WO2014178468A1 - 표적지향증폭형 항암나노입자 및 이의 제조방법 - Google Patents
표적지향증폭형 항암나노입자 및 이의 제조방법 Download PDFInfo
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- WO2014178468A1 WO2014178468A1 PCT/KR2013/004297 KR2013004297W WO2014178468A1 WO 2014178468 A1 WO2014178468 A1 WO 2014178468A1 KR 2013004297 W KR2013004297 W KR 2013004297W WO 2014178468 A1 WO2014178468 A1 WO 2014178468A1
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- Prior art keywords
- nanoparticles
- anticancer
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- cancer
- oriented
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Definitions
- the present invention relates to an anticancer nanoparticle having a feature of improved target orientation to cancer tissue and a method of manufacturing the same.
- Cancer is one of the most frightening diseases of modern people, and there is no effective and low side effect treatment, and it is difficult to cure. In the development of cancer, effective treatment is not easy, and surgery, radiation and phototherapy, and anticancer drug therapies are used alone or in combination.
- Anticancer agents used in pharmacotherapy are anticancer substances that have very good cancer cell killing ability in animal experiments, but do not cure cancer in actual clinical practice. It is due to the low cancer tissue delivery rate / tumor targeting of the drug.
- the anticancer drug circulates in the blood when administered in the body, and most of the drugs stay in normal tissues such as cells, blood vessels, and matrix that make up the body, and only a part of the cancer is delivered to the cancer tissue. Due to the low rate of anticancer drug delivery to cancer tissues, the level of anticancer drugs in cancer tissues is difficult to kill cancer cells effectively, but the amount of anticancer drugs delivered to normal tissues is too high.
- an anticancer drug when administered to a cancer patient, most of the cancer cells are actually delivered to normal tissues, thereby killing normal cells, resulting in various side effects such as bone marrow dysfunction, gastrointestinal disorders, alopecia, and decreased immune function.
- the low targeting rate of anticancer drugs leads to nonspecific toxicity and multidrug resistance in normal tissues, making the cancer very difficult to cure.
- an effective way to solve the problem of low drug efficacy and side effects of anticancer drugs is to increase the cancer tissue delivery rate of the anticancer drugs, and lower the normal tissue delivery rate.
- various basic studies have been conducted on a method of targeting targeting a delivery of anticancer drugs to cancer tissues more selectively.
- the most representative target-oriented method is the method using extended permeability and retention (EPR) of cancer tissue (Maeda et al., J Controlled release, 2000, 65: 271-284).
- Cancer tissue has a looser vascular cell gap than normal tissue, and endothelial pores of 10 to 1,000 nm are well developed in the vascular tissue.
- an anticancer agent is made with a nanoparticle size that can pass through the endothelial pores, the nanoparticle anticancer agent does not easily escape into normal tissues without endothelial pores but easily escapes into cancer tissues.
- lymphatic vessels are degenerated in cancer tissues, and nanoparticles that have escaped from the blood to cancer tissues remain for a long time and eventually accumulate selectively in cancer tissues.
- EPR Extended Permeability and Retention
- ABRAXANE is a nanoparticle that binds paclitaxel, a cell division inhibitor, to serum albumin. Since ABRAXANE is designed for passive targeting, anticancer nanoparticles are composed of only two substances, paclitaxel, an anticancer drug, and serum albumin, a nanoparticle base. ABRAXANE passively delivers anticancer agents based on EPR, rather than targeting moieties that can directly target cancer tissues.
- the cancer delivery rate / targeting rate of ABRAXANE is only 1.5 ⁇ 3 times better than paclitaxel, but is still low to solve the side effect problem affecting normal tissues (Desai et al., Clin Cancer Res, 2006, 12 1317-1324).
- the ideal anticancer nanoparticles are nanoparticles that ensure that the anticancer nanoparticles are correctly delivered only to cancer tissues.
- the target-oriented material is attached to the surface of the anti-cancer nanoparticles, and at the same time, the nano-particles are structurally stabilized, so that the target cancer can be passively directed by the structural stability and at the same time the active cancer can be active by the target material. something to do.
- research teams around the world have developed various types of nanoparticles that attach target-oriented materials to the surface of anticancer nanoparticles (A. Swami et al., Multifunctional Nanoparticles for Drug Delivery Applications: Imaging, Targeting, and Delivery, Chapter 2. Nanoparticles for Targeted and Temporally Controlled Drug Delivery, p9 ⁇ 29, Springer, 2012)
- the commercialization of “targeted anticancer nanoparticles” failed due to the following reasons.
- passive target-oriented anticancer nanoparticles consisting of only two components of anticancer agent and base material
- three different compounds such as anticancer agent, base material, and target oriented material are perfectly harmonized, and it is actually very difficult to form a single anticancer nanoparticle using only non-covalent bonds.
- anticancer nanoparticles in which an anticancer agent, a base material, and a target oriented material are combined, one of the target oriented substances or an anticancer agent is covalently connected to the base material or to each other, and then, anticancer nanoparticles are manufactured.
- covalent bonds introduced in the process of anticancer nanoparticles cause the following problems. 1) Newly formed materials with covalent bonds create new materials different from the original covalent bonds. For example, when hydrogen and oxygen are covalently bonded, the properties of hydrogen and oxygen are modified to make water. Because of the nature of these covalent bonds, the creation of new chemical entities (NCEs) in covalent bonds (eg conjugation) between nanoparticle components is inevitable.
- NCEs new chemical entities
- targeting anticancer nanoparticles attached failed to commercialize is that the targeting materials attached to nanoparticles to improve the targeting ability, rather than the structural stability of nanoparticles and passive targeting ability of nanoparticles This is because ultimately the anticancer nanoparticles' target-oriented ability is severely reduced.
- target-oriented anticancer nanoparticles with target-oriented substances Another reason for the failure of "targeting anticancer nanoparticles with target-oriented substances" is that a single nanoparticle can be introduced even if covalent bonds such as conjugation are introduced into three different compounds, such as anti-cancer agents and base-targeting substances. Because it is very difficult to configure. For this reason, a large number of nanoparticles have been developed that utilize a non-biological material such as metal as a base material to which a target-oriented material or an anticancer agent is attached to the base material (US Patent Nos. 7364919, 7829350, 82.36284, and No. 8). 8246995, European Patent No.
- the anticancer drug delivery efficiency should be much improved compared to passive anticancer nanoparticles in which the anticancer agent is encapsulated with serum albumin only. Compared with the previous, the anticancer efficacy was hardly improved. In other words, the anticancer nanoparticles that covalently bind porphyrin to serum albumin and then enclosed with anticancer drugs were not as effective at delivering anticancer agents to cancer tissues as compared to ABRAXANE, which was simply encapsulated with serum albumin (Chang et al., Pharm). Res. 2012, 29: 795-805; Desai et al. Clin Cancer Res. 2006; 12: 1317-1324).
- the anticancer nanoparticles to which the target oriented material is covalently attached to the surface of the anticancer nanoparticles may be much more ideal nanoparticles than the passive target oriented anticancer nanoparticles. Due to problems in the construction process, there is no real commercialization.
- the commercially available anticancer nanoparticles are passive target-oriented anticancer nanoparticles in which all of the base material and the anticancer agent are connected only by non-covalent bonds such as Doxil, Myocet and Daunoxome in addition to ABRAXANE. Therefore, the use of non-toxic base material, non-covalently coupled to the target-oriented material on the surface of the anti-cancer nanoparticles, and at the same time the development of a structurally stable "target-oriented substance attached anti-cancer nanoparticles" is urgently required.
- the present inventors have made diligent efforts to solve the above problems.
- the nanoparticles are composed of serum albumin as a non-toxic base material, and the porphyrin-based compound is used as a target-oriented substance to non-covalently attach to the surface of the anticancer nanoparticles.
- the ideal anti-cancer nanoparticles have active target orientation because the target-oriented material attached to the surface of the anti-cancer nanoparticles can impart active target orientation, and at the same time, since the anti-cancer nanoparticles are structurally stabilized, they have passive target orientation. And the anti-cancer nanoparticles are correctly delivered only to cancer tissue by a combination of passive targeting.
- the conventionally produced "target anti-cancer nanoparticles attached with target materials" have not been commercialized yet because they have not overcome various limitations described in the technology that is the background of the invention despite the possibility of becoming the most ideal anti-cancer nanoparticles.
