高分子修饰抗肿瘤药物的制备及细胞毒活性研究
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摘要
药物疗法是目前肿瘤患者的主要治疗方法之一,但其种种缺陷,如有毒副作用等妨碍了其进一步的发展及应用。高分子材料的运用不仅可以改善或提高药物的性能,如稳定性、渗透性、溶解性及生物相容性等,还可以提供系统所需的特殊性能,如对温度或pH的敏感性,对酶的特意选择性等。
对于抗肿瘤药物而言,高分子材料可作为载体,在病灶部位选择性的释放药物,提高药物的靶向性和生物利用率,有效地降低药物的毒副作用和用药剂量。
本论文首先分别对具有抗肿瘤活性的蛋白质及多肽类等天然高分子化合物、萜类等天然小分子化合物,及其高分子衍生物的抗肿瘤活性的研究进展进行了综述。
其次,甘草与当归是我国西部地区丰富的中草药资源,其中的活性成分18-β-甘草次酸(GA)与阿魏酸(FA)具有多种生理、药理活性。本论文用SRB法验证了18-β-甘草次酸与阿魏酸有抑制BEL-7721肿瘤细胞生长的作用,但是效果并不很好,而且,甘草次酸在过量的情况下会引起身体的不适,有一定的毒副作用。为了能够降低其毒性,并提高活性。我们以无毒且具有良好生物相容性聚合物聚乙二醇(PEG)和低聚水溶性壳聚糖(COS),首次合成了GA和FA的高分子衍生物,并对合成的高分子药物进行了一系列细胞毒活性研究。
PEG和COS对甘草次酸的结构进行了化学改性后,采用元素分析法、红外光谱法、质谱方法对化合物的结构和组成进行了表征。采用SRB法研究了GA的PEG衍生物和COS衍生物的细胞毒活性,发现经PEG(20000)改性的甘草次酸没有细胞毒活性,甘草次酸的一系列PEG(600)衍生物具有良好的细胞毒活性,而且比原料具有更好的效果:GA的IC_(50)为19.57±1.68μg/mL,而PEG(600)-GA的IC_(50)为4.82±0.15μg/mL,B-PEG(600)-GA的LC_(50)为26.58±2.6μg/mL。此外,甘草次酸的COS衍生物也具有细胞毒活性,但活性有所降低,GA-COS(5:1)的IC_(50)为27.29±0.39μg/mL。
阿魏酸的结构被PEG和COS改性后,采用元素分析法、红外光谱法、质谱方法对化合物的结构和组成进行了表征。同时,采用SRB法研究了FA的PEG衍生物和COS衍生物的细胞毒活性,发现阿魏酸PEG(600)衍生物和COS衍
A broad-spectrum antineoplastic agents has been found to be effective in combating different types of cancer. However, to achieve complete eradication of tumors, antineoplastic agents are administered systemically in high doses, and almost all drugs effective in killing cancer cells cause damage to other healthy tissues and organs. This is due to the non-specific uptake of these agents by healthy organs such as the kidney, liver, bone marrow, and heart. The adverse side-effects include severe immune suppression, myelosuppression, nephrotoxicity, and cardiotoxicity.Polymer-based antitumor drug loaded implants, pastes and microparticulates provide an opportunity to deliver high, localized doses of drug for a prolonged period directly into a tumor or at the site of tumor resection.In the part of review, it is focus on the macromolecule and small molecule compounds derived from natural products with antitumor activities, and the antitumor activities of polymer derivatives of some small molecule drugs.Liquorice and Angelica are traditional Chinese herbal medicines. Their active components are 180- glycyrrhetic acid (180-GA) and Ferulic acid (FA), which has been reported possessing strong bioactivities in physiology and phamarcology. In this paper, the cytotoxic activities of those drugs were evaluated in vitro by using SRB assay. It was found they have antitumor activities, but not so strong. And the toxicity of GA limited its use in medicine.Polyethylene glycol (PEG) is a polymer which was widely used as a covalent modifier of biological macromolecules and particles as well as a carrier for low molecular weight drugs.Chitooligosaccharide (COS) is the product of the chitosan degradation. It has many interesting biological properties, such as immunological activity, antibacterial activity etc.Because of their advansed physical and chemical properties and pharmapuetical function, PEG, COS and their derivatives have been variously applied in the
