本文關(guān)鍵詞： 紫杉醇 曲妥珠單抗 聚乙烯亞胺 脂質(zhì)納米粒 靶向傳遞系統(tǒng)　出處：《吉林大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：乳腺癌發(fā)病率呈逐年上升趨勢,已成為威脅女性健康的最大殺手。紫杉醇是乳腺癌化療治療的一線用藥,單用和聯(lián)合應(yīng)用均顯示很好的療效,但其非選擇性會引起嚴(yán)重的全身性毒副作用。腫瘤生物靶向治療是以腫瘤標(biāo)志性分子作為靶點,將藥物特異性地運送到腫瘤部位,而不影響正常細(xì)胞。HER2是公認(rèn)的重要乳腺癌分子標(biāo)志物,HER2靶向的單克隆抗體藥物曲妥珠單抗已獲得FDA批準(zhǔn)為一線治療藥物。曲妥珠單抗聯(lián)合紫杉醇化療顯著提高了乳腺癌的臨床療效,可紫杉醇的靶向性仍舊不足。雖然抗體藥物偶聯(lián)物(ADC)靶向性強,但連接物的構(gòu)建技術(shù)壁壘高,偶聯(lián)物的位置和數(shù)量不易控制。脂質(zhì)納米粒作為新型給藥系統(tǒng),具有良好的生物相容性、低毒性及緩控釋作用。曲妥珠單抗作為靶向配體與脂質(zhì)納米粒結(jié)合,不僅實現(xiàn)了化療藥物的緩釋性和靶向性,而且制備工藝相對簡單�，F(xiàn)有配體偶聯(lián)方法是將曲妥珠單抗通過化學(xué)鍵結(jié)合在納米粒表面,化學(xué)反應(yīng)易導(dǎo)致抗體變性失活,非特異性連接部位也可能出現(xiàn)在抗原識別區(qū)域。如何最大程度的保留抗體的生物活性,成為抗體作為化療藥物載體靶向配基的應(yīng)用關(guān)鍵。本文先后采用聚乙烯亞胺(PEI)和陽離子磷脂(DODMA)作為基質(zhì),與其它材料混用制備陽離子納米粒,通過靜電作用與帶負(fù)電的曲妥珠單抗相結(jié)合。通過對曲妥珠單抗的結(jié)構(gòu)及生物活性進(jìn)行表征,證明了溫和的靜電力能夠很好的保護(hù)抗體的生物活性。通過對納米粒的基質(zhì)處方、抗體連接策略及連接配比進(jìn)行優(yōu)化,制備高效低毒的靶向納米粒,并對其體外抗腫瘤效應(yīng)和腫瘤靶向進(jìn)行初步研究。具體內(nèi)容主要包括以下幾個部分:1.紫杉醇PEI陽離子納米粒的制備和評價本章選用四種類型PEI(800-b PEI,2000-b PEI,25k-b PEI和25k-l PEI)與PLGA、Egg PC混用制備PEI陽離子納米粒,以粒徑電位為指標(biāo),對PLGA/Egg PC含量比、PEI類型及含量進(jìn)行優(yōu)化,最佳的陽離子納米粒處方為PLGA/Egg PC(60:20),PEI類型為25k-b PEI,PEI含量為5%。陽離子納米粒的粒徑大小為249.9±4.76 nm,電位為35.3±2.3 m V。與游離PEI相比,空白陽離子納米粒對A549細(xì)胞和MCF7細(xì)胞無明顯毒性,相對細(xì)胞活力均在90%以上。穩(wěn)定性結(jié)果表明,靜置2周后,陽離子納米粒在PBS(10 m M,p H 7.4)中粒徑大小和PDI均未發(fā)生明顯變化。細(xì)胞毒性及細(xì)胞攝取實驗中,由25k-b PEI制備的紫杉醇PEI陽離子納米粒在A549和MCF7細(xì)胞中均具有最高的細(xì)胞毒性(P0.001),其細(xì)胞攝取效率明顯高于其它三種PEI制備的納米粒(P0.01)。2.曲妥珠單抗修飾的紫杉醇PEI陽離子納米粒的制備和評價本章分別通過靜電吸附作用和化學(xué)交聯(lián)鍵將曲妥珠單抗與紫杉醇PEI陽離子納米粒相結(jié)合。粒徑增加、電位下降以及TEM觀察到的雙層核殼結(jié)構(gòu)均證明了抗體的成功連接。靜電吸附法制備的靶向納米粒粒徑大小為280.7±7.8nm,表面電位1.00±0.73 m V。陽離子納米粒與曲妥珠單抗的最佳連接配比為1:1,BCA法檢測此時抗體結(jié)合效率為92.7±0.6%。24 h時,曲妥珠單抗在生理條件下的解離百分率為23%。靶向納米粒體外釋放呈雙相緩釋模式,6 h內(nèi)突釋率為28.6%,120 h內(nèi)累計釋放率為71.2%。細(xì)胞毒性試驗中,選用HER2過表達(dá)的BT474細(xì)胞及低表達(dá)的MCF7細(xì)胞為實驗對象。靶向納米粒的細(xì)胞增殖抑制作用呈受體依賴性和時間依賴性。72 h后,靜電吸附法和化學(xué)交聯(lián)法制備的靶向納米粒對BT474細(xì)胞的抑制率分別為53.3%和34.9%(P0.001)。采用雙熒光模式標(biāo)記靶向納米粒:FITC標(biāo)記曲妥珠單抗,Rhod·B標(biāo)記陽離子納米粒。在BT474細(xì)胞中,靜電吸附法制備的靶向納米粒的FITC和Rhod·B平均熒光強度均明顯高于化學(xué)交聯(lián)法(P0.001)。MCF7細(xì)胞中,二者顯示了同等水平的熒光強度。在細(xì)胞攝取過程中,靶向納米粒表面的曲妥珠單抗沒有發(fā)生解離現(xiàn)象。3.曲妥珠單抗修飾的紫杉醇陽離子脂質(zhì)納米粒的制備和評價本章采用毒性更低、生物相容性更好的陽離子磷脂DODMA替代陽離子聚合物PEI與PLGA混用制備陽離子脂質(zhì)納米粒,隨后結(jié)合曲妥珠單抗。為了準(zhǔn)確控制納米粒表面抗體數(shù)目,采用三種不同抗體連接策略制備靶向脂質(zhì)納米粒:(1)將曲妥珠單抗與DSPE-PEG2000-Mal分子連接,再通過靜電吸附作用結(jié)合到DODMA/PLGA納米粒表面,即Improved pre-conjugation strategy(Imp);(2)將曲妥珠單抗與DSPE-PEG2000-Mal分子連接,然后與其它基質(zhì)(DODMA/PLGA)通過物理混合制備納米粒,即Pre-conjugation strategy(Pre);(3)曲妥珠單抗通過化學(xué)交聯(lián)鍵結(jié)合到DSPE-PEG2000-Mal/DODMA/PLGA納米粒表面,即Pos-conjugation strategy(Pos)�？贵w密度分析結(jié)果顯示,Imp、Pre和Pos總抗體裝載量分別為17.8%,14.5%和4.1%,其中表面抗體含量分別為17.8%,6.12%和4.1%。Pre中,8.38%抗體在制備過程中浪費在納米粒內(nèi)部。Pos顯示了較低的抗體連接活性。Imp中,對抗體裝載量與投藥量進(jìn)行線性擬合,曲線R2為0.995。結(jié)果顯示通過Imp定量控制納米粒表面抗體的數(shù)目是可行的。細(xì)胞毒性試驗中,靶向納米粒的細(xì)胞增殖抑制作用呈受體依賴性與劑量依賴性。Imp中,當(dāng)曲妥珠單抗裝載量增加17.8%時,48 h后BT474細(xì)胞抑制率提高了7.3%(P0.001)。Imp靈活的給藥方式,有利于實現(xiàn)曲妥珠單抗和紫杉醇之間的協(xié)同效應(yīng)。三種策略構(gòu)建的納米粒的細(xì)胞毒性由高到低順序依次為ImpPrePos,均高于無抗體包被的納米粒及游離紫杉醇。