- the inventors of the present invention have attempted to invent a structurally stable anti-cancer nanoparticles by using a non-toxic base material and attaching a target-oriented substance to the surface of the anti-cancer nanoparticles only by non-covalent bonds.
- the present invention provides a target-oriented amplification-type anti-cancer nanoparticles in which the anti-cancer agent, the nanoparticles base serum serum albumin and the porphyrin-based compound non-covalently bound to the target-oriented material.
- the present invention also comprises the steps of (a) adding an anticancer agent solution to the serum albumin solution, and mixing to prepare a mixed solution; (b) preparing a nanoparticle solution in which an anticancer agent and serum albumin are aggregated by dropwise adding an organic solvent to the mixed solution; (c) preparing nanoparticles having a non-covalently bound anti-cancer agent in the center and serum albumin in the epidermis by inducing relocation by giving a temperature change to the nanoparticle solution in which the anticancer agent and serum albumin are aggregated; (d) adding a porphyrin compound solution to the nanoparticles to which the anticancer agent and serum albumin are noncovalently bound, and coating to prepare a target-oriented amplification type anticancer nanoparticle solution to which the anticancer agent, serum albumin and porphyrin compound are noncovalently bound.
- the present invention also provides a target-oriented amplification-type anticancer nanoparticles prepared by the above method, wherein the anti-cancer agent, a nanoparticle-based serum albumin, and a porphyrin-based compound as a target-oriented substance are non-covalently bound.
- the present invention also provides an anticancer pharmaceutical composition comprising the target-oriented amplification-type anticancer nanoparticles.
- Target-oriented amplification-type anticancer nanoparticles is prepared by encapsulating an anticancer agent with nontoxic serum albumin and then noncovalently coating the surface of the nanoparticles with a porphyrin-based material, thereby producing new compounds or nanoparticles. There is no deformation of the individual constituents of the particles.
- the "targeted amplification type anti-cancer nanoparticles" of the present invention 1) can prevent the toxic side effects common in anti-cancer nanoparticles; 2) there is no change in the chemical structure of the anticancer agent, thereby maintaining the inherent characteristics and functions of the anticancer agent, thereby preventing the anticancer agent from decreasing its efficacy; 3)
- the porphyrin-based compound, which is a targeting substance, is attached to the surface of the anticancer nanoparticles only by non-covalent bond, thereby maintaining the active targeting of porphyrin intact; 4) Because it is structurally stabilized, it has a passive targeting orientation to cancer tissue, and thus has an effect of maximizing cancer delivery rate / targeting ratio in a passive and active targeting orientation combination.
- Example 1 is a transmission electron microscope (TEM) high magnification observation photograph of "target oriented anticancer nanoparticles” prepared according to Example 1 of the present invention (A: paclitaxel-encapsulated target oriented anticancer nanoparticles, B: cedrol Embedded target-amplified anticancer nanoparticles).
- TEM transmission electron microscope
- FIG. 2 is a view of "paclitaxel-encapsulated target-oriented amplified anticancer nanoparticles" prepared according to Example 1 of the present invention with a low magnification Atomic Force Microscopy (AFM) and Transmission Electron Microscope (TEM).
- A Atomic Force Microscopy
- TEM Transmission Electron Microscope
- Figure 3 is a transmission electron microscope (TEM) high magnification observation photo of "target oriented anticancer nanoparticles” prepared according to Example 2 of the present invention (A: doxorubicin encapsulation target oriented anticancer nanoparticles, B: oxaliplatin encapsulation Targeted Amplified Anticancer Nanoparticles, C: Gemcitabine Encapsulated Targeted Amplified Anticancer Nanoparticles).
- A doxorubicin encapsulation target oriented anticancer nanoparticles
- B oxaliplatin encapsulation Targeted Amplified Anticancer Nanoparticles
- C Gemcitabine Encapsulated Targeted Amplified Anticancer Nanoparticles
- A Paclitaxel-encapsulated target-oriented amplification type Anticancer nanoparticles
- B doxorubicin-contained target-amplified anticancer nanoparticles
- C oxaliplatin-contained target-amplified anticancer nanoparticles
- D gemcitabine-contained target-amplified anticancer nanoparticles
- FIG. 5 is a graph showing drug delivery rates of normal and cancerous tissues of "paclitaxel-embedded target-amplified anti-cancer nanoparticles" prepared according to Example 1 (grey bar: Abraxane ® of Celgene, dark gray bar: paclitaxel inclusion) Targeted Amplified Anticancer Nanoparticles, Black bar: LED + Paclitaxel Encapsulated Targeted Amplified Anticancer Nanoparticles).
- FIG. 6 is a graph evaluating the toxicity of “paclitaxel-embedded target-amplified anticancer nanoparticles” prepared according to Example 1 of the present invention (A: LD50 measurement graph of paclitaxel (free drug) in normal mice, B: normal mouse) LD50 measurement graph of “paclitaxel-encapsulated target-amplified anticancer nanoparticles”, C, LD50 measurement graph of “paclitaxel-encapsulated target-amplified anticancer nanoparticles” in cancer-induced mice).
- A LD50 measurement graph of paclitaxel (free drug) in normal mice
- B normal mouse
- C LD50 measurement graph of “paclitaxel-encapsulated target-amplified anticancer nanoparticles” in cancer-induced mice.
- Figure 7 is a photograph and absorbance graph for confirming the effect of EPR amplified by "paclitaxel encapsulated target-oriented amplification anti-cancer nanoparticles prepared according to Example 1 of the present invention.
- Figure 8 is a mouse model photograph for confirming the initial cancer treatment efficacy of "paclitaxel encapsulated target-oriented amplification anti-cancer nanoparticles" prepared according to Example 1 of the present invention.
- Figure 9 is a mouse model photograph for confirming the terminal cancer treatment efficacy upon administration of the "paclitaxel-embedded target-amplified anti-cancer nanoparticles" prepared according to Example 1 of the present invention and adding porphyrin activation step by electromagnetic waves.
- FIG. 10 is a mouse model photograph for confirming terminal cancer treatment efficacy upon administration of the doxorubicin-encapsulated target-amplified anticancer nanoparticles prepared according to Example 2 of the present invention and adding porphyrin activation step by electromagnetic waves.
- Anti-cancer nanoparticles that have a target-oriented substance attached to the surface of the anti-cancer nanoparticles have been estimated to be ideal anti-cancer nanoparticles, but in fact, all of the anti-cancer nanoparticles whose target-oriented substances developed to date are attached to the surface of the anti-cancer nanoparticles There was no successful commercialization because of problems with anticancer efficacy or toxicity.
- the present inventors are aware that the reason why the existing "target oriented anticancer nanoparticles with target oriented substance" is less than the expectation is the covalent bond introduced in the existing "target oriented anticancer nanoparticles" manufacturing process.
- the "anti-adherent anti-cancer nanoparticles” are manufactured, the intrinsic chemical function of the target-oriented substance and the anticancer agent is maintained so that the efficiency of delivering the anticancer agent to the cancer tissue can be improved.
- the porphyrin-based compound as a non-toxic target-oriented material to select serum albumin as a nanoparticle base material; 2) attaching the targeting material to the shell of the anticancer nanoparticles so that the targeting cancer's inherent cancer targeting ability is maintained; 3) encapsulating the anticancer agent in the core surrounded by the epidermis; 4) Target-oriented amplification-type anticancer nanoparticles in which an anticancer agent, serum albumin, and porphyrin-based compounds were non-covalently bound were prepared to maintain the inherent functions of the anti-cancer agent and the target-oriented substance.
- a solution of paclitaxel dissolved in an organic solvent such as ethanol is added to a human serum albumin (HSA) solution to prepare a mixed solution, followed by dropwise mixing with an organic solvent.
- HSA human serum albumin
- Form non-covalently bound paclitaxel-human serum albumin (HSA) nanoaggregates and the solution undergoes a temperature change process to allow for the rearrangement of nanoparticle components such that human serum albumin is located at the periphery of the anticancer agent.
- the nanoparticles were coated with a solution of protoporphyrin to paclitaxel; After preparing a target-oriented amplified anticancer nanoparticle solution in which human serum albumin (HSA) and protoporphyrin are noncovalently bound, the resultant is filtered and centrifuged, followed by structurally stabilized "paclitaxel encapsulation. Targeted amplification type anti-cancer nanoparticles "was prepared. In addition, it was confirmed that the manufactured "paclitaxel-encapsulated target-oriented amplification-type anticancer nanoparticles" is structurally stable and markedly amplified in target-oriented cancer tissues, and thus, the anticancer effect was excellent in early and late stage cancers.
