KR20170137433A - Deselenide compound and oxidation-seneitive particle comprising the same and method for preparing the same - Google Patents
Deselenide compound and oxidation-seneitive particle comprising the same and method for preparing the same Download PDFInfo
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- KR20170137433A KR20170137433A KR1020160069576A KR20160069576A KR20170137433A KR 20170137433 A KR20170137433 A KR 20170137433A KR 1020160069576 A KR1020160069576 A KR 1020160069576A KR 20160069576 A KR20160069576 A KR 20160069576A KR 20170137433 A KR20170137433 A KR 20170137433A
- Authority
- KR
- South Korea
- Prior art keywords
- oxidation
- sensitive particles
- diselenide compound
- group
- diselenide
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Abstract
Description
본 발명은 디셀레나이드 화합물, 이를 포함하는 산화-감응성 입자 및 이의 제조방법에 관한 것이다.The present invention relates to a diselenide compound, an oxidation-sensitive particle comprising the same, and a process for producing the same.
암 치료 시 사용되는 방사선은 높은 에너지의 베타선 등으로 과산화수소, 일항산소, 라디칼과 같은 활성산소의 생성을 유도하여 암세포의 DNA 손상을 일으켜서 암의 생장을 억제하거나 종양을 파괴하므로, 방사선 치료 부위에는 높은 농도의 활성산소가 존재한다.Radiation used in cancer treatment induces the production of reactive oxygen species such as hydrogen peroxide, anoxic oxygen and radicals by high energy beta rays, which causes DNA damage of cancer cells to inhibit cancer growth or destroy tumors, Concentration of active oxygen is present.
셀레늄(selenium)은 체내에 미량 존재하는 항산화 미네랄로서 특히, 비타민 E와 결합하여 유해산소와 라디칼을 효과적으로 제거하는 필수적인 항산화 작용과 함께 다양한 생리·약리 작용을 하는 물질이지만, 방사선 치료는 암 환자의 혈액에서 셀레늄의 농도를 감소시키고 방사선 치료의 부작용을 증가시키는 것으로 알려져 있다. Selenium is a very small amount of antioxidant minerals present in the body. Especially, it is a substance that has various physiological and pharmacological actions together with vitamin E, which is an essential antioxidant that effectively removes harmful oxygen and radicals. However, Is known to reduce the concentration of selenium and increase the side effects of radiation therapy.
따라서 체내 셀레늄 농도를 증가시키면 암 발생을 억제하고, 암세포를 민감하게(sensitize)하여 파클리탁셀(paclitaxel)과 같은 기존 항암제의 약효를 증가시킬 수 있기 때문에 최근 셀레늄 함유 항암제 개발과 함께 항암약물을 암세포 및 암 특이적 환경에 전달하기 위해 셀레늄을 이용한 다양한 입자 개발이 연구되고 있다. Therefore, increasing the concentration of selenium in the body can inhibit cancer development and sensitize cancer cells to increase the efficacy of existing anticancer drugs such as paclitaxel. Therefore, in addition to the development of selenium-containing anticancer drugs, cancer drugs and cancer The development of various particles using selenium has been studied to transfer to a specific environment.
특히, 방사선에 의해 과생성될 수 있는 활성 산소종은 두 분자 셀레늄이 공유결합이 되어있는 디셀레나이드(diselenide)를 이용하게 되면 서로 반응하여 디셀레나이드가 높은 반응속도로 산화될 수 있기 때문에 이 성질을 활용하여 디셀레나이드(diseleneide)를 주쇄에 함유하는 산화-감응성(oxidation-sensitive) 입자를 이용한 항암용 약물전달체 개발이 가능하다. In particular, reactive oxygen species that can be generated by radiation may react with each other if the two molecular seleniums are covalently bonded to each other and the diselenide may be oxidized at a high reaction rate. It is possible to develop an anticancer drug delivery system using oxidation-sensitive particles containing diseleneide in the main chain.
본 발명은 양말단에 음이온기를 가지는 디셀레나이드 화합물 및 이를 포함하는 산화-감응성 입자 등을 제공하고자 한다. Disclosed is a diselenide compound having an anionic group at both ends and an oxidation-sensitive particle containing the same.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는, 양말단에 음이온기를 가지는 디셀레나이드 화합물을 제공한다:The present invention provides a diselenide compound having an anionic group at both terminal ends represented by the following general formula (1) or (2)
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
본 발명의 일 구현예로, 양말단에 음이온기를 가지는 디셀레나이드 화합물을 포함하는 산화-감응성 입자를 제공한다. In one embodiment of the present invention, there is provided an oxidation-sensitive particle comprising a diselenide compound having an anionic group at both ends thereof.
상기 디셀레나이드 화합물은 하기 화학식 1 또는 화학식 2로 표시될 수 있다:The diselenide compound may be represented by the following Formula 1 or Formula 2:
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
상기 디셀레나이드 화합물은 아민기 함유 생체적합성 고분자와 이온 결합될 수 있다. The diselenide compound may be ion-bonded to an amine group-containing biocompatible polymer.
상기 아민기 함유 생체적합성 고분자는 키토산, 히알루론산 및 이의 유도체, 폴리라이신(polylysine), 폴리알릴아민(polyallylamine) 및 폴리(N-이소프로필아크릴아마이드)(poly(N-isopropylacrylamide))로 이루어진 군으로부터 선택된 하나 이상을 포함할 수 있다.The amine group-containing biocompatible polymer may be selected from the group consisting of chitosan, hyaluronic acid and derivatives thereof, polylysine, polyallylamine and poly (N-isopropylacrylamide) And may include at least one selected.
상기 디셀레나이드 화합물 및 상기 아민기 함유 생체적합성 고분자의 중량비는 1:10 내지 10:1일 수 있다.The weight ratio of the diselenide compound and the amine group-containing biocompatible polymer may be 1:10 to 10: 1.
상기 산화-감응성 입자는 트리폴리인산염이 추가로 이온 결합될 수 있다.The oxidation-sensitive particles may further be ion-bonded to tripolyphosphate.
상기 산화-감응성 입자의 크기는 100nm 내지 3㎛일 수 있다.The size of the oxidation-sensitive particles may be 100 nm to 3 탆.
상기 산화-감응성 입자에 단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신, 호르몬 및 형광물질로 이루어진 군으로부터 선택된 하나 이상의 기능성 물질이 담지될 수 있다.The oxidation-sensitive particle may be loaded with at least one functional material selected from the group consisting of proteins, polypeptides, peptides, genes, anticancer agents, vaccines, hormones and fluorescent substances.
상기 디셀레나이드 화합물은 방사선 조사에 의해 생성되는 활성산소에 의해 분해되면서, 상기 담지된 기능성 물질이 방출될 수 있다.The diselenide compound is decomposed by the active oxygen generated by irradiation with radiation, so that the supported functional material can be released.
본 발명의 다른 구현예로, (a) 셀레늄(Se2) 및 C1 내지 C10의 할로겐화 알코올을 반응시켜 양말단에 하이드록시기를 가지는 디셀레나이드 화합물을 제조하는 단계; 및 (b) 상기 (a) 단계에서 제조한 디셀레나이드 화합물에 산의 염을 반응시켜 양말단에 음이온기를 가지는 디셀레나이드 화합물을 제조하는 단계를 포함하는 산화-감응성 입자의 제조방법을 제공한다. In another embodiment of the present invention, there is provided a process for producing a diselenide compound, comprising: (a) reacting selenium (Se 2 ) and a C1 to C10 halogenated alcohol to prepare a diselenide compound having a hydroxy group at both ends; And (b) reacting the diselenide compound prepared in the step (a) with a salt of an acid to prepare a diselenide compound having an anionic group at both ends thereof. .
(c-1) 상기 (b)에서 제조한 디셀레나이드 화합물과 아민기 함유 생체적합성 고분자를 반응시키는 단계를 포함할 수 있다.(c-1) reacting the diselenide compound prepared in (b) with an amine group-containing biocompatible polymer.
(c-2) 상기 (b)에서 제조한 디셀레나이드 화합물과 아민기 함유 생체적합성 고분자 및 트리폴리인산염을 반응시키는 단계를 포함할 수 있다.(c-2) reacting the diselenide compound prepared in (b) with an amine group-containing biocompatible polymer and tripolyphosphate.
단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신, 호르몬 및 형광물질로 이루어진 군으로부터 선택된 하나 이상의 기능성 물질을 추가로 반응시킬 수 있다.One or more functional substances selected from the group consisting of proteins, polypeptides, peptides, genes, anticancer agents, vaccines, hormones and fluorescent substances may be further reacted.
본 발명에 따른 양말단에 설페이트기 혹은 포스페이트기 등 음이온기를 가지는 디셀레나이드 화합물을 포함하는 산화-감응성 입자는 과산화수소, 일항산소, 라디칼과 같은 활성산소에 의해 분해가 촉진된다.The oxidation-sensitive particle comprising a diselenide compound having an anion group such as a sulfate group or a phosphate group at both ends of the present invention is decomposed by active oxygen such as hydrogen peroxide, anoxic oxygen, and radical.