pharmacyeutical field.To avoid the limitations of these small molecule compounds and to improve the antitumor activities, their derivatives have been synthesized. We used PEG and COS respectively to modify GA and FA. A series of polymer derivatives of GA and FA were synthesized.The PEG and COS derivatives of GA were characterized by element analysis, IR spectra and MS spectra. The SRB assay is now being used in our laboratory for further study of their cytotoxic activities.The GA derivatives modified by PEG(20000) have been found no activities, while the derivatives modified by PEG(600) inhibit the growth of liver tumor BEL-7721 cell and cause death of the cell. They showed stronger cytotoxic activities than GA. (IC_(50),ga =19.57±1.68 ug/mL, IC_(50, peg(600)-ga)= 4.82±0.15 μg/mL, LC_(50, b-peg(600)-ga)= 26.58±2.6 μg/mL). Furthermore, the derivatives modified by COS have less cytotoxic activities than GA(IC_(50,GA-COS(5:1))=27.29±0.399μg/mL).FA was modified by PEG and COS, and the derivatives were characterized by element analysis, IR spectra and MS spectra. By using the SRB assay, we found the FA derivatives show stronger cytotoxic activities than FA (IC—(50,fa)= 46.63±7.34μg/mL,IC—(50, PEG(600)-FA)=28.62±1.81μg/mL, IC—(50,B-PEG(600)-FA)=18.74±2.55μg/mL, IC_(50, FA-COS(5:1))= 38.79±0.85μg/mL).5-Fluorouracil (5-Fu) has been used in the therapy of different solid tumors, such as cancer of the gastrointestinal tract and breast cancer. But its use in clinic is limited by its short plasma half-life, high doses, gastrointestinal toxicity and myelotoxicity.The SRB assay indicated that the inhibition or killing activity of 5-Fu to the SGC-7901 cell, but the PEG (600) derivative of 5-Fu lost the antitumor activity.The data in the present study support some possible mechanism.
对于抗肿瘤药物而言,高分子材料可作为载体,在病灶部位选择性的释放药物,提高药物的靶向性和生物利用率,有效地降低药物的毒副作用和用药剂量。
本论文首先分别对具有抗肿瘤活性的蛋白质及多肽类等天然高分子化合物、萜类等天然小分子化合物,及其高分子衍生物的抗肿瘤活性的研究进展进行了综述。
其次,甘草与当归是我国西部地区丰富的中草药资源,其中的活性成分18-β-甘草次酸(GA)与阿魏酸(FA)具有多种生理、药理活性。本论文用SRB法验证了18-β-甘草次酸与阿魏酸有抑制BEL-7721肿瘤细胞生长的作用,但是效果并不很好,而且,甘草次酸在过量的情况下会引起身体的不适,有一定的毒副作用。为了能够降低其毒性,并提高活性。我们以无毒且具有良好生物相容性聚合物聚乙二醇(PEG)和低聚水溶性壳聚糖(COS),首次合成了GA和FA的高分子衍生物,并对合成的高分子药物进行了一系列细胞毒活性研究。
PEG和COS对甘草次酸的结构进行了化学改性后,采用元素分析法、红外光谱法、质谱方法对化合物的结构和组成进行了表征。采用SRB法研究了GA的PEG衍生物和COS衍生物的细胞毒活性,发现经PEG(20000)改性的甘草次酸没有细胞毒活性,甘草次酸的一系列PEG(600)衍生物具有良好的细胞毒活性,而且比原料具有更好的效果:GA的IC_(50)为19.57±1.68μg/mL,而PEG(600)-GA的IC_(50)为4.82±0.15μg/mL,B-PEG(600)-GA的LC_(50)为26.58±2.6μg/mL。此外,甘草次酸的COS衍生物也具有细胞毒活性,但活性有所降低,GA-COS(5:1)的IC_(50)为27.29±0.39μg/mL。
阿魏酸的结构被PEG和COS改性后,采用元素分析法、红外光谱法、质谱方法对化合物的结构和组成进行了表征。同时,采用SRB法研究了FA的PEG衍生物和COS衍生物的细胞毒活性,发现阿魏酸PEG(600)衍生物和COS衍
A broad-spectrum antineoplastic agents has been found to be effective in combating different types of cancer. However, to achieve complete eradication of tumors, antineoplastic agents are administered systemically in high doses, and almost all drugs effective in killing cancer cells cause damage to other healthy tissues and organs. This is due to the non-specific uptake of these agents by healthy organs such as the kidney, liver, bone marrow, and heart. The adverse side-effects include severe immune suppression, myelosuppression, nephrotoxicity, and cardiotoxicity.Polymer-based antitumor drug loaded implants, pastes and microparticulates provide an opportunity to