WO2018070711A2 - 히알루론산 나노입자를 함유하는 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물 - Google Patents
히알루론산 나노입자를 함유하는 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물 Download PDFInfo
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- WO2018070711A2 WO2018070711A2 PCT/KR2017/010824 KR2017010824W WO2018070711A2 WO 2018070711 A2 WO2018070711 A2 WO 2018070711A2 KR 2017010824 W KR2017010824 W KR 2017010824W WO 2018070711 A2 WO2018070711 A2 WO 2018070711A2
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Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases and metabolic diseases containing hyaluronic acid nanoparticles, and more particularly, hyaluronic acid and 5 ⁇ -cholanic acid or polycaprolactone in an aqueous solution.
- the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases and metabolic diseases containing hyaluronic acid nanoparticles formed by being bonded to a hydrophobic moiety of hyaluronic acid through an assembly).
- Hyaluronic acid is a linear polysaccharide polymer having a molecular weight ranging from 1 ⁇ 10 5 to 1 ⁇ 10 7 Da, wherein ( ⁇ , 1-4) -D-glucuronic acid (GlcUA) And a repeating sequence of ( ⁇ , 1-3) -N-acetyl-D-glucosamine (N-acetyl-Dglucosamine, GlcNAc). It is found in the extracellular matrix and cell surface of most human tissues, especially in large amounts in synovial fluid, cartilage, and the like.
- hyaluronic acid is biocompatible and is biodegradable by hyaluronatease (hyaluronidase), which is a hyaluronic acid enzyme in the blood, and thus is used as a biomaterial such as drug carriers and tissue engineering supports.
- hyaluronic acid binds to CD44, RHAMM, which is overexpressed on the surface of cancer cells or metastatic cancer cells, and is internalized through endocytosis, and is degraded in a low pH environment such as lysosomes.
- diabetes in 2014 is a representative metabolic syndrome, with about 380 million patients worldwide, and it is not only increasing in number but also increasing in cardiovascular disease, stroke, and chronic heart failure. It is known to be accompanied by complications. About 3 million people with diabetes exist in Korea, and about 6 million people with diabetes are expected in 2050. In particular, diabetes is one of the causes of death following cancer, heart disease and brain disease, and the social / economic cost is also rapidly increasing in proportion to the number of patients, which is a serious social problem.
- Current antidiabetics include metformin, sulfonylurea, DPP-4 inhibitors and GLP-1 receptor analogues, but most of them are weak or have some side effects such as hypoglycemic shock and liver toxicity. Limited.
- CD44 receptors have been reported to be deeply involved in the progression and treatment of diabetes mellitus (Kodama et al., Diabetes, 64 (3), 2015, 867-875).
- the blocking of the CD44 receptor using hyaluronic acid-based nanoparticles can be developed in the judgment that it can prevent or treat inflammatory and metabolic diseases.
- hyaluronic acid nanoparticles containing hyaluronic acid and 5 ⁇ -cholanic acid or polycaprolactone have made efforts to prepare hyaluronic acid nanoparticles containing hyaluronic acid and 5 ⁇ -cholanic acid or polycaprolactone and verify their effects, resulting in weight loss, reduced dietary weight, and GTT (Glucose).
- Tolerance Test confirmed the effect of reducing blood sugar, and confirmed the effect of reducing insulin resistance, inflammation-inducing factors (NF- ⁇ B, IL-1 ⁇ , CD44, TNF- ⁇ , NLRP3 inflammasome, etc.) and macrophage tissue infiltration This invention was completed.
- An object of the present invention to provide a pharmaceutical composition for the prevention or treatment of inflammatory diseases or metabolic diseases containing hyaluronic acid nanoparticles.
- Another object of the present invention to provide a food for the improvement of inflammatory diseases or metabolic diseases containing hyaluronic acid nanoparticles.
- the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases or metabolic diseases containing hyaluronic acid nanoparticles represented by the following [Formula 1] or [Formula 2].
- the present invention also provides a food for improving an inflammatory disease or metabolic disease containing hyaluronic acid nanoparticles represented by [Formula 1] or [Formula 2].
- FIG. 1 is a schematic diagram of hyaluronic acid nanoparticles according to an embodiment.
- Figure 2 shows the size and TEM image of the hyaluronic acid nanoparticles HA-CA according to one embodiment.
- Figure 3 shows the size and TEM image of the hyaluronic acid nanoparticles HA-PCL according to one embodiment.
- Figure 4 shows the effect of the hyaluronic acid nanoparticles on the weight according to an embodiment.
- Figure 5 shows the effect of hyaluronic acid nanoparticles on the dietary amount according to an embodiment.
- FIG. 6 illustrates the effect of hyaluronic acid nanoparticles on blood glucose according to an embodiment.
- FIG. 7 shows insulin resistance of hyaluronic acid nanoparticles according to an embodiment.
- Figure 8 shows the effect of hyaluronic acid nanoparticles on inflammatory factors in liver tissue (liver tissue) according to one embodiment.
- Figure 9 shows the effect of hyaluronic acid nanoparticles on inflammatory factors in adipose tissue (adipose tissue) according to one embodiment.
- FIG. 10 shows SEM images of adipose tissue stained with hematoxylin & eosin.
- Figure 11 shows an SEM image of adipose tissue immunostained with MAC-2.
- Figure 12 shows the effect of improving rheumatoid arthritis of hyaluronic acid nanoparticles in a rheumatoid arthritis animal model.
- Figure 13 shows the effect of inhibiting the prevalence of rheumatoid arthritis of hyaluronic acid nanoparticles.
- Figure 14 shows the image of the knee and ankle joint tissue stained with Safranin O staining method.
- FIG. 15 shows that hyaluronic acid nanoparticles can alleviate and inhibit joint inflammation and cartilage tissue destruction in degenerative arthritis.
- hyaluronic acid nanoparticles containing hyaluronic acid (HA) and 5 ⁇ -cholanic acid (5 ⁇ -cholanic acid, CA) or polycaprolactone (Polycaprolactone, PCL) the hyaluronic acid nanoparticles Weight loss, decreased diet, GTT (Glucose Tolerance Test) confirmed the effect of reducing blood sugar, insulin resistance, inflammation factors (NF- ⁇ B, IL-1 ⁇ , CD44, TNF- ⁇ , NLRP3 inflammasome, etc.) and macrophage tissue invasion is effective in reducing the inflammatory and metabolic diseases can be used as a pharmaceutical composition for the prevention or treatment of diseases.
- the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases or metabolic diseases containing hyaluronic acid nanoparticles represented by the following [Formula 1] or [Formula 2] from one aspect.
- the hyaluronic acid nanoparticles represented by [Formula 1] is composed of hyaluronic acid and 5 ⁇ -cholanic acid
- the hyaluronic acid nanoparticles represented by [Formula 2] is composed of hyaluronic acid and polycaprolactone desirable.
