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WO2018150362A1 - Préparations de nanoparticules magnétiques pour l'administration ciblée de médicaments aux poumons pour traiter des maladies pulmonaires - Google Patents

Préparations de nanoparticules magnétiques pour l'administration ciblée de médicaments aux poumons pour traiter des maladies pulmonaires Download PDF

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Publication number
WO2018150362A1
WO2018150362A1 PCT/IB2018/050952 IB2018050952W WO2018150362A1 WO 2018150362 A1 WO2018150362 A1 WO 2018150362A1 IB 2018050952 W IB2018050952 W IB 2018050952W WO 2018150362 A1 WO2018150362 A1 WO 2018150362A1
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Prior art keywords
nanoparticie
biocompatible
irinotecan
core
lung
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PCT/IB2018/050952
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English (en)
Inventor
Marina RAJADURAI
Pushkar KULKARNI
Aarti SEVILIMEDU
Uday Saxena
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Vegrandis Therapeutics Pvt. Ltd.
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Publication of WO2018150362A1 publication Critical patent/WO2018150362A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • 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
    • 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
    • A61K33/244—Lanthanides; 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
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application provides a nove nanoparticle that can selectively deliver therapeutic compounds to the lungs.
  • the particle also contains magnetic moieties so that the drug can be retained longer In t e lungs by use of arc external magnet.
  • This nanoparticle can be used for treatment of lung cancer and other diseases such as as hma, COPD, pneumonia, cystic fibrosis and TB that require delivery of therapeutics directly to lung.
  • cytotoxic drugs since they do not differentiate between cancel cells and normal healthy cells thus killing ail ceils that come in contact with them. As a result of which there Is collateral damage to several tissues along with the tumour resulting in adverse side effects.
  • Cytotoxic drugs such as Irinotecan are first line therapy for most cancers since they are effective across a variety of cancers. If they are ineffective then second tine or additive therapy is more personalized treatment with mutation specific monoclonal antibodies.
  • the other benefit of cytotoxic drugs is that they are cost-effective relative to the tailored monoclonal antibodies by a significant factor of tenfold or so.
  • One way to make these dru s more effective and reduce their side effects Is to target them largely to the organ that Is afflicted with cancer while sparing other organs and tissues.. There have been attempts to do this using ligands attached to drugs that could bind to counter receptors on the tissues of interest [See Btocanjugate Chem, 2010., 21(5 ⁇ t 979—987 ] .
  • Lung is the most vascularised organ in the body with capillaries extensively formed for the exchange of oxygen. Almost 70 to 80 of the blood vessels in th body are present in the lung. Because exchange of gases is the major function of the lung, the endothelial lining of the Sung capillaries is the thinnest of all organs to allow for crossing over of the gasses. The endothelium is lined richly with negatively charged heparin sulfate proteoglycans.. One of the functions they serve binding of positively charged growth factors, matrix protein and certain enzymes.
  • heparin sulfate proteoglycan Once a molecule is bound to to the surface heparin sulfate proteoglycan, It usually undergoes transcytosis and is transferred across the endothelium as an intact molecule. Keeping this in view, Applicants have devised a new delivery vehicle that targets drug delivery to the king.
  • Figure I Transmission electron micrograph of a iron Oxide flO ⁇ magnetic anopartlcles; b) PEGyiated Irinotecan loaded 10 nanopartlcles; c) double PEGyiated irinoteean loaded rtanoparticles and their corresponding size distribution (d,e,f). According to this data, the size of the nartoparticles even after incorporation of the second layer of PEG increased only by 2-3 ran in average, and diameter was in the range of 10-16 nm.
  • Figure 5 Solutions of VT-287 in PBS buffer; A-3.125 mg in 0,5 ml of lysine solution injected: to 1 mi PBS buffer - 0.25 mg ml; 8-3.125 mg in 0,5 ml of lysine solution injected: to 2.5 ml PBS buffer; C- 6.25mg in 0.5 ml of lysine solution injected to 1 ml PBS buffer - 0.5 mg ral; D- 6.25 mg in 0.5 ml of lysine solution injected to 2.5 ml PSS buffer.