상기 디셀레나이드 화합물이 아민기 함유 생체적합성 고분자와 이온 결합하고, 선택적으로, 트리폴리인산염과 추가 이온 결합하고, 내부에 항암제 등 약물을 담지함으로써, 항암용 약물전달체로서 유용하고, 방사선 치료와 병행하여 항암 약물 치료에 사용될 수 있다. The above diselenide compound is ion-bonded to an amine group-containing biocompatible polymer, selectively ion-bonded to tripolyphosphate, and is supported as a medicament such as an anticancer drug in the inside, thereby being useful as an anticancer drug delivery system. Can be used for anti-cancer drug treatment.
도 1은 제조예 2에서 합성한 3,3'-디셀란디일비스(프로판-1-올)의 NMR 결과와 실시예 1에서 제조한 디셀레나이드 화합물의 NMR 결과를 나타낸 그래프이다.
도 2(a)는 실시예 1에서 제조한 디셀레나이드 화합물의 과산화수소-감응성 효과를 보여주는 그래프이고, 도 2(b)는 실시예 1에서 제조한 디셀레나이드 화합물의 방사선-감응성 효과를 보여주는 그래프이다.
도 3은 실시예 3, 5, 12 및 14에서 제조한 산화-감응성 입자의 크기 및 표면전하를 나타낸 표이다.
도 4는 실시예 10에서 제조한 산화-감응성 입자의 방사선 조사량에 따른 분해 정도를 나타낸 사진이다.
도 5는 실시예 12 및 14에서 제조한 유전자 담지 산화-감응성 입자의 유전자 담지 효율 및 유전자 발현 억제 효율과, 실시예 10에서 제조한 약물 담지 산화-감응성 입자의 약물 담지 효율 및 약물 방출 효율을 나타낸 표이다.
도 6은 실시예 12에서 제조한 유전자 담지 산화-감응성 입자의 N/P 비에 따른 유전자 담지 여부를 확인한 사진이다.
도 7은 실시예 16에서 제조한 형광물질 담지 산화-감응성 입자의 세포 내 이입 여부를 확인한 사진이다.1 is a graph showing NMR results of 3,3'-dicellandiylbis (propane-1-ol) synthesized in Production Example 2 and NMR results of a diselenide compound prepared in Example 1.
FIG. 2 (a) is a graph showing the hydrogen peroxide-sensitizing effect of the diselenide compound prepared in Example 1, and FIG. 2 (b) is a graph showing the radiation-sensitizing effect of the diselenide compound prepared in Example 1 to be.
3 is a table showing the size and surface charge of the oxidation-sensitive particles prepared in Examples 3, 5, 12 and 14.
4 is a photograph showing the degree of decomposition of the oxidation-sensitive particles prepared in Example 10 according to the dose of radiation.
5 shows the gene carrying efficiency and gene expression inhibition efficiency of the gene-carrying oxidative-sensitive particles prepared in Examples 12 and 14 and the drug carrying efficiency and drug release efficiency of the drug-bearing oxidative-sensitive particles prepared in Example 10 Table.
FIG. 6 is a photograph showing the presence or absence of gene transfer according to the N / P ratio of the gene-carrying oxidation-sensitive particles prepared in Example 12. FIG.
FIG. 7 is a photograph showing the intracellular transfer of the fluorescent substance-bearing oxidation-sensitive particles prepared in Example 16. FIG.
본 발명자들은 양말단에 설페이트기 혹은 포스페이트기 등 음이온기를 가지는 디셀레나이드 화합물을 포함하는 산화-감응성 입자의 산화-감응성 효과, 특히, 방사선 조사에 따른 산화-감응성 효과를 확인하고, 본 발명을 완성하였다.The inventors of the present invention have confirmed the oxidation-sensitizing effect of the oxidation-sensitive particles including a diselenide compound having an anion group such as a sulfate group or a phosphate group at both ends, in particular, the oxidation-sensitizing effect upon irradiation, Respectively.
본 발명에서 "산화-감응성(oxidation-sensitive)"은 과산화수소, 일항산소, 라디칼과 같은 활성산소에 의해 분해가 촉진되는 정도를 의미하는 것으로, 상기 활성산소는 방사선 조사에 의해 생성될 수 있다. The term "oxidation-sensitive" in the present invention means the extent to which degradation is promoted by active oxygen such as hydrogen peroxide, anoxic oxygen, radicals, and the active oxygen can be generated by irradiation with radiation.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
디셀레나이드Diselenide 화합물 및 이를 포함하는 산화- Compounds and oxidation- 감응성Sensitivity 입자 particle
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는, 양말단에 음이온기를 가지는 디셀레나이드 화합물을 제공한다:The present invention provides a diselenide compound having an anionic group at both terminal ends represented by the following general formula (1) or (2)
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
또한, 본 발명은 양말단에 음이온기를 가지는 디셀레나이드 화합물을 포함하는 산화-감응성 입자를 제공한다. The present invention also provides an oxidation-sensitive particle comprising a diselenide compound having an anionic group at both ends thereof.
구체적으로, 상기 디셀레나이드 화합물은 두개의 셀레늄이 공유결합을 통해 형성되는 디셀레나이드를 주쇄에 함유하는 화합물로서, 양말단에 음이온성 말단으로 아민 등과 같은 양이온기와 화학적인 결합이 가능한 설페이트기 또는 포스페이트기와 같은 음이온기를 가진 것을 특징으로 한다.Specifically, the diselenide compound is a compound containing a diselenide in which two selenium is formed through covalent bonding, in which the sulfate group capable of chemically bonding with a cation group such as an amine at the anionic terminal at both ends or And an anionic group such as a phosphate group.
보다 구체적으로, 상기 디셀레나이드 화합물은 하기 화학식 1 및 화학식 2로 표시될 수 있다: More specifically, the diselenide compound may be represented by the following formulas (1) and (2): < EMI ID =
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
보다 더 구체적으로, 증류수에 셀레늄(Se)을 분산시키고, 증류수에 소듐 보로하이드라이드(Sodium borohydride)를 녹였다. 증류수에 녹인 소듐 보로하이드라이드(Sodium borohydride)를 셀레늄(Se)에 발열을 최소화 할 수 있을 정도로 소량씩 넣었다. 이 때 반응 온도는 -10℃ 내지 30℃가 바람직하나 이에 한정되지는 않는다. More specifically, selenium (Se) was dispersed in distilled water and sodium borohydride was dissolved in distilled water. Sodium borohydride dissolved in distilled water was added to selenium (Se) in such a small amount as to minimize heat generation. The reaction temperature is preferably -10 ° C to 30 ° C, but is not limited thereto.
혼합한 셀레늄(Se)와 소듐 보로하이드라이드(Sodium borohydride)는 50℃ 내지 100℃에서 색상이 변할 때까지 가열하였다. 이 때 반응시간은 30분 내지 6시간 이 바람직하나 이에 한정되지는 않는다. 20℃ 내지 50℃까지 온도를 낮춘 후, THF에 녹인 할로겐화 알코올을 첨가하였다. 이때 할로겐화 알코올의 탄소수는 1 내지 10이 바람직하나 이에 한정되지는 않는다. 6시간 내지 24시간 반응 후 디클로로메탄(dichloromethane)과 증류수를 넣어 추출한 후 여과하였다. 디클로로메탄(dichloromethane)과 증류수의 비는 10:1 내지 1:10이 바람직하나 이에 한정되지는 않는다. 이후, 에틸아세테이트(ethylacetate)와 헥산(hexane) 혼합액을 이동상으로 하여 컬럼크로마토그래피를 통해 분리하여 3,3'-디셀란디일비스(프로판-1-올) (3,3'-diselanediylbis(propan-1-ol))을 제조하였다. 에틸아세테이트(ethylacetate)와 헥산(hexane)의 비는 20:1 내지 1:20이 바람직하나 이에 한정되지는 않는다.The mixed selenium (Se) and sodium borohydride were heated at 50 ° C to 100 ° C until the color changed. The reaction time is preferably 30 minutes to 6 hours, but is not limited thereto. After lowering the temperature to 20 to 50 캜, a halogenated alcohol dissolved in THF was added. At this time, the number of carbon atoms of the halogenated alcohol is preferably 1 to 10, but is not limited thereto. After reacting for 6 hours to 24 hours, dichloromethane and distilled water were added to extract and then filtered. The ratio of dichloromethane to distilled water is preferably from 10: 1 to 1:10, but is not limited thereto. Thereafter, the mixture was separated by column chromatography using a mixture of ethylacetate and hexane as a mobile phase to obtain 3,3'-diselanediylbis (propan-1-ol) 1-ol)). The ratio of ethylacetate to hexane is preferably 20: 1 to 1:20, but is not limited thereto.