- the hyaluronic acid nanoparticles represented by [Formula 1] of the present invention preferably comprises hyaluronic acid and 5 ⁇ -cholanic acid at a mass ratio of 1: 0.05 to 1: 0.30, and is represented by [Formula 2].
- the particles are preferably composed of 1: 0.20 to 1: 0.40 in mass ratio of hyaluronic acid and polycaprolactone.
- the hyaluronic acid nanoparticles are formed by self-assembly of the hyaluronic acid conjugates of [Formula 1] and [Formula 2] in an aqueous solution state.
- the hyaluronic acid number average molecular weight of the hyaluronic acid conjugate forming the hyaluronic acid nanoparticles is preferably 180,000 to 300,000 Da, more preferably 200,000 to 250,000 Da, in the case of [Formula 1] 2], the hyaluronic acid number average molecular weight is preferably 10,000 to 15,000 Da, more preferably 11,000 to 13,000 Da.
- the size of the hyaluronic acid nanoparticles is preferably 200 to 250 nm, most preferably 220 nm.
- the hyaluronic acid number average molecular weight of the hyaluronic acid conjugate constituting the hyaluronic acid nanoparticles is less than 5,000, there is a disadvantage in that the absorption of the cell is inhibited due to the lack of binding ability with CD44 and RHAMM overexpressed on the surface of metastatic cancer cells.
- the absorption of the cell is inhibited due to the lack of binding ability with CD44 and RHAMM overexpressed on the surface of metastatic cancer cells.
- the absorption of the cell is inhibited due to the lack of binding ability with CD44 and RHAMM overexpressed on the surface of metastatic cancer cells.
- When is more than 500 nm there is a disadvantage of deterioration of the EPR effect according to the reduction of residence time.
- the pharmaceutical composition is useful for preventing or treating inflammatory diseases and metabolic diseases, wherein the inflammatory diseases and metabolic diseases are type 1 diabetes, type 2 diabetes, hypertension, hyperlipidemia, obesity, coronary atherosclerosis and arteriosclerosis , Arthritis, pancreatitis, hepatitis, dermatitis, degenerative neuro-inflammatory and the like is preferably selected from the group, but is not limited thereto.
- the pharmaceutical composition of the present invention is particularly effective for treating diabetes, arthritis or obesity.
- CD44 receptors are known to be overexpressed, and recently, it has been reported that CD44 antibodies capable of specifically binding to such CD44 receptors may be injected into the body to inhibit the progress of inflammation. Therefore, by specifically binding to the CD44 receptor using the hyaluronic acid nanoparticles of the present invention can be used as a formulation that can effectively inhibit the inflammation of the above inflammatory diseases.
- the pharmaceutical composition containing the hyaluronic acid nanoparticles of the present invention may further include a suitable carrier, excipient or diluent according to a conventional method.
- Carriers, excipients and diluents that may be included in the pharmaceutical composition containing the compound include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
- the pharmaceutical composition containing the hyaluronic acid nanoparticles of the present invention may be prepared as powders, pills, granules, capsules, suspensions, solvents, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, lyophilizers and suppositories according to conventional methods. It may be formulated in any one of the formulations selected from the group consisting of.
- Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or It may be prepared by mixing lactose, gelatin and the like.
- lubricants such as magnesium stearate, talc can also be used.
- Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories.
- the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
- As the base of the suppository witepsol, macrogol, tween 60, cacao butter, laurin butter, glycero gelatin and the like can be used.
- the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the patient's state of health, weight, age, sex, The range varies depending on the diet, the rate of excretion, the extent of the disease, the form of the drug, the time of administration, the route of administration and the duration of administration, but may be appropriately selected by those skilled in the art.
- the hyaluronic acid nanoparticles of the present invention is 0.1 mg / kg (body weight) to 30 mg / kg (body weight), 0.1 mg / kg (body weight) to 20 mg / kg based on the active ingredient per day (Body weight) or 1 mg / kg (body weight) to 10 mg / kg (body weight), the administration may be administered once a day, may be administered in several divided doses.
- the dosage does not limit the scope of the invention in any aspect.
- composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers for the prevention or treatment of inflammatory and metabolic diseases.
- the present invention relates to a food for improving inflammatory disease or metabolic disease containing hyaluronic acid nanoparticles represented by the following [Formula 1] or [Formula 2].
- Inflammatory diseases and metabolic diseases in which symptoms may be improved by the food according to the present invention are as described above.
- the food according to the present invention is particularly effective in diseases such as diabetes, arthritis and obesity among inflammatory and metabolic diseases.
- the food includes all forms such as functional food, nutritional supplement, health food and food additives.
- Health foods of this type can be prepared in various forms according to conventional methods known in the art.
- the hyaluronic acid nanoparticles of the present invention may be prepared in the form of tea, juice and drink for drinking, or granulated, encapsulated and powdered.
- Functional foods include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruit, canned foods, jams, marmalade, etc.), fish, meat and processed foods (e.g. ham, sausage corned beef, etc.), Breads and noodles (e.g.
- udon, soba, ramen, spaghetti, macaroni, etc. fruit juices, various drinks, cookies, malts, dairy products (e.g. butter, cheese, etc.), edible vegetable oils, margarine, vegetable protein, retort food, It can be prepared by adding the hyaluronic acid nanoparticles of the present invention to frozen foods, various seasonings (eg, miso, soy sauce, sauce, etc.).
- the health functional food also includes a variety of forms, such as functional foods, nutritional supplements, health foods, food additives, etc. as a food composition, according to conventional methods known in the art in various forms, for example, the aforementioned hyaluronic acid nano
- the particles may be prepared in the form of tea, juice, drink, granulated, encapsulated, powdered or these compounds or extracts may be used in beverages, fruits and processed foods, fish, meat and processed foods, breads, noodles, seasonings, etc. It can be provided by adding to the preparation.
- insulin resistance refers to the inability of insulin to lower blood sugar and thus the cells not effectively burning glucose. When insulin resistance is high, the body produces too much insulin, which can lead to high blood pressure or dyslipidemia, as well as heart disease and diabetes.
- Figure 2 shows the size and TEM image of the hyaluronic acid nanoparticles HA-CA, evenly distributed from 100 to 400 nm, the average size was confirmed to be about 221 ⁇ 3.1 nm.
- the dried hyaluronic acid nanoparticles HA-CA is dispersed in the PBS buffer, it was confirmed that the functional groups of 5 ⁇ -cholanic acid existed in a spherical shape as they aggregated together.
- hyaluronic acid nanoparticles 200 mg of alkane-modified hyaluronic acid is dissolved in 40 ml of deionized water, and 64 mg of azide-modified polycaprolactone is dissolved in 40 ml of dimethylformamide and mixed with each other. 10.60 mg of copper sulfate pentahydrate and 8.41 mg of sodium ascorbate were added together to the reaction solution and stirred at 45 ° C. for 2 days. Thereafter, the reaction solution was dialyzed for 2 days to remove unreacted material, and then lyophilized to obtain hyaluronic acid nanoparticles (HA-PCL).
