KR101775141B1 - Nano probe for diagnosing and treating cancer - Google Patents
Nano probe for diagnosing and treating cancer Download PDFInfo
- Publication number
- KR101775141B1 KR101775141B1 KR1020150058931A KR20150058931A KR101775141B1 KR 101775141 B1 KR101775141 B1 KR 101775141B1 KR 1020150058931 A KR1020150058931 A KR 1020150058931A KR 20150058931 A KR20150058931 A KR 20150058931A KR 101775141 B1 KR101775141 B1 KR 101775141B1
- Authority
- KR
- South Korea
- Prior art keywords
- nanoparticles
- independently
- cancer
- group
- ppds
- Prior art date
Links
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
Abstract
The present invention relates to a nanoprobe for diagnosing and treating cancer, wherein the nanoprobe for cancer diagnosis and treatment comprises nanoparticles comprising a conjugated polymer substituted with a hydrophilic substituent, and an antibody bound to the surface of the nanoparticle.
The nanoprobes for diagnosis and treatment of cancer are self-doped even in a neutral environment, so that they have a high electrical conductivity even in a neutral environment such as in a living body, can have high absorption characteristics in the near infrared region, can be targeted specifically to cancer cells, And it is also possible to perform specific treatment of cancer cells by the light heat effect by laser irradiation.
Description
More particularly, the present invention relates to a nanoprobe for cancer diagnosis and treatment, which is self-doped even in a neutral environment, has high electrical conductivity even in a neutral environment such as in a living body, can have a high absorption characteristic in a near infrared region, It is possible to diagnose cancer cells by performing specific targeting, and specific treatment of cancer cells is also possible by the photothermal effect of laser irradiation.
Recent advances in nanotechnology have contributed to the development of a new field of cancer therapy called nanomedicine. By developing the various functions of nanoparticles through the adjustment of the size between 10 and 200 nm, nanopharmaceutical technologies offer several advantages over traditional treatment methods.
Most importantly, it must be successful in transferring to a circulating machine with a functionally appropriate size and surface. That is, the circulation time in the blood must be prolonged and the reabsorption to the reticuloendothelial system should be reduced and targeted to the tumor functionally.
Nanoparticles should also be capable of incorporating into more than one functional moiety, which should include the therapeutic agent and the material that makes up the shape. Achieving multiple objectives with this single particle is leading to a new cancer treatment strategy called theragnosis.
TerraGinosis is an integrated strategy to develop therapeutic and diagnostic functions efficiently and reliably for individual tumor treatments. This strategy suggests the ability to visualize the size, location, and activity of tumors and the ability to treat the local area by instantly diagnosing some of them. Therefore, it shows the same promise of opening a new chapter of personalized drug that has emerged recently. This is because clinicians can quickly determine whether treatment strategies are effective for individual patients.
Various sets of diagnostic aspects are obtained using non-invasive tumor imaging techniques including MRI, X-ray tomography, ultrasound, and the like. Among them, MRI is the most clinically used technology because of its ability to provide the best spatial resolution and detailed anatomical information. For example, drugs have been loaded into magnetic nanoparticles, developed for teraginosis of breast cancer, and pH-sensitive drug-transporting nanoparticles have been developed as teragnosys protypes of efficient tumor therapy by molecular imaging. However, when all the drug is released, the nanoparticles lose their therapeutic activity and require additional doses until the tumor is reduced.
On the other hand, in the magnetic resonance imaging apparatus widely used for cancer diagnosis, diagnosis has been made using the T2 imaging method. However, this diagnostic method shows the disappearance of the signal caused by the RF frequency, so the image appears black and there is no better contrast effect than the T1 contrast method. In addition, the high sensitivity of the contrast agent used in the T2 imaging method has the disadvantage that distortion and noise are generated in the surrounding tissue. Therefore, there is a growing interest in T1 contrast without any distortion of the surrounding tissue, and many T1 contrast agents have been developed (see
However, in the case of conventional T1 contrast agent, the r1 value is low, and a large amount of contrast agent is needed for clinical use. Because large amounts of contrast agents can cause toxicity in the body, it is essential to develop high sensitivity contrast agents that exhibit high efficiency even at low concentrations.
In addition, in the case of a general magnetic resonance imaging contrast agent, most of the metal ions are bound to the surface of the particle, and in the case of such a contrast agent, there is a problem that the delivery rate and the amount of the metal ion are inferior (see Non-Patent Documents 9 and 10). These metal ions are not biodegradable and exist in the body for a long time, which causes toxicity.
Accordingly, an object of the present invention is to provide a method for detecting cancer cells, which can be self-doped even in a neutral environment, has a high electrical conductivity even in a neutral environment such as in vivo, has a high absorption characteristic in the near infrared region, And to provide a nanoprobe capable of specifically treating cancer cells by the photothermal effect of laser irradiation.
