葉酸靶向雙重載藥聚合物囊泡制備及其抗腫瘤研究
發(fā)布時(shí)間：2018-08-03 17:21
【摘要】：癌癥是一類對人類健康構(gòu)成嚴(yán)重威脅的高發(fā)、高致死率疾病,化學(xué)治療是非手術(shù)治療癌癥的重要方法。近年來,多項(xiàng)臨床研究結(jié)果表明:單一藥物化療往往已經(jīng)難以有效控制癌癥病情,在治療的后期還可能出現(xiàn)多藥耐藥性,而不同抗癌機(jī)制化療藥物的聯(lián)合使用可以達(dá)到提高治療效果、降低藥物毒副作用的目的。其中阿霉素與紫杉醇聯(lián)合用藥(即“雞尾酒療法”)在臨床治療中已廣泛應(yīng)用。但紫杉醇注射液中使用聚氧乙烯蓖麻油助溶,具有很強(qiáng)的神經(jīng)毒性和腎臟毒性,鹽酸阿霉素在抑制腫瘤增殖的同時(shí)也會抑制骨髓的造血能力,并導(dǎo)致嚴(yán)重的心臟毒性和肝臟損傷,而且兩種藥物游離給藥后在體內(nèi)的代謝途徑不同,實(shí)際進(jìn)入腫瘤細(xì)胞內(nèi)的藥量難以控制。聚合物囊泡作為藥物遞送載體,可以將不同溶解性、不同抗癌機(jī)制的化療藥物分別載入疏水性膜層內(nèi)和親水性內(nèi)腔中,以提升化療藥物的穩(wěn)定性,延緩藥物代謝,并可憑借囊泡的主動和被動靶向能力,改變藥物在生物體內(nèi)的分布,使藥物富集于病變部位,降低全身毒副作用,延緩癌細(xì)胞耐藥性的產(chǎn)生,起到協(xié)同化療作用。本課題以PEG作為引發(fā)物,引發(fā)ε-CL開環(huán)聚合,聚合成具有良好生物相容性和可生物降解性的聚己內(nèi)酯-聚乙二醇-聚己內(nèi)酯(PCL-PEG-PCL,PCEC)兩親性三嵌段共聚物作為載體材料,并以臨床廣泛使用的化學(xué)治療藥物——鹽酸阿霉素和紫杉醇作為模型藥物,葉酸作為靶向配體,構(gòu)建葉酸靶向、雙重包載藥物的聚合物靶向納米囊泡。在該囊泡中,紫杉醇分布于疏水膜層,鹽酸阿霉素包裹于親水內(nèi)腔。對所構(gòu)建的聚合物囊泡進(jìn)行結(jié)構(gòu)表征、體外細(xì)胞實(shí)驗(yàn)、動物體內(nèi)實(shí)驗(yàn)等研究,評價(jià)其主動靶向和被動靶向能力、體內(nèi)外抑瘤效果、協(xié)同化療作用以及克服全身毒副作用的效果。透射電鏡觀察結(jié)果顯示,兩親性三嵌段共聚物PCL-PEG-PCL中親水性PEG鏈段的質(zhì)量分?jǐn)?shù)約占33%時(shí),能夠形成具有較厚膜層和較大空腔結(jié)構(gòu)的聚合物囊泡。細(xì)胞攝取研究表明,在葉酸受體過表達(dá)的BEL-7404細(xì)胞中葉酸靶向修飾的雙載藥聚合物囊泡(FA-PTX-DOX-PS)內(nèi)吞效率明顯高于無葉酸靶向的雙載藥聚合物囊泡(PTX-DOX-PS)。體外細(xì)胞毒性實(shí)驗(yàn)表明,FA-PTX-DOX-PS有效降低游離紫杉醇與阿霉素混合給藥的毒性,且相比PTX-DOX-PS能更有效地抑制腫瘤的生長。體內(nèi)熒光成像實(shí)驗(yàn)結(jié)果顯示,FA-PTX-DOX-PS表現(xiàn)出高效的靶向性,可在腫瘤內(nèi)累積。此外,體內(nèi)抗腫瘤研究表明,與臨床“雞尾酒療法”游離給藥相比,所構(gòu)建的FA-PTX-DOX-PS具有顯著的腫瘤靶向性,抑瘤效果更強(qiáng),同時(shí)有效克服臨床上“雞尾酒療法”產(chǎn)生的全身毒副作用。因此,葉酸靶向雙重載藥聚合物納米囊泡是一種具有潛力的可同時(shí)遞送多種化療藥物用于腫瘤高效、靶向、協(xié)同治療的納米制劑。
[Abstract]:Cancer is a kind of high incidence of serious threat to human health, high mortality rate, and chemical therapy is an important method for non-surgical treatment of cancer. In recent years, a number of clinical research results show that single drug chemotherapy is often difficult to effectively control the cancer condition, and there may be multidrug resistance in the later period of the treatment, and different anticancer machines. The combined use of chemical and chemotherapeutic drugs can improve the therapeutic effect and reduce the side effects of drug. The combination of doxorubicin and paclitaxel ("cocktail therapy") has been widely used in clinical treatment. However, the use of polyoxyethylene castor oil in Paclitarel Injection has strong neurotoxicity and nephrotoxicity. Acid adriamycin can inhibit the proliferation of tumor and inhibit the hematopoiesis of bone marrow, and lead to severe cardiac toxicity and liver damage, and the metabolic pathways in the body are different after the two drugs are free, and the amount of drugs that actually enter the tumor cells is difficult to control. As a delivery carrier, polymer vesicles can dissolve different solubility The chemotherapeutic drugs of different anticancer mechanisms are loaded into the hydrophobic membrane and the hydrophilic inner cavity respectively to improve the stability of the chemotherapeutic drugs, delay the drug metabolism, and by virtue of the active and passive targeting ability of the vesicles, change the distribution of drugs in the organism, make the drug rich in the lesion, reduce the side effect of the whole body and delay the tolerance of cancer cells. This subject takes PEG as an initiator, triggers the epsilon -CL open ring polymerization, polymerized into a good biocompatibility and biodegradable polyhexyl polyhexyl polyhexyl polyhexyl (PCL-PEG-PCL, PCEC) two Pro three block copolymers as the carrier material, and the chemical treatment widely used in clinical treatment. Drugs - doxorubicin and taxol hydrochloric acid as a model drug, folic acid as a target ligand to construct a polymer targeted nano vesicle with a target of folic acid and double loaded drugs. In this vesicle, paclitaxel is distributed in the hydrophobic membrane and adriamycin hydrochloric acid is wrapped in the hydrophilic cavity. The results show that the mass fraction of the hydrophilic PEG segment of the two amphiphilic three block copolymer PCL-PEG-PCL can be formed when the mass fraction of the hydrophilic PEG segment is about 33%. The cell uptake studies showed that the endocytosis of the folic acid targeted double loaded polymer vesicles (FA-PTX-DOX-PS) in BEL-7404 cells expressed by folic acid receptor was significantly higher than that of the double loaded polymer vesicles (PTX-DOX-PS) without folic acid targeting. Cytotoxicity test in vitro showed that FA-PTX-DOX-PS The toxicity of free paclitaxel and doxorubicin was