  • FIG. 10 a) Tissue distribution of irinotecan after a single dose administration, in Satb/c mice, irinotecan concentration in plasma and tissue samples are reported; b) Comparative lung concentration of Irinotecan from VT-287 vs. free irinotecan after a single dose administration in Baib/c mice.
  • Figure IS Effect of VT-287 and irinotecan on ceil proliferation in lung cancer celt line MO- H129S i SCLCi.
  • Figure IS Effect of VT-287 and irinotecan on ceil proliferation in NCJ-H69ceil line.
  • the present invention delivers positive charge coated nanoparti ies containing active pharmaceutical ingredient, Irinotecan as an example, to the densely populated capillary endothelium in the lung.
  • the present invention provides a nanoparticle or nanoparticle aggregate com rising a) s core comprising ferromagnetic material; b) a double layer of biocompatible shell
  • the surface of the rjanopartlcie is coated with positively charged amino acids such as lysine bound to the surface by ionic bonds.
  • the positive charge on surface allows the nanoparticle to engage with the heparin sulfate moiety on the endothelium, i another embodiment, the invention provides momentary interaction allowing transcytosis of the nanoparticle across the endothelium into the lung space/cells. Since lungs have the most amount of capillaries this mechanism allows the nanoparticle to be delivered predominantly to the lungs and not to other orga ns...
  • the nanopa lcie is biocompatible.
  • the nanopartfcSe in another embodiment, can be used singly or as an aggregate of nanopartlcles.
  • the nanoparticle aggregate can be activated and used similar to that of single nanoparticle.
  • the nanoparticle Is essentially spherical, circular or round in shape and the outer diameter of the rtanoparticle Is In the range of ⁇ nra to SGnm.
  • the biocompatible shell of the nanoparticle has an outer diameter of 10- 65nm, preferably
  • the biocompatible shell is made of a material selected from the group consisting of PEG, polyethylene oxide) oligomer or polymer, po!yeaprolactone, pofylactide, potygiycoiide, and copolymers thereof, polyoxypropyiene, poiyoxyethylene-polyoxypropyiene dibiock, polyoxyethyêt-polyoxypropylene-poiyoxyethyEene triblock, and any mixture thereof, arranged into two layers.
  • Th ferromagnetic core material is selected from the group consisting of Iron, nickel, cobalt, gadolinium, samarium, neodymium, boron, aluminium or a mixture thereof.
  • the ferromagnetic core material is an oxide, an hydroxide or a meta!.
  • the nanoparticle comprises a targeting moiety attached via noi covalent or covalent interactions to the polymeric material of the biocompatible shell of the nanoparticle.
  • the targeting moiety of nan apart! die comprises a materia! selected: from the group consisting of negatively charged amino acid., such as aspart c acid or glutamic add, oligomers, or polymers and combination) thereof,
  • the nanopartide of the Invention is used for delivery of any therapeutic that needs to target the lung.
  • the nanopartide of the invention intends to deliver therapeutic to lungs, in conditions including but not. limited to cancer, specially Jung cancer, lung infection,, cystic fibrosis, lung edema,, asthma, pneumonia and COPO.
  • the therapeutic or drug or the compound of interest, for example a cancer dierootherapeutic is incorporated into the nanopartide via covsient or non-covalent interaction.
  • the nanopartide serves as a delivery platform, i can be loaded with other drugs that are required to act primarily in the lung.
  • the same nanopartide formulation cars be used to deliver any other cancer therapeutic induding but not limited to cytotoxic drugs, antibodies, protein and nucleic acid based treatments.
  • the nanop rtide of the invention is used to treat other lung diseases such as but not limited to asthma,. COPD, pneumonia, cystic fibrosis and tuberculosis, more effectively,
  • VT-287 the nanopartide presented as a example in the current specification, is composed of a self-contained nanopartide core, loaded with the drug Irinotecan. This allows for the nanopartide care of VT-287 to serve as a deiivery platform to deliver drugs other than
  • Magnetic field source Is generally used for triggering or generating therapeutic activity, in this context, the nanopartide of the invention along with the targeting agent: is used in combination with an external magnetic field in order to be able to retain the said nanoparttde in the lungs upon use of an external magnet.