It is another object of the present invention to provide a composition for diagnosis and treatment of cancer including the above-mentioned nano-probe for cancer diagnosis and treatment, and a kit for diagnosis and treatment of cancer.
In order to achieve the above object, a nanoprobe for cancer diagnosis and treatment according to an embodiment of the present invention includes nanoparticles including a conjugated polymer substituted with a hydrophilic substituent, and an antibody bound to the nanoparticle surface.
The hydrophilic substituent may be any one selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH, OH, and combinations thereof.
The nanoparticles may be self-doped by the hydrophilic substituent.
The nanoparticles can be self-doped by the hydrophilic substituents at pH 1-8.
The nanoparticles may have an absorption in a wavelength region of 600 to 1100 nm by the self-doping.
The nanoparticles may have a particle diameter of 1 to 500 nm.
The conjugated polymer may be selected from the group consisting of polyacetylene, polyaniline, polypyrrole, polythiophene, poly (3,4-ethylenedioxythiophene), poly (3,4-propylene dioxythiophene) , Poly (1,4-phenylenevinylene), poly (1,4-phenylenesulfide), poly (1,4-phenylenevinylene) Poly (fluorenyleneethynylene)), derivatives thereof, and mixtures thereof.
The conjugated polymer substituted with the hydrophilic substituent may be represented by the following general formula (1) or (2).
[Chemical Formula 1]
(2)
(Wherein A 1 and A 2 are each independently any hydrophilic substituent selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH and OH, and B 1 And B 2 are each independently represented by (CH 2 ) a - (X 3 ) b - (CH 2 ) c , wherein X 1 to X 3 are each independently selected from the group consisting of O, S and NR ' And R 1 , R 2 and R 'are each independently hydrogen or an alkyl group, l 1 and l 2 are each independently an integer of 4 to 5000, and m 11 , m 21 and m 22 are Independently, an integer of 1 to 5, and each of n 11 , n 12 , n 21 and n 22 is independently an integer of 0 to 5, and each of a to c is independently an integer of 0 to 5)
The composition for cancer diagnosis and treatment according to another embodiment of the present invention includes the nanoprobes for cancer diagnosis and treatment.
The composition for diagnosing and treating cancer may further comprise a pharmaceutically acceptable carrier.
The kit for cancer diagnosis and treatment according to another embodiment of the present invention includes the composition for diagnosing and treating cancer, and a device for irradiating a light beam in a wavelength range of 600 to 1100 nm.
The light beam may be a laser beam.
The nanoprobe for cancer diagnosis and treatment of the present invention is self-doped even in a neutral environment, has high electric conductivity even in a neutral environment such as in a living body, can have a high absorption characteristic in the near infrared region, can be specifically targeted for cancer cells Cancer cells can be diagnosed, and specific treatment of cancer cells is possible by the photothermal effect of laser irradiation.
In addition, the nanoprobes for diagnosis and treatment of cancer do not contain metal particles and are biocompatible. As compared with the metal particles, the conjugated polymers that are organic polymers are much more economical and mass-production is possible.
FIG. 1 (a) is a schematic view showing a method for preparing CD44-targetable PPDS nanoparticles prepared in the examples and a method for using the same in photothermal therapy.
Fig. 1 (b) is a graph showing the particle size distribution of CD44-targetable PPDS nanoparticles prepared in the examples and an atomic force microscope image. The accumulation is 500 nm.
FIG. 1 (c) is a graph showing the cyclic voltammogram of the CD44-targetable PPDS nanoparticles prepared in the examples. The cyclic voltammogram was measured on a ITO glass with a platinum wire in a H 2 O solution containing 0.1 M sodium chloride at a scan rate of 100 mV s -1 (measured in three cycles).
Figure 1 (d) is a photograph of the CD44-targetable PPDS nanoparticles prepared in the Examples, which were observed by darkfield microscopy. The accumulation is 100 탆.
FIG. 1 (e) is a graph showing the spectrum of the CD44-targetable PPDS nanoparticles prepared in the examples by X-ray photoelectron spectroscopy.
Fig. 1 (f) is a photograph showing the structure of self-doped PPDS nanoparticles prepared in the example.
FIG. 2 (a) is a graph showing the light heat rate according to the output density of the NIR laser of the CD44-targetable PPDS nanoparticles prepared in the example, and FIG. 2 (b) FIG. 5 is a graph showing temperature changes according to NIR laser irradiation. FIG.
FIG. 3 (a) is a graph showing the viability of MDA-MB-231 and MCF7 cells treated with the CD44-targetable PPDS nanoparticles prepared in the examples, and FIG. 3 (b) Lt; RTI ID = 0.0 > biosensitivity < / RTI > of PPDS nanoparticles. FIG. 3 (b) is a graph showing the relationship between the concentration of IL in the left side and the concentration of IL in the left side of the mice injected with phosphate-buffered saline (PBS; pH 7.4) and the mice injected with the CD44-targetable PPDS nanoparticles prepared in the above- -6 on the right, and TNF-α on the right.