- HA-PCL hyaluronic acid nanoparticles
- Figure 3 shows the size and TEM image of hyaluronic acid nanoparticles HA-PCL, evenly distributed from 100 to 400 nm, the average size was confirmed to be about 220 ⁇ 2.5 nm.
- the functional groups of the polycaprolactone exist as spherical particles.
- Obese / diabetic model mice were 4 weeks of age using DBA / 2 and were obtained through 60% high fat diet for 5 months.
- the experiment was injected into the tail vein at 20 mg / kg of body weight per day for about 30 days, and blood, liver, and fat cells were removed after the last day of killing.
- hyaluronic acid nanoparticles used in animal experiments were prepared according to Examples 1 and 2 (provided lyophilized at Sungkyunkwan University), and hyaluronic acid nanoparticles HA-CA and HA-PCL 8-10 mg respectively. Dissolved in 1 ml of PBS buffer solution, 20 mg / kg concentration of hyaluronic acid nanoparticles were used.
- Diabetic model mice prepared by high fat diet were administered 200 ⁇ l of hyaluronic acid nanoparticles HA-CA and HA-PCL at a concentration of 20 mg / kg for 4 weeks, and a PBS group was used as a control group.
- Diabetic mice made from a high-fat diet were administered 200 ⁇ l of hyaluronic acid nanoparticles HA-CA and HA-PCL at a concentration of 20 mg / kg, followed by intraperitoneally (IP) of 2 g / kg of glucose. Injected, PBS administration group was used as a control.
- IP intraperitoneally
- Diabetic mice treated with a high-fat diet were administered 200 ⁇ l of hyaluronic acid nanoparticles HA-CA and HA-PCL at a concentration of 20 mg / kg, followed by intraperitoneally (IP) of 0.5 unit / kg of insulin. Injected, PBS administration group was used as a control.
- IP intraperitoneally
- Figure 7 shows the blood glucose concentration of the diabetic model mice according to the hyaluronic acid nanoparticles administered over time, it was confirmed that the insulin resistance was improved compared to the control group in the drug group administered the hyaluronic acid nanoparticles.
- Complementary DNA was synthesized using reverse transcriptase and RT-qPCR was performed with primers specific to the target gene. After PCR, the expression changes of the experimental and control genes were analyzed by comparative quantification.
- Diabetic model mice prepared by high fat diet were administered 200 ⁇ l of hyaluronic acid nanoparticles HA-CA and HA-PCL at a concentration of 20 mg / kg, and liver tissues were separated, and the PBS group was used as a control group.
- Diabetic model mice prepared by high-fat diet were administered 200 ⁇ l of hyaluronic acid nanoparticles HA-CA and HA-PCL at a concentration of 20 mg / kg, and then adipose tissue was isolated, and PBS buffer was used as a control.
- Figure 10 shows the microscopic image after staining the isolated adipose tissue with hematotoxillin & eosin, it can be confirmed that the inflammation caused by macrophages infiltrated into the adipose tissue through a high fat diet, hyaluronic acid It was confirmed that the nanoparticles were improved through administration.
- FIG. 11 is a microscopic image after additional immunostaining with macrophages specific marker MAC-2 on the adipose tissue stained with hematoxylin & eosin, as shown in FIG. It was confirmed that the decrease.
- mice Three-week-old male DBA1 mice were stabilized for 1 week, followed by a 10-week Western diet (# D12079B) diet to build a high fat diet (HFD) model.
- HFD high fat diet
- mice were 7 weeks old, Type II Collagen (Chondrex) was injected subcutaneously, followed by primary immunization (1 st immunization), and 3 weeks later, arthritis was induced by secondary boosting (2 nd boosting). Thereafter, 20 mg / kg of HA-CA according to vehicle or Example 1 was administered to each group by intravenous injection for 4 weeks.
- the experimental Collagen induced arthritis (CIA) model swells the limb ankle joints after 2 nd boosting.
- the degree of swelling was baselined to analyze the progress of arthritis.
- the swelling degree of the ankles of the mice was measured once every two days using vernier calipers with drug administration for 4 weeks, and the progression of arthritis was evaluated. Three times were conducted to increase the reliability of the measurement.
- an individual with a score above a certain score score # 2
- scoring can be subdivided from 0 to 4. .
- 0 no abnormality
- 1 is lightly swollen or keeps feet closed
- 2 is one red toe swollen or swelled but not severe
- 3 is one red toe swollen and red instep But not severe, or two or more swollen toes clearly
- 4 indicates a swollen and red power generator.
- Paraffin sections were prepared by cutting and embedding the extracted tissues (ankle, knee). Sections were stained using Mayer's Hematoxylin, Fast green, and Safranin O solution and analyzed for the destruction of joints and immune cells infiltrated into the synoviium or bone tissue.
- cartilage destruction, synoviitis in the synovium, and bone erosion in the rheumatoid arthritis were confirmed to be improved in the drug group administered with the hyaluronic acid nanoparticles.
- Chondrocytes were obtained from cartilage tissue from femoral heads, femoral condyles and tibial plateaus of normal mice on day 5 of birth.
- the obtained chondrocytes were 10% (v / v) fetal bovine serum (Gibco, USA), 50 ⁇ g / ml of streptomycin (Sigma-Aldrich, USA) and 50 unit / ml penicillin (Sigma-Aldrich, USA). ) was cultured in a cell incubator at 37 °C, 5% CO 2 conditions in DMEM medium (Gibco, USA) containing.
- IL-1 ⁇ is a representative inflammatory cytokine that promotes joint inflammation and cartilage tissue destruction.
- the chondrocytes were treated with 5 ng / ml of IL-1 ⁇ over time, followed by qRT-PCR for Mmp3, Mmp13, Cox2, IL-6, and GAPDH using the conditions and primers of Table 1 below.
- the expression of Mmp3, Mmp13, Cox2, and IL-6 increased by IL-1 ⁇ in chondrocytes could be reduced in concentration-dependent manner by hyaluronic acid nanoparticles. This indicates that the hyaluronic acid nanoparticles can alleviate and inhibit arthritis and cartilage tissue breakthrough.
- the pharmaceutical composition for preventing or treating inflammatory diseases or metabolic diseases containing hyaluronic acid nanoparticles according to the present invention has a weight-lowering effect, a low dietary amount, and GTT (Glucose Tolerance Test) results in an effect of reducing blood sugar.
- Pharmacy for the prevention or treatment of inflammatory and metabolic diseases because it has the effect of reducing insulin resistance, inflammation-inducing factors (NF- ⁇ B, IL-1 ⁇ , CD44, TNF- ⁇ , NLRP3 inflammasome, etc.) and macrophage tissue infiltration It can be usefully used as a composition.
