【摘要】：“癌中之王”原發(fā)性肝癌惡性度高、病情惡化快,治療難度極大。索拉非尼是第一個批準的可用于臨床原發(fā)性肝癌治療的多靶點、多激酶抑制劑,但是索拉非尼的溶解性較差,生物利用度較低。而且索拉非尼的毒副作用較為常見,更嚴重的是會出現(xiàn)耐藥性,此時會出現(xiàn)無藥可醫(yī)的局面。這就使得需要通過改進給藥方式或其他手段來提高索拉非尼的生物利用度。聯(lián)合用藥是現(xiàn)有的常用的可以增強索拉非尼的治療效果和降低毒副作用的常用方法之一。姜黃素具有抗腫瘤作用,還具有化學增敏效果,能夠逆轉化療藥物的耐藥性,因而與索拉非尼聯(lián)用有增強療效的效果[1-3]。聚合物納米膠束給藥是解決難溶藥物生物利用度低的新型給藥方法之一,利用兩親性聚合物的特性,制備成具有納米粒徑的核殼結構的聚合物膠束,親水性外殼可以將難溶性藥物包裹在疏水性內(nèi)核中,增加溶解度同時,還可以通過主/被動將藥物輸送到目標位置,提高生物利用度,增強療效。本課題設計將索拉非尼和姜黃素制備成聚合物膠束進行聯(lián)合用藥,并結合三嵌段聚合物PCL-PEG-PCL自組裝納米膠束的被動靶向和長循環(huán)效果,將索拉非尼和姜黃素制備成三嵌段聚合物納米膠束,用于靜脈注射給藥,以期在增強索拉非尼和姜黃素的溶解性的同時,提高索拉非尼的生物利用度,降低毒副作用。本課題首先對姜黃素和索拉非尼聯(lián)合用藥效果進行考察,并通過計算藥劑學對所用的聚合物載體PCL-PEG-PCL進行了模擬篩選,隨后通過實際實驗印證模擬結果,篩選出最優(yōu)的適合制備三嵌段聚合物納米膠束的載體材料為PCL30-PEG135-PCL30,并且通過具體實驗考察了薄膜水化法制備三嵌段聚合物納米膠束的條件。最終制備的聚合物納米膠束外觀澄清透明,有膠束溶液特有的乳光;粒徑為194.9±4.6nm,透射電鏡圖從微觀層面也顯示了自組裝制備的膠束的粒徑在100~160nm左右,形狀為形態(tài)均一的核-殼同心球型結構;姜黃素和索拉非尼的包封率分別為75.62±1.08%和91.20±0.41%;載藥量分別為22.6±0.64%和13.73±0.35%,在4℃下考察,5周內(nèi)穩(wěn)定性良好,體外溶出釋放持久緩慢。在隨后進行的體外抗腫瘤活性研究研究,同姜黃素和索拉非尼原料藥給藥方式相比,隨時間增長,制備成聚合物納米膠束給藥組的抑制活性提高;藥代動力學研究顯示,同直接使用原料藥的聚氧乙烯(35)蓖麻油溶液尾靜脈給藥相比,納米膠束給藥組的姜黃素和索拉非尼的半衰期分別提高13.75倍和1.116倍;AUC0-∞分別提高15.44倍和2.74倍;MRT0-∞分別提高了15.3倍和1.28倍;CL分別降低到原來的0.087倍和0.39倍,說明制備的聚合物納米膠束具有長循環(huán)效果。
[Abstract]:The King of Cancer has a high degree of malignancy, rapid deterioration and great difficulty in treatment. Solafenib is the first approved multi-target, multi-kinase inhibitor for the treatment of primary liver cancer, but sorafenib has poor solubility and low bioavailability. And the side effects of sorafenib are more common, more serious, drug resistance, and there is no cure. This makes it necessary to improve the bioavailability of Solafenib by improving drug delivery or other means. Combination therapy is one of the commonly used methods to enhance the efficacy and reduce the side effects of sorafenil. Curcumin has antitumor effect and chemically sensitized effect, which can reverse the resistance of chemotherapeutic drugs. Polymer nano-micelle delivery is one of the new methods to solve the low bioavailability of insoluble drugs. Using the properties of amphiphilic polymers, polymer micelles with nanometer-size core-shell structure have been prepared. The hydrophilic shell can encapsulate insoluble drugs in the hydrophobic core, increase solubility and transport the drugs to the target through active / passive transport, improve bioavailability and enhance the efficacy. In this paper, the preparation of solafenil and curcumin into polymer micelles was designed to combine with the passive targeting and long cycle effects of triblock polymer PCL-PEG-PCL self-assembled nano-micelles. Solafenil and curcumin were prepared into triblock polymer nanomicelles for intravenous administration in order to enhance the solubility of solafenil and curcumin and to increase the bioavailability and reduce the side effects of sorafenil. In this paper, the effect of curcumin and sorafenil was investigated, and the polymer carrier PCL-PEG-PCL was screened by computer pharmacology, and then the simulation results were verified by practical experiments. The best carrier material for the preparation of triblock polymer nano-micelles was selected as PCL30-PEG135-PCL30,. The conditions of preparing triblock polymer nano-micelles by thin film hydration were investigated. The final prepared polymer nano-micelles have clear and transparent appearance and have the unique emulsion light of micelle solution. The particle size is 194.9 鹵4.6 nm, and the microstructure of the self-assembled micelles is about 100~160nm, and the morphology of the micelles is homogeneous and core-shell concentric spherical structure. The entrapment efficiency of curcumin and sorafenil were 75.62 鹵1.08% and 91.20 鹵0.41, respectively, and the drug loading amounts were 22.6 鹵0.64% and 13.73 鹵0.35, respectively. Compared with curcumin and solafenil, the inhibitory activity of polymer nano-micelles was increased with time. The pharmacokinetic study showed that the half-life of curcumin and sorafenil in nano-micelle group was 13.75 and 1.116 times higher than that of polyoxyethylene (35) castor oil solution. AUC0- 鈭，

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