Fig. 4 (a) is a photograph showing a mouse model of MDA-MB-231 transplanted xenotransplantation (above) and laser irradiation (below) for photothermal therapy.
Fig. 4 (b) is a NIR absorbed image of a mouse model (above) treated with the CD44 targetable PPDS nanoparticles prepared in the example and a rat model (below) treated with the CD44 target.
FIG. 4 (c) is a photon counts graph obtained from FIG. 4 (b).
4 (d) is a photograph and absorption image of the Tumor tissue extracted from the mouse model.
4 (e) is a photon counts graph of the Tumor, liver and brain tissue extracted from the mouse model.
Figure 4 (f) is an H & E stained image of a mouse model treated with the CD44 targetable PPDS nanoparticles prepared in the examples. The scale is 100 탆.
Figure 5 (a) is a photograph of the CD44-targetable PPDS nanoparticles prepared in the Examples.
Fig. 5 (b) is a photograph of a NIR laser (2.5 W cm < 2 & gt ; , 10 min) irradiated to a mouse model for the treatment of the CD44 targetable PPDS nanoparticles prepared in the Example.
5 (c) is a cross-sectional photograph and H & E staining image of a TIMER tissue after NIR laser irradiation on a mouse model with an HT1080 Tumor treated with the targetable PPDS nanoparticles prepared in the Example. In Fig. 5 (c), the upper column represents the region damaged by the laser, the middle column represents the boundary region, and the lower column represents the region not damaged by the laser. The scale is 40 탆.
The present invention is capable of various modifications and various embodiments and is intended to illustrate and describe the specific embodiments in detail. It is to be understood, however, that the invention is not to be limited to the specific embodiments, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In the present invention, the term "comprises" or "having ", etc. is intended to specify that there is a feature, number, step, operation, element, But do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or combinations thereof.
As used herein, the term "combination thereof" means that two or more substituents are bonded to each other through a single bond or a linking group, or two or more substituents are condensed and connected.
In addition, unless otherwise specified herein, the halogen atom means any one selected from the group consisting of fluorine, chlorine, bromine and iodine.
In addition, unless otherwise specified herein, alkyl groups include primary alkyl groups, secondary alkyl groups and tertiary alkyl groups.
In addition, unless otherwise specified herein, the alkyl group means an alkyl group having 1 to 10 carbon atoms, which is linear or branched.
In addition, unless otherwise specified herein, all compounds or substituents may be substituted or unsubstituted. The term "substituted" as used herein means that hydrogen is substituted with at least one substituent selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group, an amino group, a thio group, a methylthio group, an alkoxy group, a nitryl group, an aldehyde group, Substituted with any one selected from the group consisting of acetal, ketone, alkyl, perfluoroalkyl, cycloalkyl, heterocycloalkyl, allyl, benzyl, aryl, heteroaryl, .
The nanoprobe for cancer diagnosis and treatment according to an embodiment of the present invention includes nanoparticles including a conjugated polymer substituted with a hydrophilic substituent, and an antibody bound to the nanoparticle surface.
The hydrophilic substituent may be any one selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH, OH, and combinations thereof, preferably SO 3 - , PO 4 - , CO 3 - And a combination thereof. The SO 3 - , PO 4 -, and CO 3 - may be bonded to a cation such as sodium or the like, dissociated in solution, and may exist in an anion state as described above.
The nanoparticles may be self-doped by the hydrophilic substituent and have an absorption in a wavelength range of 600 to 1100 nm.
The nanoparticles can be self-doped at
As long as the conjugated polymer is self-doped by the hydrophilic substituent, the conjugated polymer having an absorption in a wavelength range of 600 to 1100 nm can be used without limitation in the present invention. The conjugated polymer does not exhibit extinction in the wavelength region outside the cell, so that only the cancer cells containing the intracellular dopant are specifically removed and the side effects are not caused in normal cells, blood vessels and the like. Therefore, in the existing photothermal therapy, it can be injected not only by direct administration of photothermic agent to cancer cells or cancer tissues but also by administration of blood vessel using an injection agent, and irradiation of light in a wavelength range of 600 to 1100 nm enables normal cells, Only cancer cells can be specifically removed.
The conjugated polymer may be selected from the group consisting of polyacetylene, polyaniline, polypyrrole, polythiophene, poly (3,4-ethylenedioxythiophene), poly (3,4-propylene dioxythiophene) , Poly (1,4-phenylenevinylene), poly (1,4-phenylenesulfide), poly (1,4-phenylenevinylene) Poly (fluorenyleneethynylene)), derivatives thereof, and mixtures thereof. However, the present invention is not limited thereto.
More specifically, the conjugated polymer substituted with the hydrophilic substituent may be represented by the following formula (1) or (2).