합성한 3,3'-디셀란디일비스(프로판-1-올) (3,3'-diselanediylbis(propan-1-ol))와 SO3-피리딘(SO3-Pyridine) 또는 PO3-피리딘(PO3-Pyridine)을 디메틸포름아마이드 (dimethylformamide)에 각각 녹인 후 -10℃ 내지 30℃에서 두 용액을 혼합하여 반응하였다. 이때 반응시간은 30분 내지 6시간이 바람직하나 이에 한정되지는 않는다. 반응물에 디클로로메탄(dichloromethane)과 증류수를 넣어 추출한 후 여과, 건조하여 3,3'-디셀란디일비스(프로판-1-설페이트) (3,3'-diselanediylbis(propan-1-sulfate))를 제조하였다. 디클로로메탄(dichloromethane)과 증류수의 비는 10:1 내지 1:10이 바람직하나 이에 한정되지는 않는다.(3,3'-diselanediylbis (propan-1-ol)) and SO 3 -pyridine (SO 3 -Pyridine) or PO 3 -pyridine (propan- PO 3 -Pyridine) was dissolved in dimethylformamide, and the two solutions were mixed at -10 ° C to 30 ° C for reaction. The reaction time is preferably 30 minutes to 6 hours, but is not limited thereto. The reaction product was extracted with dichloromethane and distilled water, filtered and dried to prepare 3,3'-diselanediylbis (propan-1-sulfate) (3,3'-diselanediylbis Respectively. The ratio of dichloromethane to distilled water is preferably from 10: 1 to 1:10, but is not limited thereto.
상기 디셀레나이드 화합물만을 이용하여 나노입자 제조가 가능하지만 아민기 함유 생체적합성 고분자와 이온 결합되는 것이 바람직하나, 이에 한정되지 않는다. 상기 디셀레나이드 화합물은 양말단에 설페이트기 또는 포스페이트기를 가짐으로써, 상기 생체적합성 고분자의 아민기와 이온 결합이 용이한 이점이 있다.Although it is possible to prepare nanoparticles using only the diselenide compound, it is preferably ion-bound to the amine group-containing biocompatible polymer, but not limited thereto. Since the diselenide compound has a sulfate group or a phosphate group at both ends, ionic bonding with the amine group of the biocompatible polymer is advantageous.
상기 아민기 함유 생체적합성 고분자는 유리 1차 아민기를 가지고 있어 화학적 변성이 용이한 키토산, 히알루론산 및 이의 유도체, 폴리라이신(polylysine), 폴리알릴아민(polyallylamine) 및 폴리(N-이소프로필아크릴아마이드)(poly(N-isopropylacrylamide))로 이루어진 군으로부터 선택된 하나 이상을 포함하는 것이 바람직하나, 이에 한정되지 않는다. 또한, 상기 트리폴리인산염은 산화-감응성 입자의 크기를 조절하고 안정성을 높이기 위해 추가로 처리될 수 있다.The amine group-containing biocompatible polymer includes chitosan, hyaluronic acid and derivatives thereof, polylysine, polyallylamine and poly (N-isopropylacrylamide), which have a free primary amine group and are easily chemically modified. (poly (N-isopropylacrylamide)), but the present invention is not limited thereto. In addition, the tripolyphosphate may be further treated to control the size of the oxidation-sensitive particles and to increase their stability.
상기 디셀레나이드 화합물 및 상기 아민기 함유 생체적합성 고분자의 중량비는 1:100 내지 100:1인 것이 바람직하나, 이에 한정되지 않는다. 이때, 디셀레나이드 화합물의 함량이 너무 높으면, 반응할 수 있는 아민기의 비율이 적어지기 때문에 추후 입자 표면 혹은 입자 중에 단백질 또는 형광 물질 등을 도입할 수 있는 반응에 제한이 있고, 아민기 함유 생체적합성 고분자의 함량이 너무 높으면, 입자의 제조가 어렵다는 문제점이 있다. The weight ratio of the diselenide compound and the amine group-containing biocompatible polymer is preferably 1: 100 to 100: 1, but is not limited thereto. At this time, if the content of the diselenide compound is too high, the proportion of the amine group capable of reacting becomes small, so that there is a limit to the reaction that can introduce a protein or a fluorescent substance into the particle surface or particles, If the content of the compatible polymer is too high, there is a problem that it is difficult to produce the particles.
상기 산화-감응성 입자의 크기는 10nm 내지 3㎛일 수 있고, 80nm 내지 1㎛의 나노 크기, 바람직하게 100nm 내지 500nm의 나노 크기인 것이 바람직하나, 이에 한정되지 않는다. The size of the oxidation-sensitive particles may be 10 nm to 3 탆, and is preferably nano size of 80 nm to 1 탆, preferably 100 nm to 500 nm, but is not limited thereto.
상기 산화-감응성 입자에 단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신, 호르몬 및 형광물질으로 이루어진 군으로부터 선택된 하나 이상의 기능성 물질이 담지됨으로써, 약물 전달체로 사용될 수 있다. The oxidation-sensitive particles may be used as a drug delivery system by supporting one or more functional substances selected from the group consisting of proteins, polypeptides, peptides, genes, anticancer agents, vaccines, hormones and fluorescent substances.
구체적으로, 상기 단백질, 폴리펩타이드, 및 펩타이드는 엑센딘-4, 에리스로포이에틴, 인터페론-알파, 인테페론-베타, 인터페론-감마, 성장 호르몬, 성장 호르몬 방출인자, 신경 성장 인자, G-CSF(granulocyte-colony stimulating factor), GM-CSF(granulocyte macrophage-colony stimulating factor), M-CSF(macrophage-colony stimulating factor), 혈액응고 인자, 인슐린, 옥시토신, 바소프레신, 부신피질 자극호르몬, 섬유아세포 성장인자, 표피성장인자, 혈소판 유래 성장인자, 인슐린유사 성장인자, 혈관내피 성장인자, 변환성장인자, 신경성장인자, 뇌신경성장인자, 뉴로트로핀-3, 뉴로트로핀-4/5, 프로락틴, 룰리베린, 황체형성호르몬 방출호르몬(LHRH), LHRH 작용제, LHRH 길항제, 성장호르몬방출 억제인자, 글루카곤, 인터루킨-2(IL-2), 인터루킨-11(IL-11), 가스트린, 테트라가스트린, 펜타가스트린, 유로가스트론, 세크레틴, 칼시토닌, 엔케팔린, 엔돌핀, 안지오텐신, 갑상선자극호르몬 방출호르몬, 종양괴사인자, 종양괴사인자관련 세포자멸사유발 리간드, 헤파린 분해효소, 골형성 단백질, hANP(human atrial natriuretic peptide), 글루카곤유사 펩타이드, 레닌, 브라디키닌, 바시트라신, 폴리믹신, 콜리스틴, 티로시딘, 그라미시딘, 사이클로스포린, 뉴로텐신, 타키티닌, 뉴로펩타이드 Y, 펩타이드 YY, 혈관활성장내폴리펩타이드, 하수체성 아데닐레이트 사이클레이즈-활성 폴리펩타이드; 상기 물질들 중 어느 하나의 합성 아날로그, 단클론항체, 항체, 및 변형되거나 약효를 나타내는 부분; 효소; 및 사이토카인류로 이루어진 군으로부터 선택된 하나 이상일 수 있다.Specifically, the proteins, polypeptides, and peptides are selected from the group consisting of exendin-4, erythropoietin, interferon-alpha, interferon-beta, interferon-gamma, growth hormone, growth hormone releasing factor, nerve growth factor, granulocyte- colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), blood coagulation factor, insulin, oxytocin, vasopressin, adrenocorticotropic hormone, fibroblast growth factor, epidermal growth factor , Platelet-derived growth factor, insulin-like growth factor, vascular endothelial growth factor, transforming growth factor, nerve growth factor, cranial growth factor, neurotropin-3, neurotropin-4/5, prolactin, (LHRH), LHRH agonist, LHRH antagonist, growth hormone releasing factor, glucagon, interleukin-2 (IL-2), interleukin-11 (IL-11), gastrin, tetragastrin, penta- A hormone releasing hormone, a tumor necrosis factor, a tumor necrosis factor-related apoptosis-inducing ligand, a heparin degrading enzyme, an osteogenic protein, a human atrial natriuretic peptide (hANP), a glucagon-like peptide , Neuropeptide Y, peptides YY, vasoactive intestinal polypeptides, sulphate-containing adenoviruses such as cysteine, cysteine, cysteine, cysteine, cysteine, Nilate cyclase-active polypeptide; A synthetic analogue, a monoclonal antibody, an antibody, and a modified or potentiated portion of any one of the above materials; enzyme; ≪ / RTI > and cytokines.