- HSA human serum albumin
- the present invention relates to a target-oriented amplification-type anticancer nanoparticle in which an anticancer agent, a serum albumin as a nanoparticle base material, and a porphyrin-based compound as a target-oriented substance are non-covalently bound.
- Target-oriented amplification type anti-cancer nanoparticles in which the anti-cancer agent, nanoparticle-based serum albumin and the porphyrin-based compound are non-covalently bound to the target-oriented substance, the core of the anti-cancer nanoparticles are composed of an anticancer agent, and the epidermis (shell) ) Is composed of serum albumin and porphyrin-based compounds.
- the core of the target-oriented amplification-type anticancer nanoparticles is a structure encapsulated so that the structure and properties of the anticancer agent are not changed, in particular, it is encapsulated without covalent bond with serum albumin or porphyrin-based compound.
- porphyrin-based compound which is a targeting moiety, is attached to the epidermis (shell) of the anticancer nanoparticles by a non-covalent bond, so that the unique cancer targeting ability of the targeting material is maintained.
- the serum albumin stabilizes the anticancer nanoparticles and has cancer targeting ability by the permeation residual enhancement (EPR) phenomenon, but is not particularly limited, but serum albumin derived from a mammal is preferable.
- EPR permeation residual enhancement
- the serum albumin is hydrophilic and very soluble in water, and thus does not form a polymer by binding itself in a solution state.
- a porphyrin-based compound is added to the serum albumin solution, the porphyrin-based compound is bound to the serum albumin in a solution state, and porphyrin-based.
- the compound and serum albumin are characterized in that they form a polymer while maintaining a non-covalent bond with each other.
- the anticancer agent may use any anticancer agent having a pharmacological effect on cancer cells, and includes taxene, antimetbolite agents, platinum agents, alkylating agents, and anns.
- taxene any anticancer agent having a pharmacological effect on cancer cells, and includes taxene, antimetbolite agents, platinum agents, alkylating agents, and anns.
- Preferred is any one selected from the group consisting of tractaline antibiotics, vinca alkaloids, proteasome inhibitors, macrolides, and topoisomerase inhibitors. It is not limited to this.
- doxorubicin dounorubicin, daunorubicin, valrubicin, epirubicin, epirubicin, idarubicin, paclitaxel, docetaxel, docetaxel, cisplatin, cisplatin, Carboplatin, oxaliplatin, camptothecin, vincristine, vinblastin, 5-fluorouracil (5-FU), mitomycin, cyclo Phosphamide, mesotrexate, mitoxantron, topotecan, capecitabine, doxifluridine, doxifluridine, irinotecan, tegaffer (tegafur), chlorambucil, belotecan, anasterozole, tamoxifen, gleevec, floxuridine, leuprolide, flo Flutamide, Zoledronate, Streptozotocin (Stre) ptozocin, vinorelbine, hydroxyure
- the porphyrin-based compound is selectively accumulated in cancer tissue through the receptor overexpressed in cancer cells, protoporphyrin IX, heme, hemin, zinc protoporphyrin ), Magnesium protoporphyrin, hematoporphyrin, benzoporphyrin, benzoporphyrin, metalloporphyrin, 5-aminolevulinic acid, texaphyrins, croxaphyrins Chlorins, purpurins, bacteriochlorins, phthalocyanines, pthalocyanines, napthalocyanine and derivatives thereof may be exemplified, but are not limited thereto.
- the porphyrin-based compound has selectivity in cancer tissues that are actively angiogenic, enters into cancer cells by interacting with low-density protein (LDL) receptors that are overexpressed in cancer tissues, and thus selectively accumulates in cancer tissues, thereby targeting anticancer nanoparticles. Directivity can be given.
- LDL low-density protein
- the porphyrin-based compound non-covalently binds to serum albumin, which is a nanoparticle base material, forms a nanoparticle shell, thereby structurally stabilizing the nanoparticles, thereby passively targeting the target due to enhancement of permeation residual (EPR) of cancer tissues.
- serum albumin which is a nanoparticle base material
- EPR permeation residual
- the anti-cancer agent according to the present invention the target-oriented amplification type anti-cancer nanoparticles in which the porphyrin-based compound is non-covalently bound to the serum albumin and the target-oriented material as the base material of the nanoparticles are non-covalently bound to the porphyrin-based compound and the serum albumin. Since there is no modification of the inherent structure and properties of the compound, it has active target orientation to cancer tissues, and further enhances the residual persistence enhancement (EPR) and target orientation upon activation by treatment of appropriate electromagnetic waves. .
- EPR residual persistence enhancement
- 10 to 300 parts by weight of the anticancer agent and 0.01 to 10 parts by weight of the porphyrin compound are added to 100 parts by weight of the serum albumin.
- the size of the nanoparticles may be excessively large or small.
- the anticancer agent, serum albumin, and porphyrin-based compound may be used alone or in solution by mixing with an organic or inorganic solvent such as NaCl solution, water, ethanol, methanol, acetone, dichloromethane, and the concentration of the solution. Is not particularly limited, but is preferably 0.1 to 100 mg / ml.
- the anti-cancer agent solution is added to the serum albumin solution and mixed to prepare a mixed solution.
- the pH 5.0 to 9.0 is preferably at room temperature when the anticancer agent is hydrophobic, and at 0 ° C. to room temperature when hydrophilic. When the pH and temperature conditions are out of range, problems of poor size control of nanoparticles may occur.
- the organic solvent is for inducing aggregation of the anticancer agent and serum albumin, but is not particularly limited to ethanol, acetone, Acetonitrile and the like may be exemplified, and the organic solvent is preferably added dropwise for 6 to 13 minutes at a rate of 0.1 to 0.9 ml / min.
- the anticancer agent and the serum albumin agglomerated nanoparticles solution by giving a temperature change to induce the rearrangement of the anticancer agent in the center, the epidermal portion of the serum albumin non-covalently bonded to prepare the nanoparticles non-cancer agent is hydrophobic
- the anticancer agent characterized in that the cooling.
- the hydrophobic anticancer agents are firmly bound to each other at the center of the nanoparticles by evaporating the organic solvent by applying heat of 40 to 60 ° C., and serum albumin is protruded to the surface of the nanoparticles.
- a hydrophobic anticancer agent such as paclitaxel
- hydrophilic anticancer agent such as doxorubicin
- the organic solvent is contained in the nanoparticle solution in which the anticancer agent and the serum albumin are aggregated, the hydrophilic anticancer agents tend to crystallize to some extent even though the solvent affinity is weak. . Therefore, when cooled to a temperature of -10 °C ⁇ -70 °C the anticancer agent is crystallized and hardened, the physicochemical properties change, serum albumin is bound to the outside can protrude to the surface of the nanoparticles.
- the heating temperature is less than 40 °C, evaporation of the organic solvent is not performed properly, when the temperature exceeds 60 °C degeneration occurs, the anti-cancer agent in the center, the serum albumin in the epidermis to prepare non-covalently bound nanoparticles
- the cooling temperature is -10 ° C or higher, the effect of rearranging the anticancer agent and albumin is insignificant, and if the cooling temperature is lower than -70 ° C, there is no particular benefit.
- the target-oriented amplification-type anticancer nanoparticle solution in which the anticancer agent, serum albumin and porphyrin-based compound are non-covalently added is added a porphyrin-based compound solution to nanoparticles in which the anti-cancer agent and serum albumin are non-covalently bound. It can be prepared by coating while stirring.
- a target-amplified anticancer nanoparticle solution in which an anticancer agent, serum albumin, and porphyrin-based compound are non-covalently bound is filtered and centrifuged to precipitate a target-amplified anticancer nanoparticle.
- the target oriented anticancer nanoparticles solution is ultrasonically treated before filtration to separate the target oriented anticancer nanoparticles entangled with each other, and the target oriented amplification It characterized in that it further comprises the step of adjusting the particle size of the anti-cancer nanoparticles.
- the target-oriented amplification-type anticancer nanoparticle solution when the target-oriented amplification-type anticancer nanoparticle solution is treated with ultrasonic waves, the anticancer nanoparticles are pulverized and dispersion occurs.