[Chemical Formula 1]
(2)
Wherein A 1 and A 2 are each independently any hydrophilic substituent group selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH and OH, preferably SO 3 - , PO 4 - and CO 3 - . In the case of SO 3 - , PO 4 - and CO 3 - , it is preferable that the conjugated polymer can be self-doped better than COOH and OH. The SO 3 - , PO 4 -, and CO 3 - may be bonded to a cation such as sodium or the like, dissociated in solution, and may exist in an anion state as described above.
Wherein B 1 and B 2 can each independently be represented by (CH 2 ) a - (X 3 ) b - (CH 2 ) c , wherein X 3 is selected from the group consisting of O, S and NR ' And each of a to c is independently an integer of 0 to 5. Specific examples of the B 1 and B 2 are each independently (CH 2) -O- (CH 2 ), (CH 2) -O- (CH 2) 2, (CH 2) -O- (CH 2 ) 3, (CH 2) 2 -O- (CH 2), (CH 2) 2 -O- (CH 2) 2, (CH 2) 2 -O- (CH 2) 3, (CH 2) 3 - O- (CH 2), (CH 2) 3 -O- (CH 2) 2, (CH 2) 3 -O- (CH 2) 3, O- (CH 2) 3, O- (CH 2), O- (CH 2) 2, ( CH 2) -O, (CH 2) 2 -O, (CH 2) 3 -O, (CH 2) -S- (CH 2), (CH 2) -S- (CH 2) 2, (CH 2) -S- (CH 2) 3, (CH 2) 2 -S- (CH 2), (CH 2) 2 -S- (CH 2) 2, (CH 2) 2 -S- (CH 2) 3, (CH 2) 3 -S- (CH 2), (CH 2) 3 -S- (CH 2) 2, (CH 2) 3 -S- (CH 2) 3 , S- (CH 2) 3, S- (CH 2), S- (CH 2) 2, (CH 2) -S, (CH 2) 2 -S, (CH 2) 3 -S, (CH 2 ) -NR '- (CH 2) , (CH 2) -NR' - (CH 2) 2, (CH 2) -NR '- (CH 2) 3, (CH 2) 2 -NR' - (CH 2 ), (CH 2) 2 -NR '- (CH 2) 2, (CH 2) 2 -NR' - (CH 2) 3, (CH 2) 3 -NR '- (CH 2), (CH 2) 3 -NR '- (CH 2) 2, (CH 2) 3 -NR' - (CH 2) 3, NR '- (CH 2) 3, NR' - (CH 2), NR '- (CH 2) 2, (CH 2) -NR ' , (CH 2) 2 -NR', (CH 2) 3 -NR ' or the like can, but this invention But it is not limited.
R 1 , R 2 and R 'are each independently hydrogen or an alkyl group, and may specifically be hydrogen, methyl, ethyl, propyl, n-butyl, isobutyl or tert-butyl.
The l 1 and l 2 may be appropriately adjusted according to the molecular weight of the conjugated polymer, and thus may be independently an integer of 4 to 5000.
M 11 , m 21 and m 22 are each independently an integer of 1 to 5, and n 11 , n 12 , n 21 and n 22 each independently may be an integer of 0 to 5. At this time, the 1≤n 11 + m 11 ≤4, 1≤n 21 + m 21 ≤2m can 22.
The nanoparticles including the conjugated polymer substituted with the hydrophilic substituent may have a particle diameter of 1 to 500 nm, preferably 100 to 200 nm. Nanoparticles having such a particle size can significantly reduce non-specific cellular uptake and accurately transmit the target cell. On the other hand, when the particle size of the nanoparticles exceeds 500 nm, the solubility is lowered due to the large particle size and the colloidal stability on the aqueous solution may be lowered.
In addition, an antibody capable of selectively targeting only specific cancer cells to the surface of the nanoparticles can be bound to the target cell. If the antibody is an antibody capable of targeting a specific cancer cell, any antibody conventionally used can be used and is not limited to the present invention. For example, the antibody may be selected from the group consisting of CD4, CD2, CD3, CD8, CD28, B7, ICAM-1, LFA-1, CTLA4Ig, CD9, CD10, CD13, CD44, CD54, CD73, CD90, CD105, CD117, CD146, CD166, antibodies to STRO-1, and the like.
In addition, the nanoparticles including the conjugated polymer substituted with the hydrophilic substituent may be substituted with a hydrophilic substituent such as carboxylmethyl polyvinyl alcohol, polyvinyl alcohol, polyacrylamide, polyethyleneimine, polyamidoamine, polyethylene glycol Or a surfactant such as polylactic acid, polyacrylic acid, polycaprolactone, polystyrene sulfonate, polyhydroxyethyl methacrylate, chitosan, polysorbate 80, polyvinyl sulfonic acid, dextran and the like, Can be dispersed well in an aqueous solvent.