상기 항암제는 독소루비신, 파클리탁셀, 5-플루오로우라실, 시스플라틴, 카보플라틴, 옥살리플라틴, 테가푸르, 이리노테칸, 도세탁셀, 사이클로포스파미드, 셈시타빈, 이포스파미드, 미토마이신 C, 빈크리스틴, 에토포사이드, 메토트렉세이트, 토포테칸, 타모시펜, 비노렐빈, 캄토테신, 다누오루비신, 클로람부실, 브리오스타틴-1, 칼리케아미신, 마이아탄신, 레바이솔, DNA 재조합 인터페론 알파-2a, 미토산트론, 니무스틴, 인터페론 알파-2a, 독시플루리딘, 포메스테인, 류프롤라이드 아세테이트, 메게스트롤 아세테이트, 카모포르, 테니포사이드, 블레오마이신, 카무스틴, 헵타플라틴, 엑세메스탄, 아나스트로졸, 에스트라무스틴, 카페시타빈, 고세렐린 아세테이트, 폴리사카라이드 칼륨, 메드록시포게스테론 아세테이트, 에피루비신, 레트로졸, 피라루비신, 토포테칸, 알트레타민, 토레미펜 시트레이트, BCNU, 탁소텔, 악티노마이신 D, 아나스트로졸, 벨로테칸, 이메티닙, 플록수리딘, 젬시타빈, 하이드로시유리아, 졸레드로네이트, 플루타마이드, 발루비신, 스트렙토조신, 폴리에틸렌글라이콜 접합 항암제; 및 상기 물질들 중 어느 하나의 합성 아날로그 및 변형되거나 동일한 약효를 나타내는 물질로 이루어진 군으로부터 선택된 하나 이상일 수 있다.Wherein the anticancer agent is selected from the group consisting of doxorubicin, paclitaxel, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, tegafur, irinotecan, docetaxel, cyclophosphamide, semcitabine, ipospamide, mitomycin C, , Methotrexate, topotecan, tamoxifen, vinorelbine, camptothecin, danuroubicin, chlorambucil, briostatin-1, calicheamicin, myatancin, revasol, DNA recombinant interferon alpha-2a, But are not limited to, cholinesterase inhibitors such as cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, Sol, estra mestin, capecitabine, goserelin acetate, polysaccharide potassium, medroxyphogesteron acetate, epirubicin, letrozole, pyrabicin, But are not limited to, topotecan, altretamine, toremifensitrate, BCNU, taxotere, actinomycin D, anastrozole, bellotecan, imetinib, fluoxurdine, gemcitabine, hydrocyanourea, zoledronate, Id, valvicin, streptozocin, polyethylene glycol conjugated anticancer agent; And synthetic analogs of any of the above materials, and materials exhibiting modified or the same pharmaceutical efficacy.
상기 백신은 간염 백신일 수 있고, 상기 호르몬은 테스토스테론, 에스트라디올, 프로게스테론, 프로스타글란딘; 및 상기 물질들 중 어느 하나의 합성 아날로그, 및 변형되거나 동일한 약효를 나타내는 물질로 이루어진 군으로부터 선택된 하나 이상일 수 있다.The vaccine may be a hepatitis vaccine, wherein the hormone is selected from the group consisting of testosterone, estradiol, progesterone, prostaglandin; And a synthetic analogue of any one of the above materials, and a material exhibiting a modified or the same pharmaceutical effect.
상기 유전자는 siRNA, miRNA 및 plasmid DNA로 이루어진 군으로부터 선택된 하나 이상일 수 있다. 그 중에서도 siPCGF5와 같은 방사선에 민감한 유전자를 이용하면 방사선 치료 효율을 높일 수 있다.The gene may be at least one selected from the group consisting of siRNA, miRNA and plasmid DNA. Among them, radiation-sensitive genes such as siPCGF5 can increase the efficiency of radiation therapy.
예를 들어, 상기 산화-감응성 입자에 항암제를 담지하는 경우 상기 입자와 항암제의 중량비는 1:100 내지 100:1인 것이 바람직하나, 이에 한정되지 않는다. 또한, 상기 산화-감응성 입자에 유전자를 담지하는 경우 N/P 비에 따라 1:10내지 1000:1인 것이 바람직하나, 이에 한정되지 않는다.For example, when the anticancer agent is carried on the oxidation-sensitive particles, the weight ratio of the particles to the anticancer agent is preferably 1: 100 to 100: 1, but is not limited thereto. In addition, when the gene is carried on the oxidation-sensitive particle, it is preferably 1:10 to 1000: 1 depending on the N / P ratio, but is not limited thereto.
이때, 단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신 및 호르몬과 같은 약물의 함량이 너무 작은 경우, 약물 전달로 인한 효과가 미미한 문제점이 있고, 단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신 및 호르몬과 같은 약물의 함량이 너무 큰 경우, 약물 담지 효율이 크게 떨어지는 문제점이 있다.At this time, when the content of a drug such as a protein, a polypeptide, a peptide, a gene, an anticancer agent, a vaccine and a hormone is too small, there is a problem that a drug delivery effect is insignificant, and a protein, a polypeptide, a peptide, a gene, When the content of a drug such as a hormone is too large, there is a problem that the efficiency of drug loading is greatly lowered.
또한, 상기 형광물질은 FITC 또는 Courmarin 6 일 수 있고, 형광물질을 도입함으로써 테라그노시스 용도로 활용가능하다. In addition, the fluorescent material may be FITC or
상기 산화-감응성 입자에 형광물질을 담지하는 경우 상기 입자와 형광물질의 중량비는 1:1 내지 1000:1인 것이 바람직하나, 이에 한정되지 않는다. 이때, 형광물질의 함량이 너무 작은 경우, 진단용도로 적용에 부적합하고, 형광물질의 함량이 너무 큰 경우 입자의 물리적 특성에 영향을 준다는 문제점이 있다.When the fluorescent substance is supported on the oxidation-sensitive particles, the weight ratio of the particles to the fluorescent substance is preferably 1: 1 to 1000: 1, but is not limited thereto. At this time, when the content of the fluorescent material is too small, it is unsuitable for the application for diagnosis, and when the content of the fluorescent material is too large, it affects the physical properties of the particles.
상기 디셀레나이드 화합물은 방사선 조사에 의해 생성되는 활성산소에 의해 분해되면서, 상기 담지된 기능성 물질이 방출될 수 있다.The diselenide compound is decomposed by the active oxygen generated by irradiation with radiation, so that the supported functional material can be released.
디셀레나이드Diselenide 화합물을 포함하는 산화- The oxidation- 감응성Sensitivity 입자의 제조방법 Method of manufacturing particles
또한, 본 발명은 (a) 셀레늄(Se2) 및 C1 내지 C10의 할로겐화 알코올을 반응시켜 양말단에 하이드록시기를 가지는 디셀레나이드 화합물을 제조하는 단계; 및 (b) 상기 (a) 단계에서 제조한 디셀레나이드 화합물에 산의 염을 반응시켜 양말단에 음이온기를 가지는 디셀레나이드 화합물을 제조하는 단계를 포함하는 산화-감응성 입자의 제조방법을 제공한다.The present invention also provides a method for producing a diselenide compound, comprising the steps of: (a) reacting selenium (Se 2 ) and a C1 to C10 halogenated alcohol to prepare a diselenide compound having a hydroxy group at both ends; And (b) reacting the diselenide compound prepared in the step (a) with a salt of an acid to prepare a diselenide compound having an anionic group at both ends thereof. .
구체적으로, 상기 산의 염은 설폰산염 또는 포스폰산염일 수 있고, 상기 음이온기는 설페이트기 또는 포스페이트기일 수 있다. Specifically, the salt of the acid may be a sulfonate or a phosphonate, and the anion group may be a sulfate group or a phosphate group.
보다 구체적으로, 상기 디셀레나이드 화합물은 하기 화학식 1 또는 화학식 2로 표시될 수 있다: More specifically, the diselenide compound may be represented by the following formula (1) or (2):
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
(c-1) 상기 (b)에서 제조한 디셀레나이드 화합물과 아민기 함유 생체적합성 고분자를 반응시키는 단계를 추가로 포함할 수 있다. 혹은, (c-2) 상기 (b)에서 제조한 디셀레나이드 화합물과 아민기 함유 생체적합성 고분자 및 트리폴리인산염을 반응시키는 단계를 추가로 포함할 수 있다. (c-1) a step of reacting the diselenide compound prepared in (b) with an amine group-containing biocompatible polymer. Or (c-2) reacting the diselenide compound prepared in (b) with an amine group-containing biocompatible polymer and tripolyphosphate.
구체적으로, 상기 아민기 함유 생체적합성 고분자는 전술한 바와 같이, 키토산, 히알루론산 및 이의 유도체, 폴리라이신(polylysine), 폴리알릴아민(polyallylamine) 및 폴리(N-이소프로필아크릴아마이드)(poly(N-isopropylacrylamide))로 이루어진 군으로부터 선택된 하나 이상을 포함하는 것이 바람직하나, 이에 한정되지 않는다. 또한, 상기 트리폴리인산염은 산화-감응성 입자의 크기를 조절하고 안정성을 높이기 위해 추가로 처리될 수 있다. Specifically, the amine group-containing biocompatible polymer may be selected from the group consisting of chitosan, hyaluronic acid and derivatives thereof, polylysine, polyallylamine and poly (N-isopropylacrylamide) (poly -isopropylacrylamide)), but it is not limited thereto. In addition, the tripolyphosphate may be further treated to control the size of the oxidation-sensitive particles and to increase their stability.
상기 (c-1) 또는 상기 (c-2) 단계에서, 단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신, 호르몬 및 형광물질로 이루어진 군으로부터 선택된 하나 이상의 기능성 물질을 추가로 반응시킬 수 있다. In the step (c-1) or (c-2), one or more functional substances selected from the group consisting of proteins, polypeptides, peptides, genes, anticancer agents, vaccines, hormones and fluorescent substances may be further reacted.
