多西他賽復(fù)合單壁碳納米管固體脂質(zhì)納米粒的初步研究
發(fā)布時間：2019-01-03 17:22
【摘要】：多西他賽(DTX)是已上市的一種紫杉烷類抗癌藥物，主要通過破壞腫瘤細(xì)胞的有絲分裂而達(dá)到抗腫瘤效果。目前多西他賽的上市劑型為注射液，其所含吐溫80黏性較大且具有溶血作用，多數(shù)患者會產(chǎn)生明顯的過敏反應(yīng)。單壁碳納米管(SWNT)具有獨(dú)特大小與中空結(jié)構(gòu)，因而具有獨(dú)特的理化性質(zhì)，并具有獨(dú)特的跨膜能力，能夠被動穿過多種細(xì)胞膜，通過內(nèi)吞作用可攜帶多種活性分子進(jìn)入細(xì)胞，因而在藥物、核酸轉(zhuǎn)運(yùn)方面具有潛在的應(yīng)用價值。但是未經(jīng)處理的單壁碳納米管（SWNT）的水溶性差，且具有一定的生物毒性，限制其在生物醫(yī)學(xué)領(lǐng)域的應(yīng)用。固體脂質(zhì)納米粒（SLN）具有生理相容性好，適用于多種給藥形式、適合包載親脂性藥物、通過對其表面進(jìn)行特征修飾，可將藥物傳遞至特定組織，具有靶向性等優(yōu)點(diǎn)，因此，SLN是一種具有發(fā)展前景的新型給藥系統(tǒng)。 本課題擬對單壁碳納米管（SWNT）進(jìn)行氧化，有效提高其水分散性；將多西他賽通過π-π堆積作用吸附到單壁碳納米管的表面，制成固體脂質(zhì)納米粒(DTX/OSWNT/SLN)，使其具有被動靶向性；通過體外抗腫瘤活性作用的考察，開展抗癌藥物腫瘤治療的初步研究。 本文首先對碳納米管進(jìn)行修飾，，使其水溶性得到一定程度的改善，且其明顯被截短，更有利于載藥和固體脂質(zhì)納米粒的構(gòu)建。本文采用熔融超聲法制備多西他賽復(fù)合單壁碳納米管固體脂質(zhì)納米粒（DTX/OSWNT/SLN），并對其進(jìn)行單因素考察和正交試驗(yàn)設(shè)計考察，最終確定其最佳制備工藝和最優(yōu)處方。制備的DTX/OSWNT/SLN納米粒呈較規(guī)則的球形或類球形，平均粒徑為181.3±3.23nm，平均Zeta電位為-33.65±1.28mV；本文采用高效液相法測定制劑中多西他賽的含量，采用超濾-離心法測定包封率為96.43±0.97%，載藥量為8.51±0.08%；選取海藻糖和蔗糖的混合物作為凍干保護(hù)劑，二者的總用量為5%（w/v）；體外釋藥試驗(yàn)結(jié)果表明原料藥DTX在48h內(nèi)釋放完全，DTX/OSWNT/SLN表現(xiàn)出緩釋作用，釋藥特征符合Weibull數(shù)學(xué)模型。 以人源性乳腺癌細(xì)胞MCF-7細(xì)胞為受試細(xì)胞，考察制劑的體外抗腫瘤活性。試驗(yàn)結(jié)果表明，DTX/OSWNT/SLN可以攜帶藥物轉(zhuǎn)運(yùn)到細(xì)胞內(nèi)部；空白載體對細(xì)胞無明顯的增殖抑制作用；制劑組和原料組對細(xì)胞的抑制率呈濃度依賴性和時間依賴性，而且DTX/OSWNT/SLN組對細(xì)胞的抑制作用強(qiáng)于原料藥DTX組，808nm激光照射有助于增強(qiáng)對腫瘤細(xì)胞的抑制作用；原料組和制劑組對MCF-7細(xì)胞周期抑制均顯著地反應(yīng)在G2/M期，且均可誘導(dǎo)MCF-7細(xì)胞的凋亡。 綜上所述，本文成功制備了多西他賽復(fù)合單壁碳納米管固體脂質(zhì)納米載體DTX/OSWNT/SLN，并對其理化性質(zhì)及體外抗腫瘤活性進(jìn)行考察，初步認(rèn)為該納米載體是一種很有潛力的抗腫瘤藥物轉(zhuǎn)運(yùn)系統(tǒng)。
[Abstract]:Docetaxel (DTX) (docetaxel) is a taxane anticancer drug, which is mainly used to destroy the mitosis of tumor cells. The dosage form of docetaxel is injection, its Tween80 is viscous and hemolytic, and most patients have obvious allergic reaction. Single walled carbon nanotubes (SWNT) have unique size and hollow structure, so they have unique physical and chemical properties and unique transmembrane capability. They can passively penetrate a variety of cell membranes and carry a variety of active molecules into cells through endocytosis. Therefore, it has potential application value in drug and nucleic acid transport. However, untreated single-walled carbon nanotubes (SWNT) have poor water solubility and biological toxicity, which limits their application in biomedical field. Solid lipid nanoparticles (SLN) have good physiological compatibility, suitable for various forms of drug delivery, suitable for encapsulating lipophilic drugs. By modifying their surface characteristics, they can be transferred to specific tissues and have the advantages of targeting. SLN is a new drug delivery system with development prospects. In order to improve the water dispersion of single-walled carbon nanotubes (SCNTs), the (SWNT) was oxidized in this paper. The docetaxel was adsorbed on the surface of single-walled carbon nanotubes by 蟺-蟺 accumulation, and the solid lipid nanoparticles (DTX/OSWNT/SLN) were prepared, which made them passive targeting. The primary study of anticancer drug tumor therapy was carried out through the investigation of anti-tumor activity in vitro. In this paper, carbon nanotubes (CNTs) were modified to some extent to improve their water solubility, and they were obviously truncated, which was more favorable to the construction of drug loading and solid lipid nanoparticles. In this paper, docetaxel composite single-walled carbon nanotube solid lipid nanoparticles (DTX/OSWNT/SLN) were prepared by melt ultrasonic method, and were investigated by single factor and orthogonal design. Finally, the optimum preparation process and the optimal formulation were determined. The prepared DTX/OSWNT/SLN nanoparticles were spherical or spherical in shape, with an average diameter of 181.3 鹵3.23 nm and an average Zeta potential of -33.65 鹵1.28 MV. In this paper, the content of docetaxel in the preparation was determined by HPLC, the entrapment efficiency was 96.43 鹵0.97 by ultrafiltration centrifugation, and the drug loading was 8.51 鹵0.08. The mixture of trehalose and sucrose was chosen as freeze-drying protectant, the total dosage of them was 5% (w / v). The results of in vitro drug release test showed that DTX was completely released within 48 hours and DTX/OSWNT/SLN showed a slow release effect. The drug release characteristics were in accordance with the Weibull mathematical model. The anti-tumor activity of human breast cancer cell line MCF-7 was investigated in vitro. The results showed that DTX/OSWNT/SLN could carry drugs into the cells, and the blank vector had no obvious inhibitory effect on cell proliferation. The inhibition rate of cells in preparation group and raw material group was concentration-dependent and time-dependent, and the inhibitory effect of DTX/OSWNT/SLN group was stronger than that of DTX group. 