- the ultrasonic wave is preferably treated at 10 to 30 KHz for 2 minutes or more at 30 second intervals.
- the solution, which has been pulverized by ultrasonication, is filtered with a 0.45 ⁇ m filter and then recovered by centrifugation.
- the target-oriented amplification-type anticancer nanoparticles are preferably adjusted to have an average particle diameter of 10 to 1,000 nm, preferably an average particle diameter of 50 to 400 nm so that the drug delivery effect is excellent in the body.
- the recovered oriented anticancer nanoparticles can be structurally stabilized by lyophilization.
- the porphyrin-based compound has a property of binding to serum albumin in a solution state, and since many porphyrin-based compounds can bind to one molecule of serum albumin, the freeze-drying process after combining serum albumin and porphyrin material in an aqueous solution state When the water is removed, porphyrin and serum albumin may form a polymer while maintaining a non-covalent bond, and then the polymer may be stably maintained.
- the lyophilized structurally-targeted amplified anticancer nanoparticles can be dissolved in 0.9% saline solution immediately before use.
- the present invention relates to a target-oriented amplification-type anticancer nanoparticles prepared by the above method, wherein anti-cancer agent, nanoparticle-based serum albumin, and a target-targeting substance are non-covalently bound to porphyrin-based compound.
- the present invention relates to an anticancer pharmaceutical composition
- an anticancer pharmaceutical composition comprising the target-oriented amplification-type anticancer nanoparticles.
- the dosage and method of administration of the target-oriented amplification-type anticancer nanoparticles or an anticancer pharmaceutical composition comprising the same can be easily determined and used according to known literature of the anticancer agent.
- the anticancer treatment using the target-oriented amplification-type anticancer nanoparticles or an anticancer pharmaceutical composition comprising the same can be used as an electromagnetic wave treatment process for activating a porphyrin compound.
- the electromagnetic wave is a wave generated when the electric field and the magnetic field change with time, and may include gamma rays, X-rays, ultraviolet rays, visible rays, infrared rays, microwaves, radio waves, and the like. It is preferable.
- the porphyrin-based compound is non-covalently bound to the target-oriented amplification-type anticancer nanoparticles, the intrinsic structure and properties of the porphyrin-based compound are maintained, and thus, by treatment of appropriate electromagnetic waves.
- EPR Persistence Retention Enhancement
- Target Orientation may be further amplified.
- porphyrin-based compounds accumulated in cancer tissue absorb energy and transfer to oxygen to generate free radicals. This results in amplification of enhanced permeation residual (EPR) in cancer tissues and improvement in cancer tissue delivery rate / targeting rate of anticancer drugs, thereby enabling more effective chemotherapy.
- EPR enhanced permeation residual
- target-oriented amplification-type anticancer nanoparticles or an anticancer pharmaceutical composition comprising the same may be administered to a patient preceded by a treatment including electromagnetic waves, and in this case, the anticancer therapeutic effect described above may be obtained.
- Electromagnetic wave treatment method associated with administration of the target-oriented amplification-type anticancer nanoparticles or an anticancer pharmaceutical composition comprising the same can be easily determined and used by known literature.
- Target-oriented amplification-type anticancer nanoparticles in which a hydrophobic anticancer agent, human serum albumin (HSA) and porphyrin were covalently bound were prepared by the following method.
- HSA HSA
- LC Laboratories, USA 10 mg of paclitaxel (LC Laboratories, USA) was added to 10 mL of pure ethanol, and the mixture was dropped into a 10 mL HSA solution having a rotating magnet at a rate of 0.5 mL / min.
- the nano-agglomerate solution is slowly evaporated with ethanol at 45 o C in a rotary evaporator to naturally bind the hydrophobic anticancer agents to the core of the nanoparticles, and albumin protrudes from the nanoparticle surface. It was.
- paclitaxel-human serum albumin nanoparticles After paclitaxel-human serum albumin nanoparticles were formed, it was added to the paclitaxel-human serum albumin nanoparticles by adding a solution of protoporphyrin IX in which 1 mg protoporphyrin IX (SIGMA-ALDRICH) was dissolved in 0.5 mL pure ethanol. Protoporphyrin IX was coated to prepare a target-oriented amplified anticancer nanoparticle solution in which paclitaxel, human serum albumin, and porphyrin-based compounds were covalently bound.
- protoporphyrin IX 1 mg protoporphyrin IX (SIGMA-ALDRICH) was dissolved in 0.5 mL pure ethanol.
- Protoporphyrin IX was coated to prepare a target-oriented amplified anticancer nanoparticle solution in which paclitaxel, human serum albumin, and porphyrin-based compounds were covalently bound.
- the target-oriented amplified anticancer nanoparticle solution in which paclitaxel-human serum albumin-protophorphyrin IX was covalently bound was treated by 20 KHz ultrasonic wave for 30 minutes or more for 2 minutes to pulverize the nanoparticles.
- the nanoparticles precipitated by centrifugation were dissolved in 1mL 10mM NaCl solution and immediately lyophilized to enhance the structural stability of the nanoparticles.
- the freeze-dried "paclitaxel encapsulated target-amplified anti-cancer nanoparticles” was stored as it was, and dissolved in 0.9% saline solution if necessary.
- "Paclitaxel-embedded target-amplified anticancer nanoparticles” was reddish brown in color.
- the "paclitaxel-encapsulated target-amplified anti-cancer nanoparticles" prepared by the above process was analyzed by particle size with an atomic force microscopy (AFM) or TEM electron microscope, and the form of "paclitaxel-encapsulated target-amplified anti-cancer nanoparticles". Redness was observed.
- AFM atomic force microscopy
- TEM electron microscope TEM electron microscope
- hydrophobic anticancer drugs may also be applied in place of the respective anticancer drugs in the above-described method.
- "target-oriented amplification-type anticancer nanoparticles” were prepared in the same manner using cedrol.
- Table 1 shows the average particle diameter of the "target oriented anticancer nanoparticles" enclosed with a hydrophobic anticancer agent
- Figure 1 is a high magnification transmission electron microscope (Transmission Electron Microscope) of the "target oriented anticancer nanoparticles enclosed with a hydrophobic anticancer agent” TEM) observation picture
- Figure 2 is a low magnification atomic force microscope (Atomic Force Microscope, AFM) and transmission electron microscope (Transmission Electron Microscope, TEM) of the observation picture.
- Table 1 nano particles average diameter (nm) Paclitaxel Encapsulated Targeted Amplified Anticancer Nanoparticles To 220 Cedrol Encapsulation Targeted Amplified Anticancer Nanoparticles To 210
- Example 2 Preparation of "target oriented amplification anti-cancer nanoparticles" containing a hydrophilic anticancer agent
- Target-oriented amplification-type anticancer nanoparticles in which a hydrophilic anticancer agent, human serum albumin (HSA) and porphyrin were covalently bound were prepared by the following method.
- HSA LEE BIOSOLUTIONS, INC, USA
- doxorubicin CHEMIELIVA, CHINA
- the ethanol is stirred at the rate of 0.5 mL / min while stirring the solution with the rod magnet at 4 ° C. Mix while dropping until nano-aggregated particles are formed.
- the doxorubicin-human serum albumin nanoaggregates formed, turning the clear solution into an opaque cloudy color.
- the doxorubicin and human serum albumin aggregated nanoparticle solution was frozen at -20 ° C. and left on ice cubes for more than 2 hours, and then slowly dissolved. Doxorubicin crystals were placed in the center of the nanoparticles so that human serum albumin was located at the periphery of the nanoparticles. .
- doxorubicin- After the formation of non-covalently bound nanoparticles of doxorubicin and human serum albumin, doxorubicin- by adding a solution of Protoporphyrin IX in which 1 mg protoporphyrin IX (SIGMA-ALDRICH) is dissolved in 0.5 mL pure ethanol. Protoporphyrin IX was coated on human serum albumin nanoparticles to prepare a target-oriented amplified anticancer nanoparticle solution in which doxorubicin, human serum albumin, and porphyrin-based compounds were noncovalently bound.
- Protoporphyrin IX 1 mg protoporphyrin IX (SIGMA-ALDRICH) is dissolved in 0.5 mL pure ethanol.