상기한 바와 같이, 본 발명에 따른 양말단에 설페이트기 혹은 포스페이트기 등 음이온기를 가지는 디셀레나이드 화합물을 포함하는 산화-감응성 입자는 과산화수소, 일항산소, 라디칼과 같은 활성산소에 의해 분해가 촉진된다.As described above, the oxidation-sensitive particles comprising a diselenide compound having an anion group such as a sulfate group or a phosphate group at both ends of the present invention are decomposed by active oxygen such as hydrogen peroxide, anoxic oxygen, and radicals.
상기 디셀레나이드 화합물이 아민기 함유 생체적합성 고분자와 이온 결합하고, 선택적으로, 트리폴리인산염과 추가 이온 결합하고, 내부에 항암제 등 약물을 담지함으로써, 항암용 약물전달체로서 유용하고, 방사선 치료와 병행하여 항암 약물 치료에 사용될 수 있다. The above diselenide compound is ion-bonded to an amine group-containing biocompatible polymer, selectively ion-bonded to tripolyphosphate, and is supported as a medicament such as an anticancer drug in the inside, thereby being useful as an anticancer drug delivery system. Can be used for anti-cancer drug treatment.
본 발명에 따른 산화-감응성 입자가 약물전달체로 이용되기 위해서는, 약제학적 분야에서 공지된 방법에 의해 제조될 수 있으며, 약학적으로 허용되는 담체, 부형제, 희석제 등과 혼합하여 분말, 과립, 정제, 캡슐제, 또는 주사제 등의 제형으로 제조되어 사용될 수 있다. 또한 이들은 비경구 투여(예컨대, 정맥 내, 피하, 복강 내 또는 국소에 적용)하거나 경구 투여될 수 있다.In order for the oxidation-sensitive particles according to the present invention to be used as a drug delivery vehicle, they may be prepared by a method well known in the pharmaceutical field and may be prepared by mixing powders, granules, tablets, capsules Or injections, and the like. They may also be administered parenterally (e. G., Intravenously, subcutaneously, intraperitoneally or topically) or orally.
이때, 투여량은 환자의 연령, 성별, 체중, 건강상태, 질병의 증상, 투여시간, 투여방법에 따라 적절히 선택될 수 있으며, 바람직하게는 성인기준 1일 0.01~100mg이 투여될 수 있다.At this time, the dose may be appropriately selected according to the patient's age, sex, weight, health condition, symptom of disease, time of administration, method of administration, and preferably 0.01 to 100 mg per day on an adult basis.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[[ 실시예Example ]]
제조예Manufacturing example 1: 21: 2 ,2'-,2'- 디셀란디일비스에탄올Dichelandyl bisethanol (2,2'-(2,2'- diselanediylbisethanoldiselenanediylbisethanol )의 합성) Synthesis of
증류수에 셀레늄(Se)을 분산시키고 교반하였고, 증류수에 소듐 보로하이드라이드(Sodium borohydride)를 녹였다. 얼음조(ice bath)에서 증류수에 녹인 소듐 보로하이드라이드(Sodium borohydride)를 셀레늄(Se)에 발열을 최소화 할 수 있는 소량씩 넣었다. 오일조(Oil bath)로 교체한 후 적갈색이 될 때까지 80℃로 가열하였다. 이후, 실온까지 온도를 낮춘 후, THF에 녹인 브로모에탄올(bromoethanol)을 한방울씩(dropwise) 넣었다. 24시간 반응 후 디클로로메탄(dichloromethane)과 증류수를 넣어 추출한 후 여과하였다. 이후, 에틸아세테이트(ethylacetate)과 헥산(hexane)을 10:3의 비율로 혼합하여 이동상으로 이용해 컬럼 크로마토그래피로 분리하였다.Selenium (Se) was dispersed in distilled water and stirred, and sodium borohydride was dissolved in distilled water. In an ice bath, sodium borohydride dissolved in distilled water was added to selenium (Se) in small amounts to minimize heat generation. After replacing with an oil bath, the mixture was heated to 80 DEG C until it became reddish brown. After the temperature was lowered to room temperature, bromoethanol dissolved in THF was dropwise added. After 24 hours of reaction, dichloromethane and distilled water were added to extract and then filtered. Then, ethylacetate and hexane were mixed at a ratio of 10: 3 and separated by column chromatography using a mobile phase.
[반응식 1][Reaction Scheme 1]
제조예Manufacturing example 2: 32: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-올) (3,3'-(Propan-1-ol) (3,3'- diselanediylbisdiselanediylbis (( propanpropane -1-ol))의 합성-1-ol))
브로모에탄올(bromoethanol) 대신 브로모프로판올(bromopropanol)을 이용한 것을 제외하고는, 제조예 1과 동일한 방법으로 수행하였다.The procedure of Production Example 1 was repeated except that bromopropanol was used instead of bromoethanol.
[반응식 2][Reaction Scheme 2]
제조예 2에서 합성한 3,3'-디셀란디일비스(프로판-1-올)의 NMR 결과는 도 1(a)에 나타난 바와 같다.The NMR results of 3,3'-dicellandiylbis (propane-1-ol) synthesized in Production Example 2 are as shown in FIG.
제조예Manufacturing example 3: 63: 6 ,6'-, 6'- 디셀란디일비스Dicerandilbis (( 헥산Hexane -1-올) (6,6'-Ol) (6,6'- diselanediybisdiselenized (( haxanhaxan -1--One- olbe ))의 합성))
브로모에탄올(bromoethanol) 대신 브로모헥산올(bromohexanol)을 이용한 것을 제외하고는, 제조예 1과 동일한 방법으로 수행하였다.The procedure of Production Example 1 was repeated except that bromohexanol was used instead of bromoethanol.
[반응식 3] [Reaction Scheme 3]
실시예Example 1: 31: 3 ,3’-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ) (3,3’-diselanediylbis(propan-1-sulfate))의 제조 및 이의 과산화수소/방사선 민감성 확인) (3,3'-diselanediylbis (propan-1-sulfate)) and its hydrogen peroxide / radiation sensitivity confirmation
DMF에 제조예 2에서 합성한 3,3’-디셀란디일비스(프로판-1-올) (3,3’-diselanediylbis(propan-1-ol))를 녹여 제1 용액을 제조하였다. DMF에 SO3-피리딘(SO3-Pyridine)이 투명해질 때까지 녹여 제2 용액을 제조하였다. 제1 용액을 얼음조(ice bath)에서 냉각시켜준 후, 제2 용액을 한방울씩(dropwise) 넣었다. 1시간 동안 교반하면서 반응시키고, 디클로로메탄(dichloromethane)과 증류수를 넣어 추출한 후, 건조하였다. The first solution was prepared by dissolving the 3,3'-diselanediylbis (propan-1-ol) synthesized in Production Example 2 in DMF. SO 3 in DMF - pyridine (SO 3 -Pyridine) to prepare a second solution by dissolving until it became transparent. The first solution was cooled in an ice bath and then the second solution was dropwise added. The reaction was carried out with stirring for 1 hour, extracted with dichloromethane and distilled water, and then dried.
[반응식 4][Reaction Scheme 4]
실시예 1에서 제조한 디셀레나이드 화합물의 NMR 결과는 도 1(b)에 나타난 바와 같다.The NMR results of the diselenide compound prepared in Example 1 are as shown in Fig. 1 (b).
실시예 1에서 제조한 디셀레나이드 화합물에 증류수를 넣어 20μM의 농도로 제조한 후, 여기에 10μM로 희석한 과산화수소(H2O2)를 각각 100㎕, 200㎕, 300㎕, 400㎕씩 넣어주었다. 각각의 샘플을 200~600nm의 파장으로 강도(intensity)를 측정하였다. Distilled water was added to the diselenide compound prepared in Example 1 at a concentration of 20 μM, followed by adding 100 μl, 200 μl, 300 μl and 400 μl of hydrogen peroxide (H 2 O 2 ) diluted to 10 μM gave. The intensity of each sample was measured at a wavelength of 200 to 600 nm.
도 2(a)는 실시예 1에서 제조한 디셀레나이드 화합물의 과산화수소-감응성 효과를 보여주는 그래프이다. FIG. 2 (a) is a graph showing the hydrogen peroxide-sensitizing effect of the diselenide compound prepared in Example 1. FIG.
도 2(a)에 나타난 바와 같이, 과산화수소의 농도가 증가할수록, 디셀레나이드의 고유 흡수 파장인 302nm에서 흡광도가 감소함을 확인할 수 있었는바, 실시예 1에서 제조한 디셀레나이드 화합물은 과산화수소와 같은 활성산소에 의해 분해가 촉진됨을 확인할 수 있었다.As shown in FIG. 2 (a), it was confirmed that as the concentration of hydrogen peroxide increases, the absorbance decreases at 302 nm, which is the intrinsic absorption wavelength of the diselenide. As a result, It was confirmed that decomposition was promoted by the same active oxygen.