在BT474細(xì)胞中,Imp內(nèi)化熒光水平最高,其次為Pre和Pos,分別為30.3,23.6和20.7。靶向納米粒在MCF7細(xì)胞中整體內(nèi)化熒光水平比BT474細(xì)胞中要低。最后考察了細(xì)胞內(nèi)吞抑制劑對靶向納米粒的內(nèi)吞途徑的影響,結(jié)果表明靶向納米粒主要是通過HER2受體及網(wǎng)格蛋白介導(dǎo)的內(nèi)吞作用進(jìn)入腫瘤細(xì)胞。目前,國內(nèi)外關(guān)于配體偶聯(lián)策略的研究報道主要集中在化學(xué)修飾法連接靶向配體。然而在化學(xué)反應(yīng)中,抗體的活性極易遭到破壞,從而影響其靶向性。高強度的化學(xué)鍵也會阻礙受體-配體識別過程及后續(xù)化療藥物的釋放。本文采用靜電力將抗體結(jié)合到陽離子納米粒表面,極大的提高了抗體的結(jié)構(gòu)穩(wěn)定性及生物活性。此外,Imp能夠準(zhǔn)確控制納米粒表面抗體數(shù)目,在一定范圍內(nèi)具備調(diào)控納米粒的靶向能力。曲妥珠單抗修飾的紫杉醇陽離子脂質(zhì)納米粒為靶向載體的研發(fā)提供理論依據(jù)、方法參考和技術(shù)借鑒。
[Abstract]:The incidence of breast cancer increased year by year, has become the biggest threat to women's health killer. Paclitaxel is the first-line chemotherapy of breast cancer treatment, the single and combined application showed good curative effect, but its non selective will cause serious side effects of systemic cancer. Targeted therapy with tumor markers molecular targeting drugs specifically delivered to the tumor site, without affecting the normal cells is.HER2 markers of breast cancer molecular recognized by monoclonal antibody trastuzumab HER2 targeted has been approved by the FDA as first-line therapy. Trastuzumab combined with paclitaxel chemotherapy significantly improved the clinical curative effect of breast cancer, paclitaxel can be targeted is still insufficient. Although antibody drug conjugates (ADC) targeted strong, but the construction technology of connection of high barriers, the position and number of conjugates of lipid nano is not easy to control. Rice as a new drug delivery system, has good biocompatibility, low toxicity and controlled-release effect. Trastuzumab as target binding to the ligand and lipid nanoparticles, not only to achieve sustained release and chemotherapeutic drugs to target, and the preparation process is relatively simple. The existing ligand coupling method is trastuzumab based on the surface of the nanoparticles by chemical bond, the chemical reaction can lead to inactivation of nonspecific antibody, joints may also occur in the area. Keep the antibody antigen recognition to the greatest degree of biological activity, become antibody as chemotherapeutic agents targeting carrier application of key ligands. This paper has by polyethyleneimine (PEI) and cationic phospholipid (DODMA) as the matrix, and other materials used for the preparation of cationic nanoparticles through electrostatic interaction with the negatively charged trastuzumab combination. Through the structure and life of trastuzumab Physical activity was characterized, proved moderate static electricity can be a very good protective antibody bioactivity. Through matrix formulation of nanoparticles, antibody connection strategy and connection ratio is optimized, the preparation of high efficiency and low toxicity targeted nanoparticles and its antitumor effect in vitro and tumor targeting of specific content. It includes the following parts: 1. paclitaxel PEI cationic nanoparticles were prepared and evaluated in this chapter selected four types of PEI (800-b PEI, 2000-b PEI, 25k-b PEI and 25k-l PEI) and PLGA Egg PC, mixed preparation of PEI