- Protoporphyrin IX was coated on human serum albumin nanoparticles to prepare a target-oriented amplified anticancer nanoparticle solution in which doxorubicin, human serum albumin, and porphyrin-
- the target-oriented amplified anti-cancer nanoparticle solution in which doxorubicin-human serum albumin-protophorphyrin IX was covalently bound was treated with 20 KHz ultrasonic wave at 30 second intervals for at least 2 minutes, and then the nanoparticles were ground.
- the dispersion was filtered through a 0.45 ⁇ m filter and then centrifuged at 50,000 g for 20 minutes.
- the nanoparticles precipitated by centrifugation were dissolved in 1mL 10mM NaCl solution and immediately lyophilized to enhance the structural stability of the nanoparticles.
- the freeze-dried "doxorubicin-encapsulated target-amplified anti-cancer nanoparticles” was stored in that state, and dissolved in 0.9% saline solution if necessary.
- "Doxorubicin encapsulated target-amplified anticancer nanoparticles” was reddish brown in color.
- the "doxorubicin-encapsulated target-amplified anti-cancer nanoparticles" prepared by the above process was analyzed by particle size with an atomic force microscopy (AFM) or a TEM electron microscope, and a form of "doxorubicin-encapsulated target-amplified anti-cancer nanoparticles". Redness was observed.
- AFM atomic force microscopy
- TEM electron microscope TEM electron microscope
- a target-oriented amplified anticancer nanoparticles were prepared by the same method using oxaliplatin (SIGMA-ALDRICH) and gemcitabine among anticancer agents having hydrophilicity, and particle diameters are shown in Table 2 below.
- FIG. 3 is a transmission electron microscope (TEM) observation photograph of a target-oriented amplified anticancer nanoparticle in which a hydrophilic anticancer agent (doxorubicin, oxaliplatin and gemcitabine), human serum albumin nanoparticles, and protoporphyrin IX are covalently bound to each other.
- a hydrophilic anticancer agent doxorubicin, oxaliplatin and gemcitabine
- human serum albumin nanoparticles a hydrophilic anticancer agent
- protoporphyrin IX protoporphyrin IX
- the nanoparticle solution obtained by dissolving the "target oriented anticancer nanoparticles" in powder form in saline solution was left at room temperature for 12 hours and 60 hours, and then observed changes such as precipitation and discoloration. Shown in
- target oriented anticancer nanoparticles (A: paclitaxel-encapsulated target-amplified anti-cancer nanoparticles, B: doxorubicin-encapsulated target-amplified anti-cancer nanoparticles, C: oxaliplatin-encapsulated target oriented amplification type Anticancer nanoparticles, D: gemcitabine-encapsulated target-amplified anticancer nanoparticles) showed stable structural and morphological characteristics for more than 60 hours.
- mice After culturing the breast cancer cell line MDA-MB-231 (KCLB ® , Korean Cell Line Bank), 5 ⁇ 10 6 cells were injected subcutaneously in 6-8 week-old female athymic nude mice (multiple science). After that, when the mouse was grown in sterile (specific pathogen free) conditions and cancer tissue grew to 100 mm 3 or more, the "targeted-amplified anticancer nanoparticles" prepared in Examples 1 and 2 were intravenously injected at a dose of 10 mg / kg / day. It was. After 16 hours of drug intravenous injection, each group of mice was isolated from each organ and then completely ground the mouse organs to BeadBeater.
- KCLB ® Korean Cell Line Bank
- Tissue completely ground with BeadBeater was extracted with acetonitrile solvent, and the solvent was analyzed by LC / MS to measure the concentration of drug in each tissue.
- concentration of drug delivered relative to drug dose (Injection Dose, ID) in each mouse was measured in normal and cancerous tissues and the results are shown in Table 3.
- cancer tissue delivery rate of the control drug free drug is similar to the normal tissue delivery rate, but almost no targeting, "targeted amplification type anti-cancer nanoparticles" prepared in Examples 1 and 2 are target-oriented for cancer tissue It was confirmed that this significantly increased.
- the anti-cancer agent Abraxane ® (Celgene Co., Ltd.) prepared in Example 1 was used. Drug delivery rates were measured for each tissue.
- cancer was induced by "paclitaxel-embedded target-amplified anti-cancer nanoparticles" (JINIS nanoparticles).
- JINIS nanoparticles "paclitaxel-embedded target-amplified anti-cancer nanoparticles”
- the drug concentration in the tissues was 7-9% ID / gram, and especially when the mice were irradiated with LED after the administration of "paclitaxel-embedded target-amplified anti-cancer nanoparticles", the cancer-targeting target was 19-26%. It was confirmed that the ID / gram significantly increased.
- Toxicity of the paclitaxel-embedded target-amplified anticancer nanoparticles prepared in Example 1 to normal tissues was evaluated.
- mice After culturing the breast cancer cell line MDA-MB-231 (KCLB ® , Korean Cell Line Bank), 5 ⁇ 10 6 cells were injected subcutaneously in 6-8 week-old female athymic nude mice (multiple science). After that, mice were grown in specific pathogen free conditions to grow cancer tissues by 200 mm 3 , thereby establishing a tumor xenograft animal model.
- MDA-MB-231 Korean Cell Line Bank
- Toxicity evaluation for paclitaxel was divided into seven groups of normal nude mice, and then injected with 20, 40, 60, 80, 100, 120, 250 mg / kg / d of paclitaxel per mouse in each group.
- Toxicity evaluation of "paclitaxel-embedded target-amplified anti-cancer nanoparticles” was divided into 10 groups of normal nude and tumor-induced nude mice, and then 20, 40, 60, 80, 100, 120, 250 for each group of mice. , 300, 350 and 400 mg / kg / d of “Paclitaxel Encapsulated Targeted Amplified Anticancer Nanoparticles”, respectively, were injected.
- mice The weight and physical changes of all mice were observed for 14 days after injection, and paclitaxel and "paclitaxel-embedded targeting by measuring LD50 (50% lethal dose) of paclitaxel and" paclitaxel-embedded target-amplified anticancer nanoparticles "from dead mice. Toxicity for the amplified anti-cancer nanoparticles was evaluated and shown in FIG. 6.
- paclitaxel encapsulated target-amplified anti-cancer nanoparticles LD50 of the present invention is 91mg / kg / d, three times more than the LD50 of paclitaxel 30mg / kg / d toxicity to normal tissues It was found that this was significantly reduced.
- the paclitaxel-encapsulated target-oriented amplification-type anticancer nanoparticles of the present invention have dramatically improved the efficiency of cancer tissue anticancer drug delivery, so that the anticancer drug is hardly delivered to normal tissues (FIG. 5).
- the value was increased to 194mg / kg / d, it was found that the toxicity is further reduced in the case of mice with cancer (FIG. 6C).
- “Target-amplified anti-cancer nanoparticles” of the present invention is characterized in that the porphyrin-based compound is distributed on the surface of the nanoparticles while the anti-cancer agent, serum albumin, and porphyrin-based compounds are all non-covalently bound. Therefore, since the intrinsic chemical structure and properties of the porphyrin-based compound are preserved as it is, it is predicted that the anti-cancer nanoparticles can increase the target delivery of the anticancer nanoparticles by amplifying the target orientation of the anticancer nanoparticles.
- Evans Blue which binds to human serum albumin after administration of "Paclitaxel-embedded target-amplified anticancer nanoparticles" (JINIS nanoparticles) prepared in Example 1 to a human animal transplanted with cancer cell lines ( By observing how much SIGMA-ALDRICH is accumulated in cancer cells, the effect of improving permeation residuals was confirmed.
- the lung cancer cell line (KCLB ® , Korean Cell Line Bank) was transplanted to nude mice (multi-science), and nude mice were grown to grow cancer tissue to 50 mg or more. 20 mg / kg dose of saline, abraxane (Celgene Abraxane ® ) and “paclitaxel-encapsulated target-amplified anticancer nanoparticles” (JINIS nanoparticles) prepared in Example 1 were used in cancer tissue induced mice. Intravenously.
- mice injected with "paclitaxel-embedded target-amplified anti-cancer nanoparticles” were irradiated with light-emitting diode (LED) light having a wavelength of 630 nm and a light intensity of 100 mmol / m 2 s 2 to each mouse for 30 minutes. It was.
- the mice were immediately injected with Evans Blue Dye (EDB) (1 mg / ml, 200 ⁇ l), and after 6 hours the cancer tissue was expelled to contain 3 ml of formamide.