실시예 1에서 제조한 디셀레나이드 화합물에 증류수를 넣어 30μM의 농도로 제조한 후, 여기에 방사선을 각각 10Gy, 50Gy, 100Gy, 300Gy, 500Gy씩 조사해 주었다. 각각의 샘플을 250~600nm의 파장으로 흡광도(absorbance)를 측정하였다. Distilled water was added to the diselenide compound prepared in Example 1 at a concentration of 30 μM and irradiated with 10 Gy, 50 Gy, 100 Gy, 300 Gy, and 500 Gy, respectively. The absorbance of each sample was measured at a wavelength of 250 to 600 nm.
도 2(b)는 실시예 1에서 제조한 디셀레나이드 화합물의 방사선-감응성 효과를 보여주는 그래프이다. FIG. 2 (b) is a graph showing the radiation-sensitizing effect of the diselenide compound prepared in Example 1. FIG.
도 2(b)에 나타난 바와 같이, 방사선 조사 선량이 증가할수록, 최대 흡광도 값을 가지는 파장이 디셀레나이드의 고유 흡수 파장인 302nm에서 더 낮은 파장대로 변화를 나타나는바, 실시예 1에서 제조한 디셀레나이드 화합물은 방사선에 의해 분해가 촉진됨을 확인 할 수 있었다.As shown in FIG. 2 (b), as the irradiation dose increases, the wavelength having the maximum absorbance value changes from 302 nm, which is the intrinsic absorption wavelength of the diselenide, to the lower wavelength band. It was confirmed that the selenide compound accelerated decomposition by radiation.
실시예Example 2: 32: 3 ,3’-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 포스페이트Phosphate ) (3,3’-diselanediylbis(propan-1-phosphate))의 제조) (3,3'-diselanediylbis (propan-1-phosphate))
SO3-피리딘(SO3-Pyridine) 대신 PO3-피리딘(PO3-Pyridine)을 이용한 것을 제외하고는, 실시예 1과 동일한 방법으로 수행하였다.Instead, pyridine (SO 3 -Pyridine) PO 3 - -
[반응식 5][Reaction Scheme 5]
실시예Example 3: 33: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ) 및 키토산이 이온 ) And chitosan ion 결합된Combined 산화-감응성 입자의 제조 Preparation of oxidation-sensitive particles
1% 아세트산 수용액에 키토산을 1 mg/ml의 농도로 녹였다. 키토산 질량의 약 1.2배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물을 증류수에 녹인 후, 키토산 용액에 실린지 펌프(syringe pump)를 이용하여 32ml/min의 속도로 넣고, 700rpm, 25℃ 조건으로 30분간 반응시키고, 20000g, 25℃ 조건으로 15분간 원심 분리하여 산화-감응성 입자를 제조하였다. 산화-감응성 입자의 크기 및 표면전하는 동적광산란법(DLS)을 이용하여 확인하였다. Chitosan was dissolved in 1% acetic acid aqueous solution at a concentration of 1 mg / ml. The diselenide compound prepared in Example 1, which corresponds to about 1.2 times the mass of chitosan, was dissolved in distilled water. The chitosan solution was loaded into the chitosan solution at a rate of 32 ml / min using a syringe pump, And the mixture was centrifuged at 20000 g and 25 ° C for 15 minutes to prepare oxidation-sensitive particles. The size and surface charge of the oxidation-sensitive particles were confirmed by dynamic light scattering (DLS).
실시예 3에서 제조한 산화-감응성 입자의 크기 및 표면전하는 각각 676.4±9.2nm, 30.6±1.1mV였다(도 3 참고).The size and surface charge of the oxidation-sensitive particles prepared in Example 3 were 676.4 ± 9.2 nm and 30.6 ± 1.1 mV, respectively (see FIG. 3).
실시예Example 4: 34: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 히알루론산이 이온 결합된 산화-), Chitosan and hyaluronic acid, 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산 질량의 약 0.5배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산 질량의 약 0.5배에 해당하는 히알루론산을 각각 증류수에 녹인 것을 제외하고는, 실시예 3과 동일한 방법으로 수행하였다.Except that the diselenide compound prepared in Example 1 corresponding to about 0.5 times the mass of chitosan and hyaluronic acid corresponding to about 0.5 times the mass of the chitosan were each dissolved in distilled water, .
실시예Example 5: 35: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 ), Chitosan and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 산화- Oxidation- 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산과 동량인 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산 질량의 약 0.3배에 해당하는 트리폴리인산염(tripolyphosphate)를 각각 증류수에 녹인 것을 제외하고는, 실시예 3과 동일한 방법으로 수행하였다.The diselenide compound prepared in Example 1, which was the same amount as that of chitosan, and tripolyphosphate corresponding to about 0.3 times the mass of chitosan were respectively dissolved in distilled water.
실시예 5에서 제조한 산화-감응성 입자의 크기 및 표면전하는 각각 234.0±1.7nm, 44.0±1.3mV였다(도 3 참고). 실시예 3에 비해, 실시예 5와 같이 트리폴리인산염을 추가로 처리한 경우, 산화-감응성 입자의 크기가 더욱 작아지고, 표면 전하는 더 높아짐을 확인할 수 있었다. The size and surface charge of the oxidation-sensitive particles prepared in Example 5 were 234.0 1.7 nm and 44.0 1.3 mV, respectively (see FIG. 3). It was confirmed that the oxidation-sensitive particle size was further reduced and the surface charge was higher when tripolyphosphate was further treated as in Example 5, compared with Example 3.
실시예Example 6: 36: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ) 및 히알루론산이 이온 ) And hyaluronic acid ion 결합된Combined 산화-감응성 입자의 제조 Preparation of oxidation-sensitive particles
3차 증류수에 히알루론산을 3 mg/ml의 농도로 녹였다. 히알루론산 질량의 약 0.7배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물을 증류수에 녹인 후, 히알루론산 용액에 실린지 펌프(syringe pump)를 이용하여 32ml/min의 속도로 넣고, 700rpm, 25℃ 조건으로 30분간 반응시키고, 20000g, 25℃ 조건으로 15분간 원심 분리하여 산화-감응성 입자를 제조하였다. Hyaluronic acid was dissolved in the third distilled water at a concentration of 3 mg / ml. The diselenide compound prepared in Example 1, which corresponds to about 0.7 times the mass of hyaluronic acid, was dissolved in distilled water, and the mixture was injected into a hyaluronic acid solution at a rate of 32 ml / min using a syringe pump. The reaction was carried out at 25 ° C for 30 minutes and centrifuged at 20000g and 25 ° C for 15 minutes to prepare oxidation-sensitive particles.
실시예Example 7: 37: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산, 히알루론산 및 ), Chitosan, hyaluronic acid and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 산화- Oxidation- 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산과 동량인 실시예 1에서 제조한 디셀레나이드 화합물과 히알루론산 및 키토산 질량의 약 0.2배에 해당하는 트리폴리인산염을 각각 증류수에 녹인 것을 제외하고는, 실시예 3과 동일한 방법으로 수행하였다.The same procedure as in Example 3 was carried out except that the diselenide compound prepared in Example 1, which was the same amount as that of chitosan, and the tripolyphosphate corresponding to about 0.2 times the mass of hyaluronic acid and chitosan were dissolved in distilled water, respectively.
실시예Example 8: 38: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ) 및 키토산이 이온 ) And chitosan ion 결합된Combined 약물 담지 산화-감응성 입자의 제조 Preparation of drug-supported oxidation-sensitive particles
1% 아세트산 수용액에 키토산을 1mg/ml의 농도로 녹이고, 키토산 및 항암제의 일종인 캄토테신을 질량비 10:1로 혼합한 것을 제외하고는, 실시예 3과 동일한 방법으로 수행하였다. The procedure of Example 3 was repeated except that chitosan was dissolved in 1% acetic acid aqueous solution at a concentration of 1 mg / ml and chitosan and camptothecin, a kind of anticancer agent, were mixed at a mass ratio of 10: 1.
실시예Example 9: 39: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 히알루론산이 이온 결합된 약물 담지 산화-), Chitosan and hyaluronic acid ion-bound drug-bearing oxidation- 감응성Sensitivity 입자의 제조 Manufacturing of particles
1% 아세트산 수용액에 키토산을 1.5 mg/ml의 농도로 녹이고, 키토산 및 항암제의 일종인 파클리탈셀을 질량비 10:1로 혼합한 것을 제외하고는, 실시예 4와 동일한 방법으로 수행하였다.Except that chitosan was dissolved in a 1% acetic acid aqueous solution at a concentration of 1.5 mg / ml, chitosan and a paclitaxel as a kind of anticancer agent were mixed at a mass ratio of 10: 1.
실시예Example 10: 310: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 ), Chitosan and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 약물 담지 산화- The drug- 감응성Sensitivity 입자의 제조 Manufacturing of particles
1% 아세트산 수용액에 키토산을 1mg/ml의 농도로 녹이고, 키토산 및 항암제의 일종인 독소루비신을 질량비 10:1로 혼합한 것을 제외하고는, 실시예 5와 동일한 방법으로 수행하였다. Except that chitosan was dissolved in a 1% acetic acid aqueous solution at a concentration of 1 mg / ml, and chitosan and doxorubicin, a kind of anticancer agent, were mixed at a mass ratio of 10: 1.