808nm laser irradiation could enhance the inhibitory effect on tumor cells. The inhibition of MCF-7 cell cycle in raw material group and preparation group was significantly inhibited in G _ 2 / M phase and could induce apoptosis of MCF-7 cells. To sum up, docetaxel composite solid lipid nanotubes (DTX/OSWNT/SLN,) was successfully prepared and its physicochemical properties and antitumor activity in vitro were investigated. It is considered that this nano-carrier is a potential anti-tumor drug transport system.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943;TB383.1
本文編號：2399670
[Abstract]:Docetaxel (DTX) (docetaxel) is a taxane anticancer drug, which is mainly used to destroy the mitosis of tumor cells. The dosage form of docetaxel is injection, its Tween80 is viscous and hemolytic, and most patients have obvious allergic reaction. Single walled carbon nanotubes (SWNT) have unique size and hollow structure, so they have unique physical and chemical properties and unique transmembrane capability. They can passively penetrate a variety of cell membranes and carry a variety of active molecules into cells through endocytosis. Therefore, it has potential application value in drug and nucleic acid transport. However, untreated single-walled carbon nanotubes (SWNT) have poor water solubility and biological toxicity, which limits their application in biomedical field. Solid lipid nanoparticles (SLN) have good physiological compatibility, suitable for various forms of drug delivery, suitable for encapsulating lipophilic drugs. By modifying their surface characteristics, they can be transferred to specific tissues and have the advantages of targeting. SLN is a new drug delivery system with development prospects. In order to improve the water dispersion of single-walled carbon nanotubes (SCNTs), the (SWNT) was oxidized in this paper. The docetaxel was adsorbed on the surface of single-walled carbon nanotubes by 蟺-蟺 accumulation, and the solid lipid nanoparticles (DTX/OSWNT/SLN) were prepared, which made them passive targeting. The primary study of anticancer drug tumor therapy was carried out through the investigation of anti-tumor activity in vitro. In this paper, carbon nanotubes (CNTs) were modified to some extent to improve their water solubility, and they were obviously truncated, which was more favorable to the construction of drug loading and solid lipid nanoparticles. In this paper, docetaxel composite single-walled carbon nanotube solid lipid nanoparticles (DTX/OSWNT/SLN) were prepared by melt ultrasonic method, and were investigated by single factor and orthogonal design. Finally, the optimum preparation process and the optimal formulation were determined. The prepared DTX/OSWNT/SLN nanoparticles were spherical or spherical in shape, with an average diameter of 181.3 鹵3.23 nm and an average Zeta potential of -33.65 鹵1.28 MV. In this paper, the content of docetaxel in the preparation was determined by HPLC, the entrapment efficiency was 96.43 鹵0.97 by ultrafiltration centrifugation, and the drug loading was 8.51 鹵0.08. The mixture of trehalose and sucrose was chosen as freeze-drying protectant, the total dosage of them was 5% (w / v). The results of in vitro drug release test showed that DTX was completely released within 48 hours and DTX/OSWNT/SLN showed a slow release effect. The drug release characteristics were in accordance with the Weibull mathematical model. The anti-tumor activity of human breast cancer cell line MCF-7 was investigated in vitro. The results showed that DTX/OSWNT/SLN could carry drugs into the cells, and the blank vector had no obvious inhibitory effect on cell proliferation. The inhibition rate of cells in preparation group and raw material group was concentration-dependent and time-dependent, and the inhibitory effect of DTX/OSWNT/SLN group was stronger than that of DTX group. 808nm laser irradiation could enhance the inhibitory effect on tumor cells. The inhibition of MCF-7 cell cycle in raw material group and preparation group was significantly inhibited in G _ 2 / M phase and could induce apoptosis of MCF-7 cells. To sum up, docetaxel composite solid lipid nanotubes (DTX/OSWNT/SLN,) was successfully prepared and its physicochemical properties and antitumor activity in vitro were investigated. It is considered that this nano-carrier is a potential anti-tumor drug transport system.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943;TB383.1
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