- EDB Evans Blue Dye
- the tube was put in a 60 ° C. constant temperature water bath for 48 hours, the amount of the extracted Evans Blue (Evans Blue Dye, EBD) was measured with a spectrophotometer (620 nm), and the results are shown in FIG. 7.
- the initial cancer treatment efficacy of the "paclitaxel-embedded target-amplified anticancer nanoparticles" prepared in Example 1 was evaluated by the following method.
- mice After culturing the breast cancer cell line MDA-MB-231 (KCLB ® , Korean Cell Line Bank), 5 ⁇ 10 6 cells were injected subcutaneously in 6-8 week-old female athymic nude mice (multiple science). After that, mice were grown in specific pathogen free conditions to grow cancer tissues of 100 mm 3 or more, and a tumor xenograft animal model was established to study therapeutic efficacy.
- MDA-MB-231 Korean Cell Line Bank
- Control group physiological saline, Abraxane (Celgene Abraxane ® ) and "Paclitaxel Encapsulated Targeted Amplified Anticancer Nanoparticles" (JINIS nanoparticles) prepared in Example 1 were dosed at 0, 3, 7, 10 at 10 mg / kg / day. Intravenous injections each day were made for 3 weeks.
- a bioluminescence imaging method of luciferase expressing cancer cell line was performed.
- D-luciferin 150mg was injected intraperitoneally into mice at a concentration of luciferin / kg to luminesce the cancer cells, inhaled anesthesia with isoflurane gas and oxygen, and then light-emitting cancer cells with Xenogen imager (IVIS 200).
- IVIS 200 Xenogen imager
- a bioluminescence imaging method of luciferase expressing cancer cell line was performed.
- D-luciferin 150mg was injected intraperitoneally into mice at a concentration of luciferin / kg to luminesce the cancer cells, inhaled anesthesia with isoflurane gas and oxygen, and then light-emitting cancer cells with Xenogen imager (IVIS 200).
- IVIS 200 Xenogen imager
- the size of the cancerous tissues after 28 days was compared with the initial size of the terminal cancerous tissues.
- the size of the cancerous tissues was increased.
- the treatment group of "Paclitaxel-embedded target-amplified anticancer nanoparticles" (JINIS nanoparticles) prepared in Example 1 significantly reduced cancer tissue.
- mice administered with "paclitaxel-encapsulated target-amplified anticancer nanoparticles" JINIS nanoparticles prepared in Example 1 of the present invention and activated porphyrin by LED irradiation showed that cancer disappeared completely between 21 and 28 days. there was.
- Example 2 of the present invention while treating the "doxorubicin-encapsulated target-amplified anti-cancer nanoparticles" (JINIS nanoparticles) prepared in Example 2 of the present invention while amplifying the target-directivity with a kind of electromagnetic wave LED, the size of the cancer tissue is significantly reduced and completely Confirmed disappearing.
- JINIS nanoparticles JINIS nanoparticles
- the "targeted amplification type anti-cancer nanoparticles” provided by the present invention have excellent anti-cancer efficacy compared to any of the previously developed anti-cancer nanoparticles by themselves, but in particular, the “target-oriented amplification type anti-cancer nanoparticles” of the present invention.
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Abstract
Description
nano particles | average diameter (nm) |
파클리탁셀 봉입 표적지향증폭형 항암나노입자 | ~220 |
세드롤 봉입 표적지향증폭형 항암나노입자 | ~210 |
nano particles | average diameter (nm) |
독소루비신 봉입 표적지향증폭형 항암나노입자 | ~180 |
옥살리플라틴 봉입 표적지향증폭형 항암나노입자 | ~220 |
젬시타빈 봉입 표적지향증폭형 항암나노입자 | ~180 |
처리구 | Normal %(ID)/g | Tumor %(ID)/g |
파크리탁셀 (free drug) | 0.1~2.3 | 0.52 |
독소루비신 (free drug) | 0.4~3.4 | 1.5 |
옥살리플라틴 (free drug) | 0.1~3.5 | 2.5 |
젬시타빈 (free drug) | 0.2~4.2 | 2.4 |
파클리탁셀 봉입 표적지향증폭형 항암나노입자 (JINIS nanoparticles) | 0.1~2.4 | 8.1 |
독소루비신 봉입 표적지향증폭형 항암나노입자 (JINIS nanoparticles) | 0.5~2.8 | 16.4 |
옥살리플라틴 봉입 표적지향증폭형 항암나노입자 (JINIS nanoparticles) | 0.1~3.9 | 10.5 |
젬시타빈 봉입 표적지향증폭형 항암나노입자 (JINIS nanoparticles) | 0.2~2.5 | 12.7 |
처리구 | 실험 시작 전 암 조직 크기(photons/sec) | 실험 28일 후 암 조직 크기 (photons/sec) |
대조군(saline) | 21.2E+08 | 120.4E+08 |
아브락산 (Celgene, Abraxane®) | 18.6E+08 | 87.3E+08 |
파클리탁셀 봉입 표적지향증폭형 항암나노입자 (JINIS nanoparticles) | 27.9E+08 | 0.8E+08 |
Claims (17)
- 항암제, 나노입자 기저재로 혈청알부민 및 표적지향물질로 포르피린계 화합물이 비공유적으로 결합된 표적지향증폭형 항암나노입자.
- 제1항에 있어서, 상기 항암나노입자의 중심부(core)는 항암제로 구성되고, 표피부(shell)는 혈청알부민 및 포르피린계 화합물로 구성된 것을 특징으로 하는 표적지향증폭형 항암나노입자.
- 제1항에 있어서, 상기 혈청알부민은 포유동물 유래의 혈청알부민으로서, 항암나노입자를 안정화시켜, 투과잔류성향상(EPR) 현상에 의한 암 표적지향성을 갖는 것을 특징으로 하는 표적지향증폭형 항암나노입자.
- 제1항에 있어서, 상기 포르피린계 화합물은 암세포에 과발현되어 있는 수용체를 통해 암 조직에 선택적으로 축적되는 것을 특징으로 하는 표적지향증폭형 항암나노입자.
- 제1항에 있어서, 상기 포르피린계 화합물은 프로토포르피린(protoporphyrin IX), 헴(heme), 헤민(hemin), 아연 프로토포피린(Zinc protoporphyrin), 마그네슘 프로토포피린(magnesium protoporphyrin), 헤마토포르피린(hematoporphyrin), 벤조포르피린(benzoporphyrin), 메탈로포르피린(metalloporphyrin), 5-아미노레불린산(5-aminolevulinic acid), 텍사피린(texaphyrins), 크로린(chlorins), 퍼퓨린(purpurins), 박테리오크로린(bacteriochlorins), 프탈로사이아닌(pthalocyanine), 나프탈로사이아닌(napthalocyanine) 및 이들의 유도체로 구성된 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 표적지향증폭형 항암나노입자.
- 제1항에 있어서, 상기 표적지향증폭형 항암나노입자는 상기 포르피린계 화합물의 활성화시 투과잔류성향상(EPR) 현상에 의해 표적지향성이 증폭되는 것을 특징으로 하는 표적지향증폭형 항암나노입자.
- 제1항에 있어서, 상기 항암제는 독소루비신(doxorubicin), 두아노루비신(daunorubicin), 발루비신(valrubicin), 에피루비신(epirubicin), 이다루비신(idarubicin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 시스플라틴(cisplatin), 카보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 캠토세신(camptothecin), 빈크리스틴(vincristine), 빈블라스틴(vinblastin), 5-플루오로우라실(5-FU), 마이토마이신(mitomycin), 시클로포스파미드(cyclophosphamide), 메소트렉세이트(methotrexate), 미토산트론(mitoxantron), 토포테칸(topotecan), 카페시타빈(capecitabine), 독시플루리딘(doxifluridine), 이리노테칸(irinotecan), 테가퍼(tegafur), 클로람부실(chlorambucil), 벨로테칸(belotecan), 아나스테로졸(anasterozole), 타목시펜(tamoxifen), 글리벡(gleevec), 플록슈리딘(floxuridine), 류프로리드(leuprolide), 플로타미드(flutamide), 졸레드로네이트(zoledronate), 스트렙토조토신(streptozocin), 비노렐빈(vinorelbine), 히도록시우레아(hydroxyurea), 레티노익산(retinoic acid), 메클로레타민(meclorethamine), 부술판(Busulfan), 프레드니손(Prednisone), 테스토스테론(testosterone), 아스피린(aspirin), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone), 코르티코스테로이드(corticosteroid), 젬시타빈(gemcitabine), 세드롤(cedrol) 및 이들의 유도체로 구성된 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 표적지향증폭형 항암나노입자.