  • the magnetic field source is selected from electromagnet or magnetic resonance imaging (MR!) equipment.
  • the invention also encompasses a: process of drug loading, involving attachment of the selected drug to the biocompatible polymeric shelf of the nanoparticie via non-covalent or covalent Interactions and includes double PEGylatksn/ double drug loading process.
  • Magnetic nanoparttcles (MPs) we e prepared using modifsed co -precipitation method according to published procedures fSee British Journal of Cancer, 2016, 114, 362—367; Journal of Science and Heakk at The University of Alabama, 2010, 7,. 16-18] .
  • Ferrous chloride tetrahydrate ⁇ FeCla .4HaO (99.4 mg in 9.2 ml of water) were dissolved in deoxygenated nano-pure water at 50 °C under nitrogen, using magnetic stirrer (the reaction performed In 2-necfe 250 ml RB, equipped with magnetic bar, nitrogen pipe-line with needle placed inside solution, and nitrogen balloon on the top). After all salts are dissolved, sodium hydroxide solution (NaOH, 2,5 M, prepared as 1,5 g dissolved In 15ml) was added drop-wise into the reaction mixture with vigorous stirring, until the pH value reached 9 (initially added 1.5 ml, checked pH, then added required amount, usually approx. another 0.5 ml, checking pH often).
  • the solution was stirred for 30 min at 50 °C under nitrogen, the magnetic nanoparti les were collected by magnetic field separation (using small magnet placed close to an R8 followed by decanting the solution), washed one time with diluted HCI solution ⁇ one drop of HCI in 5 ml of water) to reach pH 7, then washed 4-5 times wit h 20 ml of deionezedi water.
  • Wet NPs were subjected directly to the next step of PEGylation without drying.Tbe process yi lds '""160 mg of dry NPs.
  • nanoparttdes prepared thus we investigated by the ' Tra mtesim. El&cXmn Microscopy (Tecnai GZFEi F12 transmission electron microscope ( E ⁇ ?) at a ' accelerating voltage of 120 kV-j, the TEM data. showed that nanoparti es -are mono-dispersed with size In range of 8+2 nm ( Figure ia, d,)
  • Th P were transferred back into 250 ml R8, SB mi of pyre water was added, arscl stirred at . RT for ' -10 mm ' -under mtra-gen atmosphere. The water In the reaction mixture was replaced with pure water and this step was repeated -two more times, so as to. remove excess free P E3 ⁇ 43 completely from the $Fs.
  • the magnetic bar was removed from: the reaction mixture, wate was decanted using external magnet,, the slightly wet MPs were shifted to a Petri dish and dried at 40 * C under nitrogen for 24 h or lyophifized fat -SO'C, overnight!.
  • A. Primary drug loading: 6 rng of irinotecan-HCl tri ydrate was dissolved in 3ml of nanopu e water; then 3 mg of PEGyiated NPs were dispersed n the same solution with magnetic stirring at R.T. The solution was stirred far 120h ⁇ 5 days; measured absorfoance using UV spectrophotometer at 0 and 5 days or checking drug loading by LC-MS-MS). After 120h drug loaded NPs were washed 2 times with cold (T 1-5°C ⁇ lysine solution ⁇ i gfml, 2ml each . , 4 times shake sidewise), and a solvent was removed with syringe using magnet to keep MiPs aside.
  • TEM tudy of VT-287 shows size in range of 10-16 nm ⁇ Figure lc, f.J. .According to this da a, the size of the nanoparticles after incorporation of the second layer of PEG Increased only by 2-3 rsm in average. Drug loading percentage wasl-4%, measured using LC-MS-MS, Zeta potential was found to be -I8.5Mv. Table 1 further provides the characterization data. Table 1, Characterization of FT-287 ' fonnutati&n
  • nanopartides VT-287 were dispersed in water with or without lysine (1 rog mi) a d dried using speedvac for 15 h, then dry nan op articles VT-287 were re-dispersed: In water and pictures were taken: at 0 min, 5 mm and 10 mm after dispersion, i troduction of positively charged amino acid lysine f physical interaction) prior to drying step helps to prevent aggregation (solutions B), At the same time chemical conjugation of lysine molecules to VT-287 nanopartides did not help to prevent aggregation after drying step.