The nanoprobe for cancer diagnosis and treatment includes a conventionally used lanthanide metal having an atomic number of 58 to 70 or a paramagnetic metal cation such as a cation of a transition metal having an atomic number of 21 to 29, 42 or 44 It is biocompatible and economical and mass production is possible as the conjugated polymers which are organic polymers are much cheaper than particles containing the metal cations.
The composition for cancer diagnosis and treatment according to another embodiment of the present invention includes the nanoprobe for cancer diagnosis and treatment.
The composition for diagnosing and treating cancer may further comprise a pharmaceutically acceptable carrier.
Such pharmaceutically acceptable carriers include carriers and vehicles commonly used in the medical field and specifically include ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances Water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide But are not limited to, silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose based substrate, polyethylene glycol, sodium carboxymethylcellulose, polyarylate, wax, polyethylene glycol or wool.
The composition for diagnosing and treating cancer may further include a lubricant, a wetting agent, an emulsifier, a suspending agent, or a preservative in addition to the above components.
In one embodiment, the composition for diagnosing and treating cancer may be prepared as an aqueous solution for parenteral administration, preferably a buffer solution such as Hank's solution, Ringer's solution or physically buffered saline solution. Solution may be used. Aqueous injection suspensions may contain a substrate capable of increasing the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.
Other preferred embodiments of the composition for the diagnosis and treatment of cancer may be in the form of sterile injectable preparations of sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e. G., Tween 80) and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (for example, a solution in 1,3-butanediol). Vehicles and solvents that may be used include mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally used as a solvent or suspending medium. For this purpose, any non-volatile oil including synthetic mono or diglycerides and less irritant may be used.
The kit for cancer diagnosis and treatment according to another embodiment of the present invention includes the composition for diagnosing and treating cancer, and a device for irradiating a light beam in a wavelength range of 600 to 1100 nm.
The composition for diagnosing and treating cancer is used for treating various diseases related to cancer such as gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, So that it can be included in a kit for cancer diagnosis and treatment.
The light beam is preferably a laser beam.
Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily carry out the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
[ Example : CD44 The targetable poly ( sodium3 - ((3- methyl -3,4- dihydro 2H-thieno [3,4-b] [1,4] dioxepin-3-yl) methoxy) propane-1-sulfonate (PPDS)
FIG. 1 (a) is a schematic view showing a method for producing CD44-targetable PPDS nanoparticles prepared in this embodiment and a method for using the same in photothermal therapy.
Referring to Fig. 1 (a), PPDS was synthesized by oxidative chemical polymerization. To enhance the hydrophilicity of Poly-ProDOT, a sultone group was added to the ProDOT monomer (3-methyl-3,4-dihydro- 2H- thieno [3,4-b] [1,4] dioxepin- ).
Subsequently, the modified monomer (ProDOT-sultone) was oxidatively polymerized. An excess of iron (III) chloride was used during the polymerization. The resulting PPDS had an oxidized state of 6.5 kDa by MALDI-TOF. The oxidized PPDS was redispersed in phosphate-buffered saline (PBS, pH 7.4) together with ultra-sonication (190 W), and unfused aggregates were removed by centrifugation (3,500 rpm, 10 min) To obtain a finely dispersed PPDS solution.
To prepare CD44-capable PPDS nanoparticles, PPDS dispersion (4 mg / mL, 1 mL) was mixed with 3 μl of anti-CD44 antibody solution (Cell Signaling Technology) and incubated at 4 ° C. for 4 hours. Unbound antibodies were removed by centrifugation. Finally, the reactants prepared were redispersed in PBS (1 mL, pH 7.4, 10 mM).
[ Experimental Example : Manufactured CD44 Targetable PPDS Measurement of properties of nanoparticles]
FIG. 1 (b) is a graph showing the particle size distribution of the CD44-targetable PPDS nanoparticles prepared in the above example and an atomic force microscope image. The accumulation is 500 nm. Referring to FIG. 1 (b), the prepared self-assembled amphipathic PPDS nanoparticle had a particle size of 182.9 ± 9.5 nm.
The PPDS nanoparticles prepared were stable and colloidal stability was maintained for 6 months without significant aggregation. The chemical structure of the PPDS nanoparticles was confirmed by Fourier transform infrared spectroscopy (FT-IR), and the S = O bond of the sulfonate group and the C = C bond of the conjugated polymer were observed at 1,191 and 1,537 cm -1 , respectively.
FIG. 1 (c) is a graph showing the cyclic voltammogram of the CD44-targetable PPDS nanoparticles prepared in the above example. The cyclic voltammogram was measured on a ITO glass with a platinum wire in a H 2 O solution containing 0.1 M sodium chloride at a scan rate of 100 mV s -1 (measured in three cycles). Referring to FIG. 1 (c), it can be confirmed that the self-doped PPDS has been successfully synthesized.
FIG. 1 (d) is a photograph of the CD44-targetable PPDS nanoparticles prepared in the above Example by darkfield microscopy. The accumulation is 100 탆. Referring to FIG. 1 (d), the surface of the PPDS nanoparticles is smooth and its size is constant.