- 다음의 단계를 포함하는 항암제, 혈청알부민 및 포르피린계 화합물이 비공유적으로 결합된 표적지향증폭형 항암나노입자의 제조방법:(a) 혈청알부민 용액에 항암제 용액을 첨가하고, 혼합하여 혼합액을 제조하는 단계;(b) 상기 혼합액에 유기용매를 적가하면서, 혼합시켜 항암제 및 혈청알부민이 응집된 나노입자 용액을 제조하는 단계;(c) 항암제 및 혈청알부민이 응집된 나노입자 용액에 온도변화를 주어 재배치를 유도함으로써 중심부에는 항암제, 표피부에는 혈청알부민이 비공유적으로 결합된 나노입자를 제조하는 단계;(d) 항암제 및 혈청알부민이 비공유적으로 결합된 나노입자에 포르피린계 화합물 용액을 첨가하고, 코팅시켜 항암제, 혈청알부민 및 포르피린계 화합물이 비공유적으로 결합된 표적지향증폭형 항암나노입자 용액을 제조하는 단계;(e) 상기 표적지향증폭형 항암나노입자 용액을 여과하고, 원심분리한 다음 침전된 표적지향증폭형 항암나노입자를 회수하는 단계; 및(f) 상기 회수된 표적지향증폭형 항암나노입자를 동결건조시켜, 구조적으로 안정화된 표적지향증폭형 항암나노입자를 얻는 단계.
- 제8항에 있어서, 상기 혈청알부민 100중량부에 대하여 상기 항암제는 10∼300 중량부, 상기 포르피린계 화합물은 0.01∼10 중량부를 첨가하는 것을 특징으로 하는 표적지향증폭형 항암나노입자의 제조방법.
- 제8항에 있어서, 상기 온도변화를 주어 재배치를 유도하는 단계는 항암제가 소수성인 경우 가열하고, 항암제가 친수성인 경우 냉각시키는 것을 특징으로 하는 표적지향증폭형 항암나노입자의 제조방법.
- 제10항에 있어서, 상기 가열은 40 내지 60℃의 온도, 상기 냉각은 -10 내지 -70℃의 온도로 수행하는 것을 특징으로 하는 표적지향증폭형 항암나노입자의 제조방법.
- 제8항에 있어서, 여과 전에 표적지향증폭형 항암나노입자 용액을 초음파로 처리하여 표적지향증폭형 항암나노입자의 입경을 조절하는 단계를 추가로 포함하는 것을 특징으로 하는 표적지향증폭형 항암나노입자의 제조방법.
- 제8항에 있어서, 상기 항암제는 독소루비신(doxorubicin), 두아노루비신(daunorubicin), 발루비신(valrubicin), 에피루비신(epirubicin), 이다루비신(idarubicin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 시스플라틴(cisplatin), 카보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 캠토세신(camptothecin), 빈크리스틴(vincristine), 빈블라스틴(vinblastin), 5-플루오로우라실(5-FU), 마이토마이신(mitomycin), 시클로포스파미드(cyclophosphamide), 메소트렉세이트(methotrexate), 미토산트론(mitoxantron), 토포테칸(topotecan), 카페시타빈(capecitabine), 독시플루리딘(doxifluridine), 이리노테칸(irinotecan), 테가퍼(tegafur), 클로람부실(chlorambucil), 벨로테칸(belotecan), 아나스테로졸(anasterozole), 타목시펜(tamoxifen), 글리벡(gleevec), 플록슈리딘(floxuridine), 류프로리드(leuprolide), 플로타미드(flutamide), 졸레드로네이트(zoledronate), 스트렙토조토신(streptozocin), 비노렐빈(vinorelbine), 히도록시우레아(hydroxyurea), 레티노익산(retinoic acid), 메클로레타민(meclorethamine), 부술판(Busulfan), 프레드니손(Prednisone), 테스토스테론(testosterone), 아스피린(aspirin), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone), 코르티코스테로이드(corticosteroid), 젬시타빈(gemcitabine), 세드롤(cedrol) 및 이들의 유도체로 구성된 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 표적지향증폭형 항암나노입자의 제조방법.
- 제8항에 있어서, 상기 포르피린계 화합물은 프로토포르피린(protoporphyrin IX), 헴(heme), 헤민(hemin), 아연 프로토포피린(Zinc protoporphyrin), 마그네슘 프로토포피린(magnesium protoporphyrin), 헤마토포르피린(hematoporphyrin), 벤조포르피린(benzoporphyrin), 메탈로포르피린(metalloporphyrin), 5-아미노레불린산(5-aminolevulinic acid), 텍사피린(texaphyrins), 크로린(chlorins), 퍼퓨린(purpurins), 박테리오크로린(bacteriochlorins), 프탈로사이아닌(pthalocyanine), 나프탈로사이아닌(napthalocyanine) 및 이들의 유도체로 구성된 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 표적지향증폭형 항암나노입자의 제조방법.
- 제8항 내지 제14항중 어느 한 항의 제조방법에 의하여 제조되고, 항암제, 나노입자 기저재로 혈청알부민 및 표적지향물질로 포르피린계 화합물이 비공유적으로 결합된 표적지향증폭형 항암나노입자.
- 제1항 내지 제7항중 어느 한 항의 표적지향증폭형 항암나노입자를 포함하는 항암 약학조성물.
- 제15항의 표적지향증폭형 항암나노입자를 포함하는 항암 약학조성물.
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Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT2943474T (pt) | 2013-01-31 | 2017-08-08 | Chong Kun Dang Pharmaceutical Corp | Compostos biarilo ou biarilo heterocíclico como inibidores de cetp |
US9962452B2 (en) * | 2013-02-04 | 2018-05-08 | Zhuhai Beihai Biotech Co., Ltd. | Soluble complexes of drug analogs and albumin |
KR101601035B1 (ko) | 2013-02-28 | 2016-03-08 | 주식회사 종근당 | 키토산 및 액상결정 형성 물질을 포함하는 유전자 전달용 조성물 |
US9937259B2 (en) | 2014-06-27 | 2018-04-10 | Zhuhai Beihai Biotech Co., Ltd. | Abiraterone derivatives and non-covalent complexes with albumin |
WO2015018380A2 (en) * | 2014-07-03 | 2015-02-12 | Cspc Zhongqi Pharmaceutical Technology(Shijiazhuang)Co., Ltd. | Therapeutic nanoparticles and the preparation methods thereof |
WO2016065139A1 (en) | 2014-10-24 | 2016-04-28 | Fl Therapeutics Llc | 3-substituted piperidine-2, 6-diones and non-covalent complexes with albumin |
WO2017182584A1 (en) * | 2016-04-20 | 2017-10-26 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | New formulations of retinoic acid derivatives and their use for treating cancer |
TWI771315B (zh) | 2016-08-26 | 2022-07-21 | 奧野哲治 | 微小奈米化藥劑及其利用 |
CN109789226B (zh) * | 2016-09-27 | 2021-11-26 | 艾姆戈特株式会社 | 利用携带抗癌剂的人血清白蛋白纳米粒子的肝动脉化疗栓塞术用组合物及其制造方法 |
CN106420665B (zh) * | 2016-10-28 | 2019-04-16 | 浙江省林业科学研究院 | 一种包裹紫杉烷类药物的白蛋白纳米颗粒载体的制备方法 |
KR102018880B1 (ko) * | 2016-12-07 | 2019-09-05 | 서강대학교 산학협력단 | 약물을 담지한 알부민 나노입자의 제조방법 |
CA3111590A1 (en) * | 2018-10-17 | 2020-04-23 | Sunstate Biosciences, LLC | Single protein-encapsulated pharmaceutics for enhancing therapeutic effects |
CN109966267A (zh) * | 2019-05-06 | 2019-07-05 | 上海师范大学 | 纳米声敏剂在制备基于光声引导的声动力学治疗肿瘤药物中的用途 |
US11850233B2 (en) | 2019-10-28 | 2023-12-26 | Matibur Rahaman Zamadar | Reduced adaptive microbial resistance treatment for flesh eating disease (necrotizing fasciitis) |
EP4141110A1 (en) | 2020-04-24 | 2023-03-01 | Obshchestvo S Ogranichennoy Otvetstvennost'yu "Ingenik" | Method for producing particles of bacteriophages of the genus levivirus |
CN112402605B (zh) * | 2020-11-06 | 2023-09-26 | 深圳大学 | 一种仿生纳米乳剂及其制备方法与应用 |
CN112656948B (zh) * | 2020-11-12 | 2022-06-14 | 宁波大学 | 免疫治疗纳米药物载体及其制备方法和具有该载体的药物和该药物的制备方法 |
KR20230069345A (ko) | 2021-11-12 | 2023-05-19 | 닥터아이앤비(주) | 생산 시간을 단축하고 안정성이 개선된 의약품 제조방법 |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002098364A2 (en) | 2001-06-06 | 2002-12-12 | The General Hospital Corporation | Magnetic-nanoparticle conjugates and methods of use |
US6506405B1 (en) | 1993-02-22 | 2003-01-14 | American Bioscience, Inc. | Methods and formulations of cremophor-free taxanes |
US6537579B1 (en) | 1993-02-22 | 2003-03-25 | American Bioscience, Inc. | Compositions and methods for administration of pharmacologically active compounds |
EP1671625A1 (en) | 2000-10-16 | 2006-06-21 | Consejo Superior De Investigaciones Cientificas | Nanoparticles |