deliver high, localized doses of drug for a prolonged period directly into a tumor or at the site of tumor resection.In the part of review, it is focus on the macromolecule and small molecule compounds derived from natural products with antitumor activities, and the antitumor activities of polymer derivatives of some small molecule drugs.Liquorice and Angelica are traditional Chinese herbal medicines. Their active components are 180- glycyrrhetic acid (180-GA) and Ferulic acid (FA), which has been reported possessing strong bioactivities in physiology and phamarcology. In this paper, the cytotoxic activities of those drugs were evaluated in vitro by using SRB assay. It was found they have antitumor activities, but not so strong. And the toxicity of GA limited its use in medicine.Polyethylene glycol (PEG) is a polymer which was widely used as a covalent modifier of biological macromolecules and particles as well as a carrier for low molecular weight drugs.Chitooligosaccharide (COS) is the product of the chitosan degradation. It has many interesting biological properties, such as immunological activity, antibacterial activity etc.Because of their advansed physical and chemical properties and pharmapuetical function, PEG, COS and their derivatives have been variously applied in the
pharmacyeutical field.To avoid the limitations of these small molecule compounds and to improve the antitumor activities, their derivatives have been synthesized. We used PEG and COS respectively to modify GA and FA. A series of polymer derivatives of GA and FA were synthesized.The PEG and COS derivatives of GA were characterized by element analysis, IR spectra and MS spectra. The SRB assay is now being used in our laboratory for further study of their cytotoxic activities.The GA derivatives modified by PEG(20000) have been found no activities, while the derivatives modified by PEG(600) inhibit the growth of liver tumor BEL-7721 cell and cause death of the cell. They showed stronger cytotoxic activities than GA. (IC_(50),ga =19.57±1.68 ug/mL, IC_(50, peg(600)-ga)= 4.82±0.15 μg/mL, LC_(50, b-peg(600)-ga)= 26.58±2.6 μg/mL). Furthermore, the derivatives modified by COS have less cytotoxic activities than GA(IC_(50,GA-COS(5:1))=27.29±0.399μg/mL).FA was modified by PEG and COS, and the derivatives were characterized by element analysis, IR spectra and MS spectra. By using the SRB assay, we found the FA derivatives show stronger cytotoxic activities than FA (IC—(50,fa)= 46.63±7.34μg/mL,IC—(50, PEG(600)-FA)=28.62±1.81μg/mL, IC—(50,B-PEG(600)-FA)=18.74±2.55μg/mL, IC_(50, FA-COS(5:1))= 38.79±0.85μg/mL).5-Fluorouracil (5-Fu) has been used in the therapy of different solid tumors, such as cancer of the gastrointestinal tract and breast cancer. But its use in clinic is limited by its short plasma half-life, high doses, gastrointestinal toxicity and myelotoxicity.The SRB assay indicated that the inhibition or killing activity of 5-Fu to the SGC-7901 cell, but the PEG (600) derivative of 5-Fu lost the antitumor activity.The data in the present study support some possible mechanism.
引文
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