  • the reason for this is that when lysine is cova!entiy conjugated with the nanopartie!e, the amino groups in: lysine are engaged in the conjugation and as such the nanopartide is no longer positively charged.
  • Solutions of nanopartides VT-287 treated with lysine were stable in PBS buffer for more than 2hrs ⁇ at different concentrations) and: complete precipitation was observed at 6 hrs at room temperature ⁇ Figure 5).
  • Irinotecan in VT-287 was found to be 3 % ⁇ , 10 ⁇ ! of lysine buffer stock was spiked Into 1 ml of human plasma. The samples were incubated at 37-C for 24hr, with shaking at 400 rpm. At Q.0G, 0.25,. 0.5, 1.00, 2.00 and 24 hr, an aliquot of 100 pi sample were removed.
  • test Item VT-287 at 5 ⁇ (equivalent concentration of Irinotecan) was prepared by spiking 80 ⁇ of 0.5 mM lysine buffer stock (Irinotecan equivalent
  • test item Irinotecan hydrochloride trihydrate at 5 ⁇ was prepared by spiking 8 ⁇ of 5 mM DMSO stock to 7992 ⁇ of MCD& 131 media ⁇ with serum).
  • VT-287 Dose formulation analysis was performed on the batch of VT-287 used for the study and Irinotecan loading was determined to be 0.97% and this data was used to calculate Irinotecan-equivended concentration of VT-287 for the experiments.
  • the dosing solutions of test items were added to HuLEC-5a cell monolayers end incubated for specified incubation period ⁇ 15 min and 2 hour individually, with or without a magnet under the cell culture plate) at 37 ⁇ 1 S C with 5 ⁇ 1 % &3 ⁇ 4 using a G3 ⁇ 4 incubator.
  • VT-287 was tested at 5 ⁇ test concentration ⁇ equivalent concentration of Irinotecan).
  • tissue samples were collected by retro-orbital puncture method using capillary tubes into pre- labeled tubes containing anticoagulant K2E0TA; 2 mg mi blood J during the next 4 hours of post-dose.
  • blood collection animals were euthanized and the organs under study were collected, blotted, weighed and transferred into pre-ia elted containers.
  • the tissue samples were added to 1 ml deio ized water and homogenized by using T10 basic homogenizer ULTRA-TURRAX*) on ice, After homogenization samples were stored at -80 ⁇ 5 -C until analysis. Concentrations of the analyte irinotecan and active metabolite (SM-3S) in tissue samples were determined by using API 3200 Q-trap LC-MS-MS system, after
  • irinotecan gets metabolized Into 5 38 in viva and this conversion is essential for the potent cytotoxicity of irinotecan against cancer cells.
  • the mouse studies were carried out as described in the previous section. Concentrations of the anaiyte Irinotecan and active metabolite (SN-38) in tissue samples were determined by usin API 3200 Q-trap LC-MS-MS system, after homogenization.
  • the first group animals received the VT-2S7 test Item in a solution form containing 0.05 % (w/v) of lysine buffer ⁇ 0,5 mg equivalent to Irinotecan Hydrochloride); the second group animals received VT-287 test item In a solution form containing 0.05 % (w/v) of l sin buffer ⁇ 0.5 mg equivalent to Irinotecan Hydrochloride) under influence of magnet and the third group animals received plain Irinotecan In a solution form containing 100 % (w/ ) of Sterile Water for injection.
  • Rabbit were restrained and blood samples were collected by auricular artery puncture method using 21 - 22 gauge needle with a syringe Into pre- labeled tubes containing anticoagulant ( 2 EDTA; 2 mg/rnl blood) during the next 0.5 hours of post-dose. After blood collection animals were euthanized by over dose of Sodium thiopental; and lung and brain samples were collected, blotted, weighed and t ransferred into pre-iabeled contalners.Concentrations of the anaiyte Irinotecan and active metabolite (SM-38) in tissue samples were determined by using API 3200 Q-trap LC-MS-MS system., after homogenization.
  • Irinotecan There Is 5-7 fold more SN-38 in the lung in the case of VT-287 as compared to Irinotecan administration:.