US20070231375A1 (en) * | 2006-04-03 | 2007-10-04 | Taipei Medical University | Liposome combination and the use thereof |
KR100789008B1 (ko) * | 1997-06-27 | 2007-12-26 | 아브락시스 바이오사이언스 인크. | 신규 약물 제제 |
KR20100094664A (ko) * | 2009-02-19 | 2010-08-27 | 한국과학기술연구원 | 암 표적성이 우수한 단백질 복합체 및 이의 제조방법 |
US20110142948A1 (en) * | 2009-12-11 | 2011-06-16 | Biolitec, Inc. | Nanoparticle Carrier Systems based on Human Serum Albumin for Photodynamic Therapy |
US20120052006A1 (en) | 2008-08-22 | 2012-03-01 | Colorado School Of Mines | Gold/lanthanide nanoparticle conjugates and uses thereof |
WO2012075087A2 (en) | 2010-11-30 | 2012-06-07 | Board Of Trustees Of The University Of Illinois | Silica nanoparticle agent conjugates |
US8236284B1 (en) | 2008-04-02 | 2012-08-07 | University Of Central Florida Research Foundation, Inc. | Multimodal, multifunctional polymer coated nanoparticles |
WO2012106713A2 (en) | 2011-02-04 | 2012-08-09 | Case Western Reserve University | Targeted nanoparticle conjugates |
US8246995B2 (en) | 2005-05-10 | 2012-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070122465A1 (en) | 1993-02-22 | 2007-05-31 | Desai Neil P | Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
US5916596A (en) * | 1993-02-22 | 1999-06-29 | Vivorx Pharmaceuticals, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
HUE038768T2 (hu) * | 2005-02-18 | 2018-11-28 | Abraxis Bioscience Llc | Terápiás szerek kombinációi, valamint beadásukra szolgáló módszerek, és kombinációs terápia |
CN101730526A (zh) * | 2007-03-07 | 2010-06-09 | 阿布拉科斯生物科学有限公司 | 作为抗癌剂的包含雷帕霉素和白蛋白的纳米颗粒 |
MX2009009537A (es) * | 2007-03-07 | 2009-09-16 | Abraxis Bioscience Llc | Nanoparticula que comprende rapamicina y albumina como agente anticancer. |
US8697661B2 (en) * | 2009-06-24 | 2014-04-15 | Christine Kritikou | Use of spinosyns and spinosyn compositions against herpesviridae viral infections |
-
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-
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Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6506405B1 (en) | 1993-02-22 | 2003-01-14 | American Bioscience, Inc. | Methods and formulations of cremophor-free taxanes |
US6537579B1 (en) | 1993-02-22 | 2003-03-25 | American Bioscience, Inc. | Compositions and methods for administration of pharmacologically active compounds |
KR100789008B1 (ko) * | 1997-06-27 | 2007-12-26 | 아브락시스 바이오사이언스 인크. | 신규 약물 제제 |
US7364919B2 (en) | 2000-10-16 | 2008-04-29 | Midatech Limited | Nanoparticles |
EP1671625A1 (en) | 2000-10-16 | 2006-06-21 | Consejo Superior De Investigaciones Cientificas | Nanoparticles |
WO2002098364A2 (en) | 2001-06-06 | 2002-12-12 | The General Hospital Corporation | Magnetic-nanoparticle conjugates and methods of use |
US7829350B2 (en) | 2001-06-06 | 2010-11-09 | The General Hospital Corporation | Magnetic-nanoparticle conjugates and methods of use |
US8246995B2 (en) | 2005-05-10 | 2012-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells |
US20070231375A1 (en) * | 2006-04-03 | 2007-10-04 | Taipei Medical University | Liposome combination and the use thereof |
US8236284B1 (en) | 2008-04-02 | 2012-08-07 | University Of Central Florida Research Foundation, Inc. | Multimodal, multifunctional polymer coated nanoparticles |
US20120052006A1 (en) | 2008-08-22 | 2012-03-01 | Colorado School Of Mines | Gold/lanthanide nanoparticle conjugates and uses thereof |
KR20100094664A (ko) * | 2009-02-19 | 2010-08-27 | 한국과학기술연구원 | 암 표적성이 우수한 단백질 복합체 및 이의 제조방법 |
US20110142948A1 (en) * | 2009-12-11 | 2011-06-16 | Biolitec, Inc. | Nanoparticle Carrier Systems based on Human Serum Albumin for Photodynamic Therapy |
WO2012075087A2 (en) | 2010-11-30 | 2012-06-07 | Board Of Trustees Of The University Of Illinois | Silica nanoparticle agent conjugates |
WO2012106713A2 (en) | 2011-02-04 | 2012-08-09 | Case Western Reserve University | Targeted nanoparticle conjugates |
Non-Patent Citations (9)
Title |
---|
A. SWAMI ET AL.: "Multifunctional Nanoparticles for Drug Delivery Applications: Imaging, Targeting, and Delivery", 2012, SPRINGER, article "Nanoparticles for Targeted and Temporally Controlled Drug Delivery", pages: 9,29 |
CHANG ET AL., PHARM. RES., vol. 29, 2012, pages 795 - 805 |
DANHIER ET AL., J CONTROLLED RELEASE, vol. 148, 2010, pages 135 - 146 |
DESAI ET AL., CLIN CANCER RES, vol. 12, 2006, pages 1317 - 1324 |
DESAI ET AL., CLIN CANCER RES., vol. 12, 2006, pages 1317 - 1324 |
FANG ET AL., ADV. DRUG DELIVERY REV., vol. 63, 2011, pages 136 - 151 |
JI-EUN CHANG ET AL.: "Liver Cancer Targeting of Doxorubicin with Reduced Distribution to the Heart Using Hematoporphyrin-Modified Albumin Nanoparticles in Rats", PHARM. RES., vol. 29, 2012, pages 795 - 805, XP035016537 * |
MAEDA ET AL., J CONTROLLED RELEASE, vol. 65, 2000, pages 271 - 284 |
See also references of EP2937080A4 |
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Publication number | Publication date |
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EP2937080A4 (en) | 2016-08-03 |
US9662401B2 (en) | 2017-05-30 |
CA2911157A1 (en) | 2014-11-06 |
US20170239369A1 (en) | 2017-08-24 |
EP2937080B1 (en) | 2017-12-20 |
US20150290332A1 (en) | 2015-10-15 |
CN105283174B (zh) | 2019-09-24 |
JP2016517881A (ja) | 2016-06-20 |
US10286004B2 (en) | 2019-05-14 |
RU2652436C2 (ru) | 2018-04-26 |
KR101329646B1 (ko) | 2013-11-14 |
EP2937080A1 (en) | 2015-10-28 |
CN105283174A (zh) | 2016-01-27 |
JP6162326B2 (ja) | 2017-07-12 |
RU2015150725A (ru) | 2017-06-06 |
CA2911157C (en) | 2019-01-15 |
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