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Abstract
본 발명은 히알루론산 나노입자를 함유하는 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물에 관한 것으로, 보다 상세하게는 수용액 상태에서 히알루론산과 5β-콜란산 또는 폴리카프로락톤이 자기조립(self-assembly)를 통해 히알루론산의 소수성 부분(hydrophobic moiety)에 결합되어 형성된 히알루론산 나노입자를 함유하는 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물에 관한 것이다. 본 발명에 따른 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 예방 또는 치료용 약학 조성물은, 체중을 감소시키고, 식이량을 저하시켰으며, GTT(Glucose Tolerance Test) 결과 혈당을 감소시키는 효과가 있으며, 인슐린 저항성, 염증 유발인자들(NF-κB, IL-1β, CD44, TNF-α, NLRP3 inflammasome 등) 및 대식세포 조직침윤을 저하시키는 효과뿐만 아니라 관절염 증상완화 및 유별율 감소효과가 있으므로 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물로 유용하게 사용될 수 있다.
Description
본 발명은 히알루론산 나노입자를 함유하는 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물에 관한 것으로, 보다 상세하게는 수용액 상태에서 히알루론산과 5β-콜란산 또는 폴리카프로락톤이 자기조립(self-assembly)를 통해 히알루론산의 소수성 부분(hydrophobic moiety)에 결합되어 형성된 히알루론산 나노입자를 함유하는 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물에 관한 것이다.
히알루론산(Hyaluronic acid, HA)은 1×105 내지 1×107 Da 범위의 분자량을 갖는 선형 다당 중합체로서, (β,1-4)-D-글루쿠론산(D-glucuronic acid, GlcUA)과 (β,1-3)-N-아세틸-D-글루코사민(N-acetyl-Dglucosamine, GlcNAc) 단위의 반복 서열로 구성되어 있다. 대부분의 인체 조직의 세포외 기질(extracellular matrix) 및 세포 표면에서 발견되며, 특히 관절 활액(synovial fluid), 연골 등에 다량 존재한다. 따라서 히알루론산은 생체적합성을 가지며, 혈액 내의 히알루론산효소인 히알루로니다아제(hyaluronidase)에 의해 생분해되기 때문에 약물 전달체, 조직공학용 지지체 등 생체 재료로 이용된다. 특히 히알루론산은 암세포 또는 전이암세포 표면에서 과발현되는 CD44, RHAMM과 결합하여 엔도사이토시스를 통해 세포 내 흡수(internalization)되며, 리소좀과 같은 낮은 pH 환경에서 분해된다.
2015년 국제당뇨병 연맹의 보고에 따르면, 2014년 기준 당뇨병은 전 세계적으로 약 3억 8천명 정도의 환자가 존재할 정도로 대표적인 대사증후군으로서, 점차 발생증가폭이 커지고 있을 뿐만 아니라 심혈관 질환, 뇌졸중, 만성심부전 등의 합병증을 동반하는 것으로 알려져 있다. 우리나라에도 약 300만 명 정도의 당뇨병환자가 존재하며 2050년에는 약 600만의 당뇨병환자가 존재할 것으로 예상되고 있다. 특히 당뇨병은 암, 심장질환, 뇌질환에 이은 사망원인 중 하나로서 사회/경제적 비용 또한 환자 수에 비례해서 급격하게 증가하고 있어 큰 사회적 문제가 되고 있는 실정이다. 현재 출시된 항당뇨제에는 메트포르민, 설포닐유레아, DPP-4 억제제, GLP-1 수용체 유사체 등이 있으나 대부분이 효능이 약하거나 저혈당 쇼크, 간에 대한 독성과 같은 일부 부작용이 문제가 되고 있어 효과적인 당뇨 치료에 제한적이다. 이에 최근 CD44 수용체가 당뇨의 진행과 치료에 깊은 관련이 있는 것으로 보고되고 있으며(Kodama et al., Diabetes, 64(3), 2015, 867-875), 이를 바탕으로 CD44 수용체와 특이적으로 결합할 수 있는 히알루론산 기반 나노입자를 이용한 CD44 수용체의 막음(blocking)을 통해, 염증질환 및 대사질환의 예방 또는 치료해줄 수 있다는 판단 하에 개발하게 되었다.
이에, 본 발명자들은 히알루론산과 5β-콜란산 또는 폴리카프로락톤을 함유하는 히알루론산 나노입자를 제조하고 그 효과를 검증하고자 예의 노력한 결과, 체중을 감소시키고, 식이량을 저하시켰으며, GTT(Glucose Tolerance Test) 결과 혈당을 감소시키는 효과를 확인하였고, 인슐린 저항성, 염증 유발인자들(NF-κB, IL-1β, CD44, TNF-α, NLRP3 inflammasome 등) 및 대식세포 조직침윤을 저하시키는 효과를 확인하고, 본 발명을 완성하게 되었다.
발명의 요약
본 발명의 목적은 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 예방 또는 치료용 약학 조성물을 제공하는데 있다.
본 발명의 다른 목적은 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 개선용 식품을 제공하는데 있다.
상기 목적을 달성하기 위하여, 본 발명은 하기 [화학식 1] 또는 [화학식 2]로 표시되는 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 예방 또는 치료용 약학 조성물을 제공한다.
[화학식 1]
[화학식 2]
본 발명은 또한, [화학식 1] 또는 [화학식 2]로 표시되는 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 개선용 식품을 제공한다.
도 1은 일 실시예에 따른 히알루론산 나노입자를 도식화한 것이다.
도 2는 일 실시예에 따른 히알루론산 나노입자 HA-CA의 크기 및 TEM 이미지를 나타낸 것이다.
도 3은 일 실시예에 따른 히알루론산 나노입자 HA-PCL의 크기 및 TEM 이미지를 나타낸 것이다.
도 4는 일 실시예에 따른 히알루론산 나노입자가 체중에 미치는 영향을 나타낸 것이다.
도 5는 일 실시예에 따른 히알루론산 나노입자가 식이량에 미치는 영향을 나타낸 것이다.
도 6은 일 실시예에 따른 히알루론산 나노입자가 혈당에 미치는 영향을 나타낸 것이다.
도 7은 일 실시예에 따른 히알루론산 나노입자의 인슐린 저항성을 나타낸 것이다.
도 8은 간 조직(liver tissue)에서 일 실시예에 따른 히알루론산 나노입자가 염증 인자에 미치는 영향을 나타낸 것이다.
도 9는 지방 조직(adipose tissue)에서 일 실시예에 따른 히알루론산 나노입자가 염증 인자에 미치는 영향을 나타낸 것이다.
도 10은 헤마톡실린 & 에오신으로 염색한 지방 조직의 SEM 이미지를 나타낸 것이다.
도 11은 MAC-2로 면역 염색한 지방 조직의 SEM 이미지를 나타낸 것이다.
