions using peptides and proteins with c-terminal elements
US20110262347A1 (en) 2010-04-08 2011-10-27 The Salk Institute For Biological Studies Methods and compositions for enhanced delivery of compounds

Non-Patent Citations (56)

* Cited by examiner, † Cited by third party
Title
AGUIRRE ET AL., GENE DEV, vol. 17, 2003, pages 3112 - 3126
ALTINOGLU ET AL.: "Wiley Interdiscip Rev Nanomed Nanobiotech", vol. 2, 2010, pages: 461 - 477
BARRETO ET AL., ADV MATER, vol. 23, 2011, pages H18 - H40
BOULDING ET AL., LANCET, vol. 270, 1957, pages 985
BRAUN ET AL., NAT MATER, vol. 13, 2014, pages 904 - 911
CARNAZZA ET AL., BIOSENSORS AND BIOELECTRONICS, vol. 23, 2008, pages 1137 - 1144
CASEY J L ET AL: "CLEARANCE OF YTTRIUM-90-LABELLED ANTI-TUMOR ANTIBODIES WITH ANTIBODIES RAISED AGAINST THE 12N4 DOTA MACROCYCLE", BRITISH JOURNAL OF CANCER, NATURE PUBLISHING GROUP, GB, vol. 78, no. 10, 1 November 1998 (1998-11-01), pages 1307 - 1312, XP000986994, ISSN: 0007-0920 *
CHEN ET AL., NAT MATER, vol. 12, 2013, pages 445 - 451
CHEN ET AL., PLOS ONE, vol. 8, no. 12, 2013, pages e83805
CHOI ET AL., NAT BIOTECHNOL, vol. 25, 2007, pages 1165 - 1170
CHOI ET AL., NAT NANOTECHNOL, vol. 5, 2010, pages 42 - 47
FAN ET AL., PHARM RES, vol. 24, 2007, pages 868 - 879
GAO ET AL., BIOCONJUGATE CHEM, vol. 21, 2010, pages 604 - 609
HAK SOO CHOI ET AL: "Design considerations for tumour-targeted nanoparticles", NATURE NANOTECHNOLOGY, vol. 5, no. 1, 1 November 2009 (2009-11-01), GB, pages 42 - 47, XP055444144, ISSN: 1748-3387, DOI: 10.1038/nnano.2009.314 *
HAMZAH ET AL., PROC NATL ACAD SCI USA, vol. 108, 2011, pages 7154 - 7159
HATCHER ET AL., FUTURE MEDICINAL CHEMISTRY, vol. 1, 2009, pages 1643 - 1670
HE ET AL., SCI REP, vol. 3, 2013
HELDIN ET AL., NAT REV CANCER, vol. 4, 2004, pages 806 - 813
HOCKETT ET AL., ENVIRON TOXICOL CHEM, vol. 15, 1996, pages 1687 - 1693
JIANG ET AL., PROC NATL ACAD SCI, vol. 101, 2004, pages 17867 - 17872
JOKERST ET AL., NANOMEDICINE, vol. 6, 2011, pages 715 - 728
KAZUKI N. SUGAHARA ET AL: "A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis", JOURNAL OF CONTROLLED RELEASE, vol. 212, 1 August 2015 (2015-08-01), NL, pages 59 - 69, XP055444180, ISSN: 0168-3659, DOI: 10.1016/j.jconrel.2015.06.009 *
KOIVUNEN ET AL., JBIOL CHEM, vol. 268, 1993, pages 20205 - 20210
LI ET AL., CANCER RES, vol. 42, 1982, pages 999 - 1004
LI-HUA JIN ET AL: "Ultrasensitive and Selective Fluorimetric Detection of Copper Ions Using Thiosulfate-Involved Quantum Dots", ANALYTICAL CHEMISTRY, vol. 86, no. 15, 5 August 2014 (2014-08-05), US, pages 7209 - 7213, XP055444667, ISSN: 0003-2700, DOI: 10.1021/ac501515f *
LIU ET AL., ADV FUND MATER, vol. 26, 2016, pages 267 - 276
MAEDA ET AL., INT IMMUNOPHARMACOL, vol. 3, 2003, pages 319 - 328
MANN ET AL., NATURE COMM., vol. 7, 2016, pages 11980
MENGXIAO YU ET AL: "Clearance Pathways and Tumor Targeting of Imaging Nanoparticles", ACS NANO, vol. 9, no. 7, 28 July 2015 (2015-07-28), US, pages 6655 - 6674, XP055444153, ISSN: 1936-0851, DOI: 10.1021/acsnano.5b01320 *
MITCHEM ET AL., CANCER RES, vol. 73, 2013, pages 1128 - 1141