cationic nanoparticles, with diameter of PLGA/Egg potential as an index, the content of PC, PEI type and the content is optimized, the best prescription for cationic nanoparticles PLGA/Egg PC (60:20), PEI type 25k-b PEI, PEI content of cationic 5%. nanoparticle size was 249.9 + 4.76 nm + 2.3 m V. potential was 35.3 compared with the free PEI Blank, cationic nanoparticles has no obvious toxicity to A549 cells and MCF7 cells, the relative cell viability was above 90%. The stability results showed that after 2 weeks of incubation, cationic nanoparticles in PBS (10 m M, P H 7.4) in size and PDI were not significantly changed. The cytotoxicity and cellular uptake experiments by 25k-b PEI, the preparation of paclitaxel PEI cationic nanoparticles has the highest cytotoxicity in A549 and MCF7 cells (P0.001), the cellular uptake efficiency was higher than that of other three kinds of preparation of PEI nanoparticles (P0.01).2. trastuzumab paclitaxel modified PEI cationic nanoparticles were prepared and evaluated in this chapter respectively by electrostatic adsorption and chemical cross-linking to trastuzumab and paclitaxel combined with PEI cationic nanoparticles. The particle size increases, the potential drop and double core shell structure observed by TEM showed antibody successfully connected electrostatic adsorption. Preparation of targeted nano particle size is 280.7 + 7.8nm, 1 + 0.73 m surface potential V. cationic nanoparticles and trastuzumab optimal connection ratio is 1:1, the BCA method was used to detect the antibody binding efficiency was 92.7 + 0.6%.24 h, trastuzumab under physiological conditions the dissociation rate of 23%. per cent target the in vitro release showed a biphasic release pattern, 6 h burst release rate was 28.6%, 120 h cumulative release rate of 71.2%. cell toxicity test, selection of BT474 cells and low expression of HER2 overexpressing MCF7 cells as the experimental object. Nanoparticles targeting to cell proliferation inhibition in the receptor and time dependent..72 h, electrostatic adsorption and chemical crosslinking prepared by targeting nanoparticles on BT474 cells were 53.3% and 34.9% (P0.001). Using double fluorescence pattern marker targeting nanoparticles: FITC labeled trastuzumab, Rhod labeled B cation Sub nanoparticles. In BT474 cells, electrostatic adsorption of prepared nanoparticles targeting to FITC and Rhod. The mean fluorescence intensity of B was significantly higher than that of chemical crosslinking method (P0.001) in.MCF7 cells, two showed the fluorescence intensity of the same level. In the process of cell uptake, targeting nanoparticle paclitaxel lipid nanoparticles surface cationic surface trastuzumab no dissociation of trastuzumab modified.3. were prepared and evaluated in this chapter with less toxicity, better biocompatibility of the cationic phospholipid substitution of DODMA cationic polymer PEI and PLGA mixture preparation of cationic lipid nanoparticles, then combined with trastuzumab. In order to accurately control the number of nanoparticles surface antibody, using three different antibodies connection