effectively reduced and the tumor growth was inhibited more effectively than PTX-DOX-PS. In vivo fluorescence imaging results showed that FA-PTX-DOX-PS showed highly effective targeting and could accumulate in the tumor. In addition, in vivo antitumor studies showed that the clinical "cocktail therapy" was free to the drug. FA-PTX-DOX-PS has significant tumor targeting, stronger tumor suppressor effect and effective overcoming the systemic toxic side effects of "cocktail therapy" in clinical. Therefore, folic acid targeted double drug loaded polymer nanoscale is a potential delivery of multiple chemotherapeutic drugs for tumor efficiency, targeting and synergistic treatment. Nanoscale preparation.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943;R96
本文編號：2162444
[Abstract]:Cancer is a kind of high incidence of serious threat to human health, high mortality rate, and chemical therapy is an important method for non-surgical treatment of cancer. In recent years, a number of clinical research results show that single drug chemotherapy is often difficult to effectively control the cancer condition, and there may be multidrug resistance in the later period of the treatment, and different anticancer machines. The combined use of chemical and chemotherapeutic drugs can improve the therapeutic effect and reduce the side effects of drug. The combination of doxorubicin and paclitaxel ("cocktail therapy") has been widely used in clinical treatment. However, the use of polyoxyethylene castor oil in Paclitarel Injection has strong neurotoxicity and nephrotoxicity. Acid adriamycin can inhibit the proliferation of tumor and inhibit the hematopoiesis of bone marrow, and lead to severe cardiac toxicity and liver damage, and the metabolic pathways in the body are different after the two drugs are free, and the amount of drugs that actually enter the tumor cells is difficult to control. As a delivery carrier, polymer vesicles can dissolve different solubility The chemotherapeutic drugs of different anticancer mechanisms are loaded into the hydrophobic membrane and the hydrophilic inner cavity respectively to improve the stability of the chemotherapeutic drugs, delay the drug metabolism, and by virtue of the active and passive targeting ability of the vesicles, change the distribution of drugs in the organism, make the drug rich in the lesion, reduce the side effect of the whole body and delay the tolerance of cancer cells. This subject takes PEG as an initiator, triggers the epsilon -CL open ring polymerization, polymerized into a good biocompatibility and biodegradable polyhexyl polyhexyl polyhexyl polyhexyl (PCL-PEG-PCL, PCEC) two Pro three block copolymers as the carrier material, and the chemical treatment widely used in clinical treatment. Drugs - doxorubicin and taxol hydrochloric acid as a model drug, folic acid as a target ligand to construct a polymer targeted nano vesicle with a target of folic acid and double loaded drugs. In this vesicle, paclitaxel is distributed in the hydrophobic membrane and adriamycin hydrochloric acid is wrapped in the hydrophilic cavity. The results show that the mass fraction of the hydrophilic PEG segment of the two amphiphilic three block copolymer PCL-PEG-PCL can be formed when the mass fraction of the hydrophilic PEG segment is about 33%. The cell uptake studies showed that the endocytosis of the folic acid targeted double loaded polymer vesicles (FA-PTX-DOX-PS) in BEL-7404 cells expressed by folic acid receptor was significantly higher than that of the double loaded polymer vesicles (PTX-DOX-PS) without folic acid targeting. Cytotoxicity test in vitro showed that FA-PTX-DOX-PS The toxicity of free paclitaxel and doxorubicin was effectively reduced and the tumor growth was inhibited more effectively than PTX-DOX-PS. In vivo fluorescence imaging results showed that FA-PTX-DOX-PS showed highly effective targeting and could accumulate in the tumor. In addition, in vivo antitumor studies showed that the clinical "cocktail therapy" was free to the drug. FA-PTX-DOX-PS has significant tumor targeting, stronger tumor suppressor effect and effective overcoming the systemic toxic side effects of "cocktail therapy" in clinical. Therefore, folic acid targeted double drug loaded polymer nanoscale is a potential delivery of multiple chemotherapeutic drugs for tumor efficiency, targeting and synergistic treatment. Nanoscale preparation.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943;R96
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