  • SN-38 is undetectable in the lung tissue upon administration of Ct-Srrtg/kg of rtakedirinotecan.
  • VT-287 a significant concentration of S -38 is detected in the lung, suggesting an improved, specific delve y to this tissue by the formulation.
  • Test compound VT-287 and irinotecan hydrochloride trihydrate were added to the cells at: 0.781, 1.562, 3,125, 6.25, 12.5, 25.0, 50.0 and 100 ⁇ cone, along with controls (0.1% DMiSO and 0.05 mg/rrsi of lysine) in triplicates/concentrations and incubated at 37 e C, 5% CQ2 for 96 hours.
  • Cell viability assay was performed using Afamar blue (resaiurin).
  • VT-287 showed a dose dependent Inhibition of ceil proliferation and results were comparable to Irinotecan after 96 hours of Incubation, NCI-H1293 f SCLC
  • VT-287 is a stable narto-formulation that Is able to transport and deliver Irinotecan So its active form.
  • the physical properties of VT-287 we believe, prevent aggregation in solution, and the novel idea of coating the nanc-parti e with: positively charged lysine facilitates interaction with specific DCi-surf ce receptors thus leading to targeted delivery and permeability in lungs .
  • cytotoxic drug irinotecan is merely a representative example to establish the efficacy of the nanopartide as delivery platform and it can be extended to other therapeutics and disease conditions as described In this specification
  • the data is merely representative and anno be construed to be limiting the i ven io In any way.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Physics & Mathematics (AREA)
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  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Les médicaments cytotoxiques tels que l'irinotécan sont utilisés en tant que premier niveau de traitement pour de nombreux cancers. Les médicaments cytotoxiques sont très efficaces pour détruire les cellules tumorales mais ont un effet indésirable en ce qu'ils détruisent également les cellules saines normales. D'autre part, même si les médicaments pénètrent dans un tissu, ils peuvent être transportés à l'extérieur par des protéines de transport des cellules, provoquant une diminution de leur concentration au fil du temps, ce qui conduit à une perte d'efficacité. Une façon d'augmenter leur efficacité et de diminuer leurs effets indésirables est de les orienter sélectivement vers l'organe ou tissu contenant le cancer. Nous avons conçu une nouvelle nanoparticule qui peut administrer de l'irinotécan sélectivement aux poumons. Ladite nanoparticule contient également des molécules de fer ce qui permet de retenir le médicament plus longtemps dans les poumons, au moyen d'un aimant externe. Cette nanoparticule peut être utilisée pour le traitement du cancer du poumon et autres maladies pulmonaires.
PCT/IB2018/050952 2017-02-16 2018-02-16 Préparations de nanoparticules magnétiques pour l'administration ciblée de médicaments aux poumons pour traiter des maladies pulmonaires WO2018150362A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117887661A (zh) * 2023-05-25 2024-04-16 南昌大学第二附属医院 一种用于富集肺癌循环肿瘤细胞的磁分离方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035113A1 (fr) * 2001-10-26 2003-05-01 Berlin Heart Ag Nanodispersion magnetique comprenant des cyclodextrines et procedes pour la produire
WO2007118884A1 (fr) * 2006-04-19 2007-10-25 Nanobiotix Compositions de nanoparticules magnetiques et leurs utilisations
US20130302252A1 (en) * 2012-05-11 2013-11-14 University Of Washington Through Its Center For Commercialization Polyarginine-coated magnetic nanovector and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035113A1 (fr) * 2001-10-26 2003-05-01 Berlin Heart Ag Nanodispersion magnetique comprenant des cyclodextrines et procedes pour la produire
WO2007118884A1 (fr) * 2006-04-19 2007-10-25 Nanobiotix Compositions de nanoparticules magnetiques et leurs utilisations
US20130302252A1 (en) * 2012-05-11 2013-11-14 University Of Washington Through Its Center For Commercialization Polyarginine-coated magnetic nanovector and methods of use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117887661A (zh) * 2023-05-25 2024-04-16 南昌大学第二附属医院 一种用于富集肺癌循环肿瘤细胞的磁分离方法

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