실시예 10에서 제조한 약물 담지 산화-감응성 입자에 대하여, 방사선을 각각 0Gy(대조군), 2Gy, 4Gy, 10Gy, 50Gy, 100Gy씩 조사하였고, 투과전자현미경(TEM)을 이용하여 방사선 조사 전과 조사 후 약물 담지 산화-감응성 입자의 형상 변화를 관찰하였다. Each of the drug-bearing oxidative-sensitive particles prepared in Example 10 was irradiated with 0 Gy (control group), 2 Gy, 4 Gy, 10 Gy, 50 Gy and 100 Gy for each of the radiation, and a transmission electron microscope (TEM) The morphological changes of the drug-bearing oxidation-sensitive particles were observed.
도 4는 실시예 10에서 제조한 약물 담지 산화-감응성 입자의 방사선 조사량에 따른 분해 정도를 나타낸 사진으로, 도 4에 나타난 바와 같이, 방사선 조사량이 0Gy에서 100Gy로 증가할수록, 실시예 10에서 약물 담지 산화-감응성 입자는 분해가 촉진됨을 확인할 수 있었다((a): 방사선 조사량=0Gy, (b): 방사선 조사량=50Gy, (c): 방사선 조사량=100Gy). FIG. 4 is a photograph showing the degree of decomposition of the drug-bearing oxidation-sensitive particles prepared in Example 10 according to the irradiation dose. As shown in FIG. 4, as the irradiation dose was increased from 0 Gy to 100 Gy, (A): irradiation dose = 0 Gy, (b): irradiation dose = 50 Gy, (c): irradiation dose = 100 Gy).
실시예 10에서 제조한 약물 담지 산화-감응성 입자에 대하여, 하기 식으로 약물 담지 효율을 평가한 결과, 도 5에 나타난 바와 같이, 키토산 및 트리폴리인산염만 결합된 경우 또는 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산만 결합된 경우에 비해, 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산에 트리폴리인산염을 추가로 처리한 경우, 약물 담지 효율이 증가함을 확인할 수 있었다. As a result of evaluating the drug-supporting efficiency of the drug-bearing oxidation-sensitive particles prepared in Example 10 as shown in the following formula, it was found that when only chitosan and tripolyphosphate were bound, It was confirmed that when the diselenide compound prepared in Example 1 and chitosan were further treated with tripolyphosphate, the drug loading efficiency was increased as compared with the case where only the nide compound and chitosan were combined.
또한, 실시예 10에서 제조한 약물 담지 산화-감응성 입자에 대하여, 37℃ 항온수조에서 3일간 약물 방출을 유도한 후 480nm이 파장에서 측정한 결과, 도 5에 나타난 바와 같이, 키토산 및 트리폴리인산염만 결합된 경우에 비해, 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산에 트리폴리인산염을 추가로 처리한 경우, 약물 방출 효율이 증가함을 확인할 수 있었다. As shown in FIG. 5, when the drug-releasing oxide-sensitive particles prepared in Example 10 were subjected to drug release for 3 days in a constant temperature water bath at 37 ° C. and measured at a wavelength of 480 nm, only chitosan and tripolyphosphate It was confirmed that the drug release efficiency was increased when the diselenide compound prepared in Example 1 and chitosan were further treated with tripolyphosphate.
실시예Example 11: 311: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산, 히알루론산 및 ), Chitosan, hyaluronic acid and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 약물 담지 산화- The drug- 감응성Sensitivity 입자의 제조 Manufacturing of particles
1% 아세트산 수용액에 키토산을 0.5 mg/ml의 농도로 녹이고, 키토산 및 항암제의 일종인 독소루비신을 질량비 10:1로 혼합한 것을 제외하고는, 실시예 7과 동일한 방법으로 수행하였다.Except that chitosan was dissolved in a 1% acetic acid aqueous solution at a concentration of 0.5 mg / ml, and chitosan and doxorubicin, a kind of anticancer agent, were mixed at a mass ratio of 10: 1.
실시예Example 12: 312: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ) 및 키토산이 이온 ) And chitosan ion 결합된Combined 유전자 담지 산화- Gene bearing oxidation - 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산 질량의 약 1.5배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물에 N/P 비가 10:1이 되도록 siGFP를 혼합한 것을 제외하고는, 실시예 3과 동일한 방법으로 수행하였다.Except that the diselenide compound prepared in Example 1, which corresponds to about 1.5 times the mass of chitosan, was mixed with siGFP so that the N / P ratio was 10: 1.
실시예 12에서 제조한 산화-감응성 입자의 크기 및 표면전하는 각각 1395±9.5nm, 28.4±1.8mV였다(도 3 참고).The size and surface charge of the oxidation-sensitive particles prepared in Example 12 were 1395 ± 9.5 nm and 28.4 ± 1.8 mV, respectively (see FIG. 3).
실시예 12에서 제조한 유전자 담지 산화-감응성 입자에 대하여, 4% agarose gel을 이용한 전기영동을 통해 유전자 담지 효율을 평가한 결과, 도 5에 나타난 바와 같이, 유전자 담지 효율이 우수함을 확인할 수 있었다. As shown in FIG. 5, the gene carrying efficiency of the gene-bearing oxidative-sensitive particles prepared in Example 12 was evaluated by electrophoresis using 4% agarose gel. As a result, it was confirmed that the gene carrying efficiency was excellent.
또한, 실시예 12에서 제조한 유전자 담지 산화-감응성 입자에 대하여, 형광 현미경을 이용한 녹생 형광 단백질(Green Fluorescence Protein)의 감소를 통해 유전자 발현 억제 효율을 평가한 결과, 도 5에 나타난 바와 같이, 키토산 및 트리폴리인산염만 결합된 경우에 비해, 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산이 결합된 경우, 유전자 발현 억제 효율이 증가함을 확인할 수 있었다.In addition, the gene-inhibiting oxidation-sensitive particles prepared in Example 12 were evaluated for gene expression inhibition efficiency by reduction of Green Fluorescence Protein using a fluorescence microscope. As a result, as shown in FIG. 5, And tripolyphosphate were bound, it was confirmed that the gene expression suppression efficiency was increased when the diselenide compound prepared in Example 1 and chitosan were bound to each other.
실시예Example 13: 313: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 히알루론산이 이온 ), Chitosan and hyaluronic acid ions 결합된Combined 유전자 담지 산화- Gene bearing oxidation - 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산 질량의 약 0.8배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물에 N/P 비가 30:1이 되도록 shPCGF5를 혼합한 것을 제외하고는, 실시예 4와 동일한 방법으로 수행하였다. Except that the diselenide compound prepared in Example 1, which corresponds to about 0.8 times the mass of chitosan, was mixed with shPCGF5 such that the N / P ratio was 30: 1.
실시예Example 14: 314: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 ), Chitosan and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 유전자 담지 산화- Gene bearing oxidation - 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산 질량의 약 1.5배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물에 N/P 비가 20:1이 되도록 siPCGF5를 혼합한 것을 제외하고는, 실시예 5와 동일한 방법으로 수행하였다. Except that the diselenide compound prepared in Example 1, which corresponds to about 1.5 times the mass of chitosan, was mixed with siPCGF5 so that the N / P ratio was 20: 1.
실시예 14에서 제조한 유전자 담지 산화-감응성 입자의 크기 및 표면전하는 각각 299.7±2.5nm, 44.4±0.8mV였다(도 3 참고). 실시예 12에 비해, 실시예 14와 같이 트리폴리인산염을 추가로 처리한 경우, 산화-감응성 입자의 크기가 더욱 작아지고, 표면 전하는 더 높아짐을 확인할 수 있었다.The size and surface charge of the gene-carrying oxidation-sensitive particles prepared in Example 14 were 299.7 ± 2.5 nm and 44.4 ± 0.8 mV, respectively (see FIG. 3). It was confirmed that, when the tripolyphosphate was further treated as in Example 14, the size of the oxidation-sensitive particles was further reduced and the surface charge was higher than that of Example 12. [
실시예 14에서 제조한 유전자 담지 산화-감응성 입자에 대하여, 4% agarose gel을 이용한 전기영동을 통해 유전자 담지 효율을 평가한 결과, 도 5에 나타난 바와 같이, 유전자 담지 효율이 우수함을 확인할 수 있었다. As shown in FIG. 5, the gene carrying efficiency of the gene-bearing oxidation-sensitive particles prepared in Example 14 was evaluated by electrophoresis using 4% agarose gel. As shown in FIG.