FIG. 1 (e) is a graph showing the spectrum of the CD44-targetable PPDS nanoparticles prepared in the above examples by X-ray photoelectron spectroscopy. Referring to FIG. 1 (e), it can be confirmed that the zeta-potential of the PPDS is -29.6 ± 7.3 mV by the sultone group.
1 (f) is a photograph showing the structure of self-doped PPDS nanoparticles prepared in the above example. Referring to FIG. 1 (f) above, the SO 3 - group, which is a strong doping group, is substituted for the PPDS itself and has high NIR light absorption even at physiological pH levels (pH 7.4) because the PPDS is self-doped Able to know.
FIG. 2 (a) is a graph showing the photoheat rate depending on the power density of the NIR laser of the CD44-targetable PPDS nanoparticles prepared in the above embodiment, and FIG. 2 (b) Fig. 5 is a graph showing the temperature change due to NIR laser irradiation of the particles. Fig.
Referring to FIG. 2 (a), the photothermal properties of PPDS nanoparticles induced by NIR laser (808 nm) were measured at various output densities (0.5, 1.0, 2.0, and 5.0 W cm -2 ) The heating rate of PPDS nanoparticles (4 mg mL -1 , 1 mL) due to the light heat was 0.4 ° s -1 at an output density of cm -2 , and linearly increased with increasing output density.
2 (b), the temperature of the PPDS nanoparticles increased to 52 ° C. within 2 minutes at an output density of 5 W cm -2 , and the photothermal conversion efficiency (η) of the PPDS nanoparticles was 31.4% Respectively. It can be seen that the PPDS nanoparticles have excellent photo-thermal conversion efficiency as compared with those in which the photo-thermal conversion efficiencies of other conjugated polymers and gold nanoparticles are 13 to 40%.
In order to measure the light-heat chemotherapy ability of the nano particles, through the MTT assay (MTT assay) method were evaluated for breast cancer cells (MDA-MB-231 and MCF7 cells) in vitro (in vitro) viability.
FIG. 3 (a) is a graph showing the viability of MDA-MB-231 and MCF7 cells treated with CD44-targetable PPDS nanoparticles prepared in the above example, and FIG. 3 (b) Is a graph showing in vivo biocompatibility of targetable PPDS nanoparticles. FIG. 3 (b) is a graph showing the results of the blood drawn from the rats injected with phosphate-buffered saline (PBS; pH 7.4) and the rats injected with the CD44-targetable PPDS nanoparticles prepared in the above example IL-6, and on the right was the concentration of TNF-α.
Referring to FIG. 3 (a) and FIG. 3 (b), when two cell lines were treated with PPDS nanoparticles (up to 20 mg mL -1 ), the cells did not die and no decrease in cell proliferation was observed. This means that the PPDS nanoparticles are not toxic.
The PPDS nanoparticles in vivo ( in The concentration of IL-6 and TNF- [alpha] in the blood of the enzyme-linked immunosorbent assay and PPDS-treated rats was measured to investigate the vivo compliance and the inflammatory response. As a result, the CD44-targetable PPDS nanoparticles Were suitable for in vivo use.
Specifically, FIG. 4 (a) is a photograph showing a mouse model (top) of MDA-MB-231 transplanted with xenotransplantation and a laser irradiation (below) for photothermal therapy. As shown in FIG. 4 (a), targeted delivery of CD44-capable PPDS nanoparticles and photothermal therapeutic effect were measured using a tumor-bearing mouse model with a Timer.
4 (b) is a NIR absorption image of a mouse model (above) treated with CD44-targetable PPDS nanoparticles prepared in the above example and a mouse model (not shown) 4 (d) is a photograph and absorption image of the Tumor tissue extracted from the rat model, and FIG. 4 (e) is a photograph of the Tumor and liver extracted from the rat model And FIG. 4 (f) is a H & E staining image of a mouse model treated with the CD44-targetable PPDS nanoparticles prepared in the above example. The scale is 100 탆.
Referring to FIGS. 4 (b) to 4 (e), 30 minutes after injection of CD44-targetable PPDS nanoparticles into a rat model in which orthotopic xenografts of MDA-MB-231 were performed, A significant increase in NIR uptake was observed at the site. At this time, the NIR absorption was not significantly different from the NIR absorption of the CD44-targetable PPDS nanoparticle itself.
Referring to FIG. 4 (f), NIR imaging of the Tumor tissues and organs (liver and brain) extracted from the mouse model showed that the CD44-targetable PPDS nanoparticles exhibited Tumor target transfer. At this time, NIR laser (808 nm, 2.5 W cm -2 ) was irradiated to the Tumor site for 10 minutes.
In order to confirm the target transfer and the broad thermal effect of the CD44-targetable PPDS nanoparticles, in vivo photothermal effects were measured using the above-described method using an HT1080 cell (fibrosarcoma) expressing CD44.