도 12는 류마티스 관절염 동물모델에서 히알루론산 나노입자의 류마티스 관절염 개선 효과를 나타낸 것이다.
도 13은 히알루론산 나노입자의 류마티스 관절염 유병률 억제효과를 나타낸 것이다.
도 14는 사프라닌 오(Safranin O) 염색법으로 염색한 무릎과 발목 관절 조직의 이미지를 나타낸 것이다.
도 15는 히알루론산 나노입자에 의해 퇴행성 관절염에서의 관절 염증 및 연골 조직 파괴가 완화 및 억제될 수 있음을 나타낸 것이다.
발명의 상세한 설명 및 바람직한
구현예
본 발명은 하기의 설명에 의하여 모두 달성될 수 있다. 하기의 설명은 본 발명의 바람직한 구체적인 예를 기술하는 것으로 이해되어야 하며, 본 발명이 반드시 이에 한정되는 것은 아니다. 또한, 첨부된 도면은 이해를 돕기 위한 것으로, 본 발명이 이에 한정되는 것은 아니며, 개별 구성에 관한 세부 사항은 후술하는 관련 기재의 구체적 취지에 의하여 적절히 이해될 수 있다.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 가진다. 일반적으로, 본 명세서에서 사용된 명명법은 본 기술 분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.
본 발명에서는 히알루론산(hyaluronic acid, HA)과 5β-콜란산(5β-cholanic acid, CA) 또는 폴리카프로락톤(Polycaprolactone, PCL)을 함유하는 히알루론산 나노입자를 제조하였으며, 상기 히알루론산 나노입자가 체중을 감소시키고, 식이량을 저하시켰으며, GTT(Glucose Tolerance Test) 결과 혈당을 감소시키는 효과를 확인하였고, 인슐린 저항성, 염증 유발인자들(NF-κB, IL-1β, CD44, TNF-α, NLRP3 inflammasome 등) 및 대식세포 조직침윤을 저하시키는 효과가 있으므로 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물로 유용하게 사용될 수 있다.
따라서, 본 발명은 일 관점에서 하기 [화학식 1] 또는 [화학식 2]로 표시되는 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 예방 또는 치료용 약학 조성물에 관한 것이다.
[화학식 1]
[화학식 2]
본 발명에 있어서, [화학식 1]로 표시되는 히알루론산 나노입자는 히알루론산과 5β-콜란산으로 구성되고, [화학식 2]로 표시되는 히알루론산 나노입자는 히알루론산과 폴리카프로락톤으로 구성되는 것이 바람직하다.
또한, 본 발명의 [화학식 1]로 표시되는 히알루론산 나노입자는 히알루론산과 5β-콜란산이 질량비로 1:0.05 내지 1:0.30으로 구성되는 것이 바람직하고, [화학식 2]로 표시되는 히알루론산 나노입자는 히알루론산과 폴리카프로락톤이 질량비로 1:0.20 내지 1:0.40으로 구성되는 것이 바람직하다.
본 발명에 있어서, 히알루론산 나노입자는 [화학식 1]과 [화학식 2]의 히알루론산 접합체가 수용액 상태에서 자기조립(self-assembly)을 통해 형성된 것이 바람직하다.
본 발명에 있어서, 히알루론산 나노입자를 형성하는 히알루론산 접합체의 히알루론산 수평균 분자량은 [화학식 1]의 경우, 180,000 내지 300,000 Da인 것이 바람직하고, 200,000 내지 250,000 Da인 것이 더욱 바람직하며, [화학식 2]의 경우, 히알루론산 수평균 분자량이 10,000 내지 15,000 Da인 것이 바람직하고, 11,000 내지 13,000 Da인 것이 더욱 바람직하다. 또한, 히알루론산 나노입자의 크기는 200 내지 250 nm인 것이 바람직하고, 220 nm인 것이 가장 바람직하다. 여기서 히알루론산 나노입자를 구성하는 히알루론산 접합체의 히알루론산 수평균 분자량이 5,000 미만인 경우에는 전이 암세포 표면에서 과발현하는 CD44, RHAMM과의 결합능이 떨어져 세포 내 흡수가 저해되는 단점이 있으며, 나노입자의 크기가 500 nm 이상인 경우에는 체류시간 감소에 따른 EPR effect의 저하의 단점이 있다.
본 발명에 있어서, 약학 조성물은 염증질환 및 대사질환을 예방 또는 치료하는데 유용하며, 상기 염증질환 및 대사질환은 제1형 당뇨병, 제2형 당뇨병, 고혈압, 고지혈증, 비만, 관상동맥경화증 및 동맥경화증, 관절염, 췌장염, 간염, 피부염, 퇴행성 신경염증 등으로 구성되는 군에서 선택되는 것이 바람직하나 이에 한정되는 것은 아니다. 본 발명의 약학 조성물은 당뇨병, 관절염 또는 비만 치료에 특히 효과적이다.
상기의 염증 질환에서는 CD44 수용체가 과발현되는 것으로 알려져 있으며, 최근에는 이러한 CD44 수용체와 특이적으로 결합할 수 있는 CD44 항체를 체내에 주입함에 따라 염증의 진행을 억제할 수 있다는 보고가 있다. 따라서 본 발명의 히알루론산 나노입자를 이용하여 CD44 수용체와 특이적으로 결합함에 따라 상기의 염증 질환을 대상으로 염증을 효과적으로 억제할 수 있는 하나의 제형으로 사용될 수 있다.
또한, 본 발명의 히알루론산 나노입자를 함유하는 약학 조성물은 통상의 방법에 따라 적절한 담체, 부형제 또는 희석제를 추가적으로 포함할 수 있다. 화합물을 함유하는 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있으나, 이에 한정되는 것은 아니다.
본 발명의 히알루론산 나노입자를 함유하는 약학 조성물은 통상의 방법에 따라 산제, 환제, 과립제, 캡슐제, 현탁액, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수용액제, 현탁액, 동결 건조제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형으로 제제화 될 수 있다.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스 또는 락토오스, 젤라틴 등을 섞어 제조될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 60, 카카오지, 라우린지, 글리세로 제라틴 등이 사용될 수 있다.
본 발명의 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소 적용)할 수 있으며, 투여량은 환자의 건강상태, 체중, 연령, 성별, 식이, 배설율, 질병의 정도, 약물형태, 투여시간, 투여경로 및 투여기간에 따라 그 범위가 다양하지만, 당업자에 의해 적절하게 선택될 수 있다. 하지만, 바람직한 효과를 위해서, 본 발명의 히알루론산 나노입자는 1일 유효성분을 기준으로 0.1 mg/kg(체중) 내지 30 mg/kg(체중), 0.1 mg/kg(체중) 내지 20 mg/kg(체중) 또는 1 mg/kg(체중) 내지 10 mg/kg(체중)으로 투여할 수 있으며, 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.
또한, 본 발명의 약학 조성물은 염증질환 및 대사질환의 예방 또는 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.