NOMURA ET AL., JNUCIMED, vol. 55, 2014, pages 845 - 851
PANG ET AL., J CONTROL RELEASE, vol. 175, 2014, pages 48 - 53
PANG ET AL., NAT COMMUN, vol. 5, 2014, pages 4904
PASCH ET AL., KIDNEY INT, vol. 74, 2008, pages 1444 - 1453
RAJOTTE ET AL., J CLIN INVEST, vol. 102, 1998, pages 430 - 437
S. NOMURA ET AL: "PET Imaging Analysis with 64Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model", THE JOURNAL OF NUCLEAR MEDICINE, vol. 55, no. 5, 1 May 2014 (2014-05-01), US, pages 845 - 851, XP055444159, ISSN: 0161-5505, DOI: 10.2967/jnumed.113.131797 *
SANTNER ET AL., BREAST CANCER RES TR, vol. 65, 2001, pages 101 - 110
SIMON-GRACIA ET AL., BIOMATERIALS, vol. 104, 2016, pages 247 - 257
SUGAHARA ET AL., CANCER CELL, vol. 16, 2009, pages 510 - 520
SUGAHARA ET AL., J CONTROL RELEASE, vol. 212, 2015, pages 59 - 69
SUGAHARA ET AL., SCIENCE, vol. 328, 2010, pages 1031 - 1035
SUGARBAKER ET AL., CANCER TREAT REV, vol. 48, 2016, pages 42 - 49
TAVITIAN ET AL.: "Textbook of in vivo Imaging in Vertebrates", 2007, JOHN WILEY & SONS, LTD.
TEESALU ET AL., FRONT ONCOL, vol. 3, 2013, pages 216
TEESALU ET AL., PROC NATL ACAD SCI USA, vol. 106, 2009, pages 16157 - 16162
TEESALU ET AL., PROC NATL ACAD SCI, vol. 106, 2009, pages 16157 - 16162
WEGNER ET AL., CHEM SOC REV, vol. 44, 2015, pages 4792 - 4834
WU ET AL., EXPERT OPIN DRUG MET, vol. 9, 2013, pages 1265 - 1277
XIANGYOU LIU ET AL: "In vivo cation exchange in quantum dots for tumor-specific imaging", NATURE COMMUNICATIONS, vol. 8, no. 1, 24 August 2017 (2017-08-24), XP055444196, DOI: 10.1038/s41467-017-00153-y *
YERRAM ET AL., CLIN JAM SOC NEPHRO, vol. 2, 2007, pages 258 - 263
YIN ET AL., CHINESE PHYS B, vol. 21, 2012, pages 116101
ZHANG ET AL., BIOMATERIALS, vol. 34, 2013, pages 3639 - 3646
ZHANG Y ET AL: "Improving the visualization of fluorescently tagged nanoparticles and fluorophore-labeled molecular probes by treatment with CuSO4 to quench autofluorescence in the rat inner ear", HEARING RESEARCH, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 269, no. 1-2, 1 October 2010 (2010-10-01), pages 1 - 11, XP027261278, ISSN: 0378-5955, [retrieved on 20100724] *
ZONGHAI SHENG ET AL: "Cation exchange in aptamer-conjugated CdSe nanoclusters: a novel fluorescence signal amplification for cancer cell detection - Supporting information", CHEMICAL COMMUNICATIONS, vol. 48, no. 35, 1 January 2012 (2012-01-01), pages 4202, XP055444205, ISSN: 1359-7345, DOI: 10.1039/c2cc00033d *
ZONGHAI SHENG ET AL: "Cation exchange in aptamer-conjugated CdSe nanoclusters: a novel fluorescence signal amplification for cancer cell detection", CHEMICAL COMMUNICATIONS, vol. 48, no. 35, 1 January 2012 (2012-01-01), pages 4202 - 4204, XP055444208, ISSN: 1359-7345, DOI: 10.1039/c2cc00033d *
ZRAZHEVSKIY ET AL., NAT COMMUN, vol. 4, 2013, pages 1619

Cited By (2)

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CN114045168A (zh) * 2021-11-19 2022-02-15 复旦大学 一种水溶性合金量子点纳米酶及其制备方法和应用
CN114045168B (zh) * 2021-11-19 2023-09-05 复旦大学 一种水溶性合金量子点纳米酶及其制备方法和应用

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