strategy for the preparation of targeting lipid nanoparticles: (1) the trastuzumab is connected with the DSPE-PEG2000-Mal molecule, then binds to DODMA/ PLGA nano by electrostatic adsorption The rice surface, (Imp) Improved pre-conjugation strategy; (2) the trastuzumab connected with DSPE-PEG2000-Mal molecules, and other matrix (DODMA/PLGA) nanoparticles prepared by physical mixing system, namely Pre-conjugation strategy (Pre); (3) trastuzumab combined with DSPE-PEG2000-Mal/DODMA/PLGA nanoparticles by chemical cross-linking, Pos-conjugation strategy (Pos). The results showed the antibody density, Imp, Pre and Pos antibodies loading were 17.8%, 14.5% and 4.1%, of which the surface antibody levels were 17.8%, 6.12% and 4.1%.Pre, 8.38% antibody in the preparation process of waste in the internal.Pos shows the nanoparticles showed low antibody activity in.Imp were connected. Linear fitting of the antibody load and the dosage of R2 curve 0.995. results showed that the number of control nanoparticles surface antibody by Imp quantitative is feasible. The cell toxicity test, target The nanoparticles cell proliferation inhibition was receptor dependent and dose-dependent.Imp, when trastuzumab loading increased 17.8%, 48 h after the BT474 cell inhibition rate was increased by 7.3% (P0.001).Imp flexible mode of administration, is conducive to the realization of the synergistic effect of trastuzumab and paclitaxel between cells. The toxicity of nanoparticles construction three strategies from high to low order of ImpPrePos, were higher than those of non antibody coated nanoparticles and free paclitaxel. In BT474 cells, Imp internalization fluorescence level is the highest, followed by Pre and Pos, respectively 30.3,23.6 and 20.7. targeted nanoparticles in MCF7 cells to internalize the overall level of fluorescence low than BT474 cells. Finally we investigated the endocytosis inhibitor on the endocytic pathway targeted nanoparticles. The results show that targeting nanoparticles mainly through HER2 receptor endocytosis and clathrin mediated into the tumor Cells. At present, the domestic and foreign research reports on the ligand coupling strategy mainly focuses on the chemical modification method to connect target ligands. However in a chemical reaction, the activity of antibody easily destroyed, thus affecting its targeting. Chemical bonds of high strength will hinder the process of receptor ligand recognition and subsequent chemotherapy drug release the static electricity will be. The antibodies bind to the cationic nanoparticles surface, which greatly improves the structure stability and biological activity of antibody. In addition, Imp can accurately control the number of nanoparticles surface antibody, in a certain range with the regulation of nanoparticle targeting ability. Paclitaxel cationic lipid nanoparticles modified with trastuzumab as target and provide a theoretical basis for the to support R & D, using the methods of reference and technology.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R943

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