본 발명은 다른 관점에서, 하기 [화학식 1] 또는 [화학식 2]로 표시되는 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환 개선용 식품에 관한 것이다.
[화학식 1]
[화학식 2]
본 발명에 따른 식품에 의해 증상이 개선될 수 있는 염증질환 및 대사질환은 전술한 바와 같다. 본 발명에 따른 식품은 염증질환 및 대사질환 중에서도 특히 당뇨병, 관절염 및 비만과 같은 질환에 효과가 있다.
본 발명에 있어서, 상기 식품은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형의 건강기능 식품은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. 예를 들면, 건강식품으로는 본 발명의 히알루론산 나노입자를 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마말레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지 콘비프등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치즈 등), 식용식물유지, 마가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 히알루론산 나노입자를 첨가하여 제조할 수 있다.
상기 건강 기능식품 또한, 식품조성물로서 기능성 식품, 영양보조제, 건강 식품, 식품 첨가제 등의 다양한 형태를 포함하는 것이며, 당업계에 공지된 통상적인 방법에 따라 다양한 형태, 예컨대, 앞서 언급한 히알루론산 나노입자를 차, 쥬스, 드링크의 형태로 제조하거나, 과립화, 캡슐화, 분말화하거나, 이러한 화합물 또는 추출물을 음료, 과실 및 가공식품, 어류, 육류 및 그 가공식품, 빵류, 면류, 조미료 등 각종 식품에 첨가하여 제조함으로써 제공될 수 있다.
본 명세서에서 사용되는 용어는 하기와 같이 정의될 수 있다.
본 명세서에서 사용되는 용어 “인슐린 저항성”은 혈당을 낮추는 인슐린의 기능이 떨어져 세포가 포도당을 효과적으로 연소하지 못하는 것을 말한다. 인슐린 저항성이 높을 경우, 인체는 너무 많은 인슐린을 만들어 내고 이로 인해 고혈압이나 이상지방혈증은 물론 심장병, 당뇨병 등까지 초래할 수 있다.
[실시예]
이하 본 발명을 실시예에 의하여 더욱 상세히 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 이에 의해 본 발명의 기술적 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
실시예 1: 히알루론산 나노입자 HA-CA의 제조
600 mg의 히알루론산을 120 ml의 포름아마이드(formamide)에 녹이고 200 ml의 디메틸포름아마이드(dimethyl formamide)에 아미노에틸-5-β-콜라노아마이드(aminoethyl-5-β-cholanoamide) 199 mg을 녹여 글리콜 히알루론산 용액에 천천히 적하하였고, 364 mg의 1-에틸-3-(3-디메틸-아미노프로필) 카보디이미드(1-ethyl-3-(3- dimethyl-aminopropyl) carbodiimide; EDC)와 219 mg의 N-히드로숙시니미드(N-hydrosuccinimide; NHS)를 40 ml의 디메틸포름아마이드에 녹여 반응액에 가한 다음 상온에서 24시간 동안 교반하였다. 이후, 상기 반응액을 2일간 투석하여 미반응 물질을 제거한 후, 동결건조하여 히알루론산 나노입자(HA-CA)를 수득하였다.
도 2는 히알루론산 나노입자 HA-CA의 크기 및 TEM 이미지를 나타낸 것으로, 100 내지 400 nm까지 고루 분포하고 있으며, 평균적인 크기는 약 221±3.1 nm로 확인되었다. 또한, 건조된 히알루론산 나노입자 HA-CA를 PBS 버퍼에 분산시킬 경우 5β-콜란산의 작용기가 서로 응집됨으로서 구형으로 존재하는 것을 확인하였다.
실시예 2: 히알루론산 나노입자 HA-PCL의 제조
640 mg의 히알루론산과 290 mg의 프로파길아민을 0.4 M 염화클로라이드가 포함된 pH 8.5의 0.1M 붕산염완충용액에 녹인 후, 330 mg의 시아노수소화붕소를 천천히 적하하였고 50℃에서 5일간 교반을 진행하였다. 이후, 상기 반응액을 3일간 투석하여 미반응 물질을 제거한 후, 동결건조를 하여 알카인으로 개질된 히알루론산을 제조하였다. 알카인으로 개질된 히알루론산은 아지드로 개질된 폴리카프로락톤과의 클릭화학반응을 통해 아래와 같은 조건으로 진행하였다. 200 mg의 알카인으로 개질된 히알루론산을 40 ml의 탈이온화수에 녹이고, 64 mg의 아지드로 개질된 폴리카프로락톤을 40 ml의 디메틸포름아마이드에 각각 녹인 후 서로 섞어 준다. 상기 반응액에 10.60 mg의 황산구리5수화물과 8.41 mg의 아스코르브산나트륨을 함께 넣고 45℃에서 2일간 교반하였다. 이후, 반응액은 2일간 투석하여 미반응된 물질을 제거한 후, 동결건조하여 히알루론산 나노입자(HA-PCL)를 수득하였다.
도 3은 히알루론산 나노입자 HA-PCL의 크기 및 TEM 이미지를 나타낸 것으로, 100 내지 400 nm까지 고루 분포하고 있으며, 평균적인 크기는 약 220±2.5 nm로 확인되었다. 또한, 건조된 히알루론산 나노입자 HA-PCL을 PBS 버퍼에 분산시킬 경우 폴리카프로락톤의 작용기가 서로 응집됨으로서 구형으로 존재하는 것을 확인하였다.
실험예 1: 히알루론산 나노입자가 대사질환(비만, 당뇨병)에 미치는 영향
[동물실험]
모든 동물실험은 아주대학교 동물실험윤리규정을 준수하여 수행하였다.
비만/당뇨병 모델 생쥐는 4주령의 DBA/2를 사용하였고, 5개월간 60% 고지방 식이 급여를 통해 확보하였다.
실험은 약 30일간 매일 생쥐 각 개체마다 몸무게 기준 20 mg/kg으로 꼬리정맥으로 주사하였으며 마지막 날 사살 후 피, 간, 지방세포 등을 적출하였다.
[히알루론산 나노입자]
동물실험에서 사용된 모든 히알루론산 나노입자는 실시예 1 및 2에 따라 제조되었으며(성균관대학교에서 동결 건조된 상태로 제공받음), 히알루론산 나노입자 HA-CA 및 HA-PCL 8-10 mg을 각각 PBS 버퍼용액 1 ml에 녹여, 20 mg/kg 농도의 히알루론산 나노입자를 사용하였다.
1-1. 히알루론산 나노입자가 체중 및 식이량에 미치는 영향
고지방 식이 급여를 통해 만들어진 당뇨병모델 생쥐에 20 mg/kg의 농도의 히알루론산 나노입자 HA-CA 및 HA-PCL를 4주간 일 200 μl 투여하였으며, PBS 투여군을 대조군으로 사용하였다.