FIG. 5 (a) is a photograph of a mouse model of the CD44-targetable PPDS nanoparticles prepared in the above example, FIG. 5 (b) is a photograph of the mouse model of the CD44-targetable PPDS nanoparticles prepared in the above- (2.5 W cm < -2 & gt ; , 10 min).
Referring to FIG. 5 (b), the NIR laser alone can not damage the Tumor site. However, referring to FIG. 5 (a), when the CD44-targetable PPDS nanoparticles and the NIR laser are combined, It can be seen that
FIG. 5 (c) is a cross-sectional photograph and H & E staining image of a TIMER tissue after NIR laser irradiation in a rat model with HT1080 Tumor treated with the targetable PPDS nanoparticles prepared in the above example. In FIG. 5C, the upper column represents a region damaged by a laser, the middle column represents a boundary region, and the lower column represents a region that is not damaged by a laser. The scale is 40 탆. Referring to FIG. 5 (c), it can be confirmed that the tumbler treated with the CD44-targetable PPDS nanoparticles was subjected to light heat damage. Therefore, it can be seen that the CD44-targetable PPDS nanoparticles can be stably applied in vivo as an optical teraginosse preparation.
Claims (12)
An antibody bound to the nanoparticle surface,
Wherein the conjugated polymer is selected from the group consisting of polypyrrole, polythiophene, poly (3,4-ethylenedioxythiophene), poly (3,4-propylenedioxythiophene), derivatives thereof, , ≪ / RTI >
Wherein the hydrophilic substituent is represented by the following formula (3).
(3)
- [(B 1 ) n 12 -A 1 ] m 11
(Wherein, in Formula 3,
A 1 is any hydrophilic substituent selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH and OH,
Wherein B 1 is represented by (CH 2 ) a - (X 3 ) b - (CH 2 ) c ,
X 3 is any one selected from the group consisting of O, S and NR '
Wherein R 'is hydrogen or an alkyl group,
M 11 is an integer of 1 to 5,
N 12 is an integer of 1 to 5,
Each of a to c is independently an integer of 1 to 5)
Wherein the hydrophilic substituent is any one selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH, OH, and combinations thereof.
Wherein the nanoparticles are self-doped with the hydrophilic substituent.
Wherein said nanoparticles are self-doped by said hydrophilic substituents at a pH of from 1 to 8.
Wherein the nanoparticles have an absorption in a wavelength range of 600 to 1100 nm by the self-doping.
Wherein the nanoparticles have a particle diameter of 1 to 500 nm.
Wherein the conjugated polymer substituted with the hydrophilic substituent is represented by the following general formula (1) or (2).
[Chemical Formula 1]
(2)
(In the above formulas (1) and (2)
A 1 and A 2 are each independently any hydrophilic substituent selected from the group consisting of SO 3 - , PO 4 - , CO 3 - , COOH and OH,
Wherein B 1 and B 2 each independently represent (CH 2 ) a - (X 3 ) b - (CH 2 ) c ,
X 1 to X 3 are each independently any one selected from the group consisting of O, S and NR '
Wherein R 1 , R 2 and R 'are each independently hydrogen or an alkyl group,
Each of l 1 and l 2 is independently an integer of 4 to 5000,
M 11 , m 21 and m 22 are each independently an integer of 1 to 5,
N 11 and n 21 each independently represents an integer of 0 to 5,
Each of n 12 and n 22 is independently an integer of 1 to 5,
Each of a to c is independently an integer of 1 to 5)
Wherein the composition for diagnosing and treating cancer further comprises a pharmaceutically acceptable carrier.
A kit for diagnosing and treating cancer, comprising an apparatus for irradiating light in a wavelength range of 600 to 1100 nm.