또한, 실시예 14에서 제조한 유전자 담지 산화-감응성 입자에 대하여, 형광 현미경을 이용한 녹생 형광 단백질(Green Fluorescence Protein)의 감소를 통해 유전자 발현 억제 효율을 평가한 결과, 도 5에 나타난 바와 같이, 키토산 및 트리폴리인산염만 결합된 경우 또는 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산이 결합된 경우에 비해, 실시예 1에서 제조한 디셀레나이드 화합물 및 키토산에 트리폴리인산염을 추가로 처리한 경우, 유전자 발현 억제 효율이 증가함을 확인할 수 있었다.In addition, the gene-inhibiting oxidation-sensitive particles prepared in Example 14 were evaluated for gene expression inhibition efficiency by reduction of Green Fluorescence Protein using a fluorescence microscope. As a result, as shown in FIG. 5, And tripolyphosphate were further added to the diselenide compound and chitosan prepared in Example 1 as compared to the case where only the tripolyphosphate or the case where the diselenide compound and chitosan prepared in Example 1 were combined, It was confirmed that the expression inhibition efficiency was increased.
도 6은 전기영동을 통해 N/P 비에 따른 유전자 담지 여부를 확인한 결과, 도 6에 나타난 바와 같이, N/P 비가 20:1일 때 유전자 담지 효율이 가장 우수함을 확인할 수 있었다. As shown in FIG. 6, when the N / P ratio was 20: 1, it was confirmed that the gene carrying efficiency was the best in the case of carrying the gene according to the N / P ratio through the electrophoresis.
실시예Example 15: 315: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산, 히알루론산 및 ), Chitosan, hyaluronic acid and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 유전자 담지 산화- Gene bearing oxidation - 감응성Sensitivity 입자의 제조 Manufacturing of particles
키토산 질량의 약 1.7배에 해당하는 실시예 1에서 제조한 디셀레나이드 화합물에 N/P 비가 100:1이 되도록 plasmid DNA를 혼합한 것을 제외하고는, 실시예 7과 동일한 방법으로 수행하였다. The plasmid DNA was mixed with the diselenide compound prepared in Example 1 to give an N / P ratio of 100: 1, which corresponds to about 1.7 times the mass of chitosan.
실시예Example 16: 316: 3 ,3'-, 3'- 디셀란디일비스Dicerandilbis (프로판-1-(Propane-1- 설페이트Sulfate ), 키토산 및 ), Chitosan and 트리폴리인산염이Tripolyphosphate 이온 ion 결합된Combined 형광 물질 담지 산화- Fluorescent substance supported Oxidation- 감응성Sensitivity 입자의 제조 Manufacturing of particles
1% 아세트산 수용액에 키토산을 0.9 mg/ml의 농도로 녹이고, 키토산 질량의 약 0.1배에 해당하는 FITC를 키토산 용액과 1시간 동안 반응시킨 것을 제외하고는, 실시예 5와 동일한 방법으로 수행하였다. Except that chitosan was dissolved in a 1% acetic acid aqueous solution at a concentration of 0.9 mg / ml, and FITC corresponding to about 0.1 times the chitosan mass was reacted with the chitosan solution for 1 hour.
실시예 16에서 제조한 형광물질 담지 산화-감응성 입자의 세포 내 이입 여부를 확인하기 위해서, 유방암 세포라인(Breast cancer cell line)의 일종인 MDA-MB-468 세포를 6 웰 플레이트에 배양한 후, 실시예 16에서 제조한 형광물질 담지 산화-감응성 입자를 100μg/ml, 200μg/ml의 농도로 처리하였고, 3일간 배양 후 공초점 현미경(confocal microscope)를 이용하여 세포 내 이입됨을 확인하였다(도 7 참고). MDA-MB-468 cells, a type of breast cancer cell line, were cultured on a 6-well plate in order to confirm the intracellular entry of the fluorescent substance-bearing oxidation-sensitive particles prepared in Example 16, The phosphor-supported oxidative-sensitive particles prepared in Example 16 were treated at a concentration of 100 μg / ml and 200 μg / ml, and after 3 days of culture, they were confirmed to be intracellularly introduced using a confocal microscope (FIG. 7 Reference).
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
Claims (14)
[화학식 1]
[화학식 2]
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.
A diselenide compound having an anionic group at both terminal ends represented by the following general formula (1) or (2)
[Chemical Formula 1]
(2)
In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
산화-감응성 입자.
A diselenide compound having an anionic group at both ends thereof
Oxidation-sensitive particles.
상기 디셀레나이드 화합물은 하기 화학식 1 또는 화학식 2로 표시되는
산화-감응성 입자:
[화학식 1]
[화학식 2]
상기 식들에서, n1 및 n2는 서로 동일하거나 서로 상이하고, 1 내지 10의 정수이다.
3. The method of claim 2,
The diselenide compound is represented by the following general formula (1) or (2)
Oxidation-sensitive particles:
[Chemical Formula 1]
(2)
In the above formulas, n1 and n2 are the same as or different from each other, and are an integer of 1 to 10.
상기 디셀레나이드 화합물은 아민기 함유 생체적합성 고분자와 이온 결합된
산화-감응성 입자.
3. The method of claim 2,
The diselenide compound is ion-bonded to an amine group-containing biocompatible polymer
Oxidation-sensitive particles.
상기 아민기 함유 생체적합성 고분자는 키토산, 히알루론산 및 이의 유도체, 폴리라이신(polylysine), 폴리알릴아민(polyallylamine) 및 폴리(N-이소프로필아크릴아마이드)(poly(N-isopropylacrylamide))로 이루어진 군으로부터 선택된 하나 이상을 포함하는
산화-감응성 입자.
5. The method of claim 4,
The amine group-containing biocompatible polymer may be selected from the group consisting of chitosan, hyaluronic acid and derivatives thereof, polylysine, polyallylamine and poly (N-isopropylacrylamide) Comprising one or more selected
Oxidation-sensitive particles.
상기 디셀레나이드 화합물 및 상기 아민기 함유 생체적합성 고분자의 중량비는 1:10 내지 10:1인
산화-감응성 입자.
5. The method of claim 4,
The weight ratio of the diselenide compound and the amine group-containing biocompatible polymer is from 1:10 to 10: 1
Oxidation-sensitive particles.
상기 산화-감응성 입자는 트리폴리인산염이 추가로 이온 결합된
산화-감응성 입자.
5. The method of claim 4,
The oxidation-sensitive particle may further comprise a transition metal salt, wherein the tripolyphosphate is further ion-
Oxidation-sensitive particles.
상기 산화-감응성 입자의 크기는 100nm 내지 3㎛인
산화-감응성 입자.
3. The method of claim 2,
The size of the oxidation-sensitive particles is preferably from 100 nm to 3 占 퐉
Oxidation-sensitive particles.
상기 산화-감응성 입자에 단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신, 호르몬 및 형광물질로 이루어진 군으로부터 선택된 하나 이상의 기능성 물질이 담지된
산화-감응성 입자.
8. The method according to claim 4 or 7,
Wherein at least one functional substance selected from the group consisting of a protein, a polypeptide, a peptide, a gene, an anticancer agent, a vaccine, a hormone, and a fluorescent substance is carried on the oxidation-
Oxidation-sensitive particles.
상기 디셀레나이드 화합물은 방사선 조사에 의해 생성되는 활성산소에 의해 분해되면서, 상기 담지된 기능성 물질이 방출되는
산화-감응성 입자.
10. The method of claim 9,
The diselenide compound is decomposed by active oxygen generated by irradiation with radiation, and the supported functional material is released
Oxidation-sensitive particles.
(b) 상기 (a) 단계에서 제조한 디셀레나이드 화합물에 산의 염을 반응시켜 양말단에 음이온기를 가지는 디셀레나이드 화합물을 제조하는 단계를 포함하는
산화-감응성 입자의 제조방법.
(a) reacting selenium (Se 2 ) and a C1 to C10 halogenated alcohol to prepare a diselenide compound having a hydroxy group at both ends; And
(b) reacting the diselenide compound prepared in the step (a) with an acid salt to prepare a diselenide compound having an anionic group at both ends thereof
A method for producing oxidation-sensitive particles.
(c-1) 상기 (b)에서 제조한 디셀레나이드 화합물과 아민기 함유 생체적합성 고분자를 반응시키는 단계를 포함하는
산화-감응성 입자의 제조방법.
12. The method of claim 11,
(c-1) a step of reacting the diselenide compound prepared in (b) with an amine group-containing biocompatible polymer
A method for producing oxidation-sensitive particles.
(c-2) 상기 (b)에서 제조한 디셀레나이드 화합물과 아민기 함유 생체적합성 고분자 및 트리폴리인산염을 반응시키는 단계를 포함하는
산화-감응성 입자의 제조방법.
12. The method of claim 11,
(c-2) reacting the diselenide compound prepared in (b) with an amine group-containing biocompatible polymer and tripolyphosphate
A method for producing oxidation-sensitive particles.
단백질, 폴리펩타이드, 펩타이드, 유전자, 항암제, 백신, 호르몬 및 형광물질로 이루어진 군으로부터 선택된 하나 이상의 기능성 물질을 추가로 반응시키는
산화-감응성 입자의 제조방법.
The method according to claim 12 or 13,
The method further comprises the step of further reacting one or more functional substances selected from the group consisting of proteins, polypeptides, peptides, genes, anticancer agents, vaccines, hormones and fluorescent substances
A method for producing oxidation-sensitive particles.
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