도 4 및 도 5는 히알루론산 나노입자 투여에 따른 당뇨병모델 생쥐의 체중 및 식이량의 변화를 각각 분석한 것으로, 히알루론산 나노입자를 투여한 약물군의 경우 대조군과 비교하였을 때 체중과 식이량 모두 감소하는 것을 확인할 수 있었다.
1-2. 히알루론산 나노입자가 혈당에 미치는 영향
고지방 식이 급여를 통해 만들어진 당뇨병모델 생쥐에 20 mg/kg의 농도의 히알루론산 나노입자 HA-CA 및 HA-PCL를 200 μl 투여한 다음, 2 g/kg 농도의 포도당을 복강내(intraperitoneally, IP) 주입하였으며, PBS 투여군을 대조군으로 사용하였다.
도 6은 히알루론산 나노입자 투여에 따른 당뇨병모델 생쥐의 혈액 내 포도당 농도를 시간별로 관찰한 것으로, 히알루론산 나노입자를 투여한 약물군의 경우 대조군과 비교하였을 때 포도당 항상성이 개선된 것을 확인할 수 있었다.
1-3. 히알루론산 나노입자의 인슐린 저항성
고지방 식이 급여를 통해 만들어진 당뇨병모델 생쥐에 20 mg/kg의 농도의 히알루론산 나노입자 HA-CA 및 HA-PCL를 200 μl 투여한 다음, 0.5 unit/kg 농도의 인슐린을 복강내(intraperitoneally, IP) 주입하였으며, PBS 투여군을 대조군으로 사용하였다.
도 7은 히알루론산 나노입자 투여에 따른 당뇨병모델 생쥐의 혈액 내 포도당 농도를 시간별로 관찰한 것으로, 히알루론산 나노입자를 투여한 약물군의 경우 대조군과 비교하였을 때 인슐린 저항성이 개선된 것을 확인할 수 있었다.
실험예 2: 히알루론산 나노입자가 고지방식이 유발 염증에 미치는 영향
[유전자 발현 변화 분석]
- RNA 분리 및 RT-Quantitative PCR 분석
Trizol reagent를 사용하여 RNA를 분리한 후 Nanodrop을 이용하여 260/280 ratio 2.0 이상의 샘플로 분석하였다.
Complementary DNA는 reverse transcriptase를 이용하여 합성하였고, target 유전자 특이적인 primer와 함께 RT-qPCR을 수행하였다. PCR 후 실험군 및 대조군 유전자의 발현 변화를 상대정량법 (Comparative quantification)으로 분석하였다.
- 면역화학염색(Immunohistochemistry)
생쥐의 간조직과 지방조직이 포함된 슬라이드를 각 단백질 특이적인 항체 또는 헤마톡실린 & 에오신을 이용하여 면역염색하였다.
2-1. 간 조직(liver tissue)에서 히알루론산 나노입자가 염증 인자에 미치는 영향
고지방 식이 급여를 통해 만들어진 당뇨병모델 생쥐에 20 mg/kg의 농도의 히알루론산 나노입자 HA-CA 및 HA-PCL를 200 μl 투여한 다음 간 조직을 분리하였으며, PBS 투여군을 대조군으로 사용하였다.
도 8은 간 조직에서 히알루론산 나노입자 투여에 따른 염증 인자; NF-κB 및 IL-1β를 분석한 것으로, 염증과 관련된 인자들을 대조군과 비교했을 때 히알루론산 나노입자를 투여한 약물군에서 유의하게 낮아진 것을 확인할 수 있었다.
2-2. 지방 조직(adipose tissue)에서 히알루론산 나노입자가 염증 인자에 미치는 영향
고지방 식이 급여를 통해 만들어진 당뇨병모델 생쥐에 20 mg/kg의 농도의 히알루론산 나노입자 HA-CA 및 HA-PCL를 200 μl 투여한 다음 지방 조직을 분리하였으며, PBS 버퍼를 대조군으로 사용하였다.
도 9는 지방 조직에서 히알루론산 나노입자 투여에 따른 염증 인자; CD44, IL-1β, TNF-α, NF-κB 및 NLRP3을 분석한 것으로, NLRP3 Inflammasome과 염증 반응 유발 인자들의 발현양이 대조군과 비교했을 때 히알루론산 나노입자를 투여한 약물군에서 유의하게 낮아진 것을 확인할 수 있었다.
도 10은 상기 분리한 지방 조직을 헤마토톡실린 & 에오신으로 염색한 다음 현미경 이미지를 나타낸 것으로, 고지방 식이 급여를 통해 지방 조직에 침윤된 대식세포에 의해 염증이 유발된 것을 확인할 수 있으며, 히알루론산 나노입자를 투여를 통해 호전된 것을 확인할 수 있었다.
도 11은 상기 헤마톡실린 & 에오신으로 염색된 지방 조직에 대식세포 특이적인 마커 MAC-2로 추가적인 면역 염색을 한 다음 현미경 이미지를 나타낸 것으로, 도 8과 마찬가지로 지방 조직 내 대식세포의 침윤이 약물군에서 감소한 것을 확인할 수 있었다.
실험예 3: 히알루론산 나노입자가 류마티스 관절염에 미치는 영향
[류마티스 관절염(CIA-HFD) 동물모델 구축]
3주령 수컷 DBA1 마우스를 1주간 안정화 시킨 후, 10주간 Western diet(#D12079B) 식이를 통해 고지방식이(High fat diet, HFD) 모델 구축하였다. 마우스가 7 주령이 되었을 때, Type II Collagen(Chondrex)을 꼬리피하로 주입하여, 1차 면역화(1st immunization)를 시행하고 3주 후 2차 부스팅(2nd boosting)을 통하여 관절염을 유도하였다. 이후 vehicle 혹은 실시예 1에 따른 HA-CA 20mg/kg 를 각각의 그룹에 정맥주사로 4주간 투여하였다.
3-1. 히알루론산 나노입자가 류마티스 관절염 증상 및 유병율에 미치는 영향
실험적인 류마티스 관절염(Collagen induced arthritis, CIA) 모델은 2차 부스팅(2nd boosting) 후 사지 발목 관절부분이 팽윤(swelling)된다. 이러한 팽윤된 정도를 기준 관찰(scoring)하여 관절염의 진행 정도를 분석하였다. 4주간 약물을 투여하며 버니어 캘리퍼스를 사용하여 2일에 한번 마우스의 발목의 팽윤된 정도를 측정하였고, 관절염의 진행 정도를 평가하였다. 측정의 신뢰성을 높이기 위해 3회씩 시행하였다. 또한, 특정 Score 이상(score #2)의 개체를 관절염 발병개체로 규정하였을 때, 얼마나 더 빨리 혹은 더 많이 해당 관절염 발병개체가 증가하는가를 분석하였다.