Wherein the light beam is a laser beam.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150058931A KR101775141B1 (en) | 2015-04-27 | 2015-04-27 | Nano probe for diagnosing and treating cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150058931A KR101775141B1 (en) | 2015-04-27 | 2015-04-27 | Nano probe for diagnosing and treating cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20160127479A KR20160127479A (en) | 2016-11-04 |
| KR101775141B1 true KR101775141B1 (en) | 2017-09-05 |
Family
ID=57530172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150058931A KR101775141B1 (en) | 2015-04-27 | 2015-04-27 | Nano probe for diagnosing and treating cancer |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101775141B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200043114A (en) * | 2018-10-17 | 2020-04-27 | 고려대학교 세종산학협력단 | Dipeptide based Near-infrared imaging probes targeting hepsin, NIR imaging agent for detecting metastatic cancer and pharmaceutical composition for prevention and treatment of the metastatic cancer having the same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2668060B2 (en) * | 1986-03-24 | 1997-10-27 | 昭和電工株式会社 | Polymer conductor with self-doping function |
| KR101267313B1 (en) * | 2011-03-22 | 2013-05-27 | 연세대학교 산학협력단 | Photothermal ablation of cancer cells using organic nanoparticles |
| KR101473078B1 (en) * | 2013-01-02 | 2014-12-17 | 연세대학교 산학협력단 | Organic/inorganic nanocomposite for diagnosis and treatment of cancer |
| KR101507645B1 (en) * | 2012-10-26 | 2015-04-01 | 연세대학교 산학협력단 | Organic/inorganic nanocomposite for diagnosis and treatment of cancer |
-
2015
- 2015-04-27 KR KR1020150058931A patent/KR101775141B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2668060B2 (en) * | 1986-03-24 | 1997-10-27 | 昭和電工株式会社 | Polymer conductor with self-doping function |
| KR101267313B1 (en) * | 2011-03-22 | 2013-05-27 | 연세대학교 산학협력단 | Photothermal ablation of cancer cells using organic nanoparticles |
| KR101507645B1 (en) * | 2012-10-26 | 2015-04-01 | 연세대학교 산학협력단 | Organic/inorganic nanocomposite for diagnosis and treatment of cancer |
| KR101473078B1 (en) * | 2013-01-02 | 2014-12-17 | 연세대학교 산학협력단 | Organic/inorganic nanocomposite for diagnosis and treatment of cancer |
Non-Patent Citations (1)
| Title |
|---|
| 논문1-MOLECULAR CRYSTALS AND LIQUID CRYSTALS INCORPORATING NONLINEAR OPTICS(1990) |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20160127479A (en) | 2016-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhang et al. | Recent advances of AIE dots in NIR imaging and phototherapy | |
| Yang et al. | Albumin-bioinspired Gd: CuS nanotheranostic agent for in vivo photoacoustic/magnetic resonance imaging-guided tumor-targeted photothermal therapy | |
| Cha et al. | Functional mesoporous silica nanoparticles for bio‐imaging applications | |
| Tian et al. | Poly (acrylic acid) bridged gadolinium metal–organic framework–gold nanoparticle composites as contrast agents for computed tomography and magnetic resonance bimodal imaging | |
| Su et al. | Cetuximab-conjugated iodine doped carbon dots as a dual fluorescent/CT probe for targeted imaging of lung cancer cells | |
| Xing et al. | A NaYbF4: Tm3+ nanoprobe for CT and NIR-to-NIR fluorescent bimodal imaging | |
| Ai et al. | Near infrared-emitting persistent luminescent nanoparticles for hepatocellular carcinoma imaging and luminescence-guided surgery | |
| Chen et al. | Fabrication of fluorescent nanoparticles based on AIE luminogens (AIE dots) and their applications in bioimaging | |
| Zhang et al. | Albumin-mediated biomineralization of paramagnetic NIR Ag2S QDs for tiny tumor bimodal targeted imaging in vivo | |
| Pansare et al. | Review of long-wavelength optical and NIR imaging materials: contrast agents, fluorophores, and multifunctional nano carriers | |
| Bhirde et al. | Nanoparticles for cell labeling | |
| Chan et al. | Nanogels as imaging agents for modalities spanning the electromagnetic spectrum | |
| Rowe et al. | Tuning the magnetic resonance imaging properties of positive contrast agent nanoparticles by surface modification with RAFT polymers | |
| US20170266323A1 (en) | Near-infrared-ii fluorescent agents, methods of making near-infrared-ii fluorescent agents, and methods of using water-soluble nir-ii fluorescent agents | |
| Han et al. | Synthesis of a multifunctional manganese (II)–carbon dots hybrid and its application as an efficient magnetic-fluorescent imaging probe for ovarian cancer cell imaging | |
| Singh et al. | Application of nanotechnology in medical diagnosis and imaging | |
| Yang et al. | Long-term in vivo biodistribution and toxicity of Gd (OH) 3 nanorods | |
| Li et al. | Peptide-enhanced tumor accumulation of upconversion nanoparticles for sensitive upconversion luminescence/magnetic resonance dual-mode bioimaging of colorectal tumors | |
| Zhang et al. | Ultra‐Small Nano‐Assemblies as Tumor‐Targeted and Renal Clearable Theranostic Agent for Photodynamic Therapy | |
| Ma et al. | Cross‐link‐functionalized nanoparticles for rapid excretion in nanotheranostic applications | |
| Zhang et al. | Affibody-functionalized Ag 2 S quantum dots for photoacoustic imaging of epidermal growth factor receptor overexpressed tumors | |
| Li et al. | Self-assembled NIR-II fluorophores with ultralong blood circulation for cancer imaging and image-guided surgery | |
| KR101473078B1 (en) | Organic/inorganic nanocomposite for diagnosis and treatment of cancer | |
| Su et al. | A design strategy for D–A conjugated polymers for NIR-II fluorescence imaging | |
| KR101507645B1 (en) | Organic/inorganic nanocomposite for diagnosis and treatment of cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right |