구체적인 Scoring 기준은 공지된 논문(Inglis JJ et al., Protocol for the induction of arthritis in C57BL/6 mice. Nat Protoc 2008; 3:612-8)을 참고하였으며, scoring은 0~4로 세분화할 수 있다. 0은 이상 없음, 1은 살짝 붓거나 발을 계속 오므리고 있는 상태, 2는 발가락 1개가 확실하게 빨갛게 부은 상태 또는 확실하게 부었지만 심하지 않은 상태, 3은 발가락 1개가 확실하게 빨갛게 붓고 발등이 확실하게 부었지만 심하지 않은 상태 또는 발가락이 2개 이상 확실하게 부은 상태, 4는 발전체가 붓고 빨갛게 된 상태를 나타내는 것이다.
도 12 및 도 13은 류마티스 관절염 동물모델을 이용하여 류마티스 관절염 증상과 유병률(incidence)에서 히알루론산 나노입자의 효과를 나타낸 것으로, 고지방식이에 의해 악화된 류마티스 관절염 증상과 유병률이 히알루론산 나노입자를 투여한 약물군에서 호전되는 것을 확인할 수 있었다.
3-2. 히알루론산 나노입자가 류마티스 관절염 동물모델의 관절조직 파괴정도에 미치는 영향
적출한 조직(ankle, knee)을 고정 및 포매 후 박절하여 파라핀 절편을 만들었다. Mayer’s Hematoxylin 과 Fast green, Safranin O solution 를 이용하여 절편을 염색하고, 관절조직 활막(synovium)내 혹은 뼈(bone)로 침윤된 면역세포들과, 관절의 파괴 정도를 분석하였다.
도 14를 살펴보면, 류마티스 관절염에서 나타나는 연골 파괴, 활막내 면역세포 침윤(synovitis) 및 뼈로의 침투(bone erosion)가 히알루론산 나노입자를 투여한 약물군에서 호전되는 것을 확인할 수 있었다.
실험예 4: 히알루론산 나노입자가 퇴행성 관절염에 미치는 영향
[연골세포 배양 및 히알루론산 나노입자에 의한 관절염증 억제 및 연골파괴 억제 확인]
연골세포(Chondrocyte)는 생후 5일 정상 마우스의 대퇴골두(femoral heads), 대퇴골 관절(femoral condyles) 및 경골 고원부(tibial plateaus) 유래의 연골 조직으로부터 수득하였다. 수득한 연골세포는 10%(v/v) 우태아혈청(fetal bovine serum, Gibco, USA), 50μg/ml의 스트렙토마이신(Sigma-Aldrich, USA) 및 50 unit/ml 페니실린(Sigma-Aldrich, USA)이 함유된 DMEM 배지(Gibco, USA)에서 37℃, 5% CO2 조건으로 세포 인큐베이터(cell incubator)에서 배양하였다.
IL-1β는 관절 염증 및 연골 조직 파괴를 촉진하는 대표적인 염증성 사이토카인이다. 연골세포에 5ng/ml의 IL-1β을 시간별로 처리한 다음, 하기 표 1의 조건 및 프라이머(primer)를 사용하여 Mmp3, Mmp13, Cox2, IL-6, GAPDH에 대한 qRT-PCR을 수행하였다.
도 15를 살펴보면, 연골세포에서 IL-1β에 의해 증가된 Mmp3, Mmp13, Cox2, IL-6의 발현이 히알루론산 나노입자에 의해 농도 의존적으로 감소하는 것을 할 수 있었다. 이는 히알루론산 나노입자에 의해 관절염증 및 연골 조직 파과가 완화 및 억제될 수 있음을 나타낸다.
본 발명에 따른 히알루론산 나노입자를 함유하는 염증질환 또는 대사질환의 예방 또는 치료용 약학 조성물은, 체중을 감소시키고, 식이량을 저하시켰으며, GTT(Glucose Tolerance Test) 결과 혈당을 감소시키는 효과가 있으며, 인슐린 저항성, 염증 유발인자들(NF-κB, IL-1β, CD44, TNF-α, NLRP3 inflammasome 등) 및 대식세포 조직침윤을 저하시키는 효과가 있으므로 염증질환 및 대사질환의 예방 또는 치료용 약학 조성물로 유용하게 사용될 수 있다.
전자파일 첨부하였음.
Claims (8)
- 제1항에 있어서, 상기 [화학식 1]로 표시되는 히알루론산 나노입자는 히알루론산과 5β-콜란산이 질량비로 1:0.05 내지 1:0.30으로 구성되는 것을 특징으로 하는 조성물.
- 제1항에 있어서, 상기 [화학식 2]로 표시되는 히알루론산 나노입자는 히알루론산과 폴리카프로락톤이 질량비로 1:0.20 내지 1:0.40으로 구성되는 것을 특징으로 하는 조성물.
- 제1항에 있어서, 상기 히알루론산 나노입자는 수용액 상태에서 자기조립(self-assembly)을 통해 형성된 것을 특징으로 하는 조성물.
- 제1항에 있어서, 상기 히알루론산 나노입자는 입자의 직경이 100 내지 500 nm인 것을 특징으로 하는 조성물.
- 제1항에 있어서, 상기 염증질환은 관절염, 비염, 간염, 각막염, 위염, 장염, 신장염, 기관지염, 흉막염, 복막염, 척추염, 췌장염, 염증성 통증, 요도염, 방광염, 화상 염증, 피부염, 치주염, 치은염 및 퇴행성 신경염증으로 구성되는 군에서 선택된 1종 이상인 것을 특징으로 하는 조성물.
- 제1항에 있어서, 상기 대사질환은 제1형 당뇨병, 제2형 당뇨병, 고혈압, 고지혈증, 비만, 관상동맥경화증 및 동맥경화증으로 구성되는 군에서 선택된 1종 이상인 것을 특징으로 하는 조성물.
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KR20110032561A (ko) | 2009-09-23 | 2011-03-30 | 포항공과대학교 산학협력단 | 약물 전달체의 표적 특이성 조절 방법, 표적 특이적 약물 전달체, 및 표적-비특이적 약효 장기 지속성 약물 전달체 |
US11617804B2 (en) | 2014-07-18 | 2023-04-04 | Wake Forest University | Hyaluronic acid-based nanoparticles as biosensors for imaging-guided surgery and drug delivery vehicles and methods associated therewith |
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2016
- 2016-10-11 KR KR1020160131347A patent/KR101905863B1/ko active IP Right Grant
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2017
- 2017-09-28 WO PCT/KR2017/010824 patent/WO2018070711A2/ko active Application Filing
- 2017-09-28 US US16/340,897 patent/US10806800B2/en active Active
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KR101905863B1 (ko) | 2018-10-08 |
KR20180039937A (ko) | 2018-04-19 |
WO2018070711A3 (ko) | 2018-06-07 |
US10806800B2 (en) | 2020-10-20 |
US20190231898A1 (en) | 2019-08-01 |
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