本文選題：聚乙烯亞胺 + 疏水性修飾�。� 參考：《吉林大學(xué)》2016年博士論文

【摘要】：在腫瘤治療領(lǐng)域中,反義寡核苷酸(Antisense oligonucleotide,AS-ODN)類藥物及相關(guān)治療技術(shù)越來(lái)越得到大家的重視。目前雖然已有AS-ODN類藥物進(jìn)入臨床階段,但仍存在穩(wěn)定性差、跨膜能力弱、易被核酸酶降解等問(wèn)題。LOR-2501是一種含有20個(gè)堿基的AS-ODN,因?yàn)槟軌蚺c核糖核苷酸還原酶(Ribonucleotide reductase,RNR)大亞基R1的m RNA編碼區(qū)互補(bǔ),具有一定的抗腫瘤活性。目前大量的研究集中于AS-ODN類藥物載體的開(kāi)發(fā)和應(yīng)用領(lǐng)域。聚乙烯亞胺(Polyethyleneimine,PEI)與其他陽(yáng)離子聚合物相比,有著獨(dú)特的“質(zhì)子海綿效應(yīng)”,PEI裝載藥物后能夠通過(guò)大量的氨基吸收質(zhì)子,導(dǎo)致溶酶體滲透性腫脹,破裂后將藥物釋放到細(xì)胞質(zhì)中。PEI作為AS-ODN載體時(shí),高分子量的PEI(25k Da)轉(zhuǎn)染效率相對(duì)較高但是毒性較大,而低分子量的PEI(800 Da)毒性較小但轉(zhuǎn)染效率也相對(duì)較低,因此如何通過(guò)PEI的改性和靶向配體修飾等研究方法在提高PEI轉(zhuǎn)染效率的同時(shí)減少其毒性成為了研究熱點(diǎn)。本論文研究?jī)?nèi)容主要包括以下幾部分:1.PEI-SS-OA的合成及載藥系統(tǒng)的建立本文首先在PEI的基礎(chǔ)上,合成了一種含有二硫鍵(S-S)的聚合物,使用油胺(Oleylamine,OA)對(duì)其進(jìn)行了疏水性修飾(命名為PEI-SS-OA)。同時(shí)采用乙醇注入法制備了PEI-SS-OA載藥系統(tǒng)。制備的PEI-SS-OA載藥系統(tǒng)具有一定的緩沖容量,進(jìn)入細(xì)胞后能夠有效地釋放自身攜帶的藥物。在最優(yōu)制備條件下的粒徑為201.0±5.9 nm,zeta電位值為43.5±0.9 m V。PEI-SS-OA對(duì)He La和A549細(xì)胞無(wú)明顯毒性,細(xì)胞活力均在90%以上。在30天內(nèi),PEI-SS-OA載藥系統(tǒng)的粒徑略有增加,zeta電位值無(wú)明顯變化。2.PEI-SS-OA/LOR-2501傳遞系統(tǒng)的建立和評(píng)價(jià)為了對(duì)制備的PEI-SS-OA載體的轉(zhuǎn)染效率進(jìn)行評(píng)價(jià),本文選擇了一種AS-ODN類藥物L(fēng)OR-2501,建立了PEI-SS-OA/LOR-2501傳遞系統(tǒng)。首先以粒徑和zeta電位為指標(biāo),得到了最佳的氮磷比(N/P)為8:1。此時(shí),PEI-SS-OA與LOR-2501已完全結(jié)合,還原劑的加入能夠促使LOR-2501的釋放。體外細(xì)胞評(píng)價(jià)實(shí)驗(yàn)中,MTT抗腫瘤實(shí)驗(yàn)和流式細(xì)胞計(jì)數(shù)法測(cè)定轉(zhuǎn)染效率實(shí)驗(yàn)結(jié)果表明制備的PEI-SS-OA載體能夠?qū)OR-2501轉(zhuǎn)染進(jìn)入到He La和A549細(xì)胞中,抑制腫瘤細(xì)胞的生長(zhǎng)。采用激光共聚焦顯微鏡觀察到PEI-SS-OA/LOR-2501復(fù)合物能夠大量地進(jìn)入到腫瘤細(xì)胞。實(shí)時(shí)熒光定量PCR測(cè)定R1 m RNA結(jié)果顯示,復(fù)合物在He La和A549細(xì)胞中對(duì)R1 m RNA的下調(diào)效率分別為40.8%和43.6%,與PEI相比分別提高了17.8%和23.3%。Western-blot測(cè)定R1蛋白結(jié)果顯示,PEI-SS-OA組的R1蛋白下調(diào)效率明顯高于PEI組。3.PEI-NH-OA的合成及載藥系統(tǒng)的建立本文同時(shí)在PEI的基礎(chǔ)上,合成了一種含有酰胺鍵(N-H)的聚合物,使用油酰(Oleoacyl,OA)對(duì)其進(jìn)行了疏水性修飾(命名為PEI-NH-OA)。采用乙醇注入法制備了PEI-NH-OA載藥系統(tǒng)。PEI-NH-OA同樣具有一定的緩沖容量。在最優(yōu)制備條件下的粒徑為102.0±3.9 nm,zeta電位值為54.5±3.1 m V。PEI-NH-OA與PEI本身相比毒性明顯減小,He La和A549細(xì)胞活力均在90%以上。在30天內(nèi),PEI-NH-OA載藥系統(tǒng)粒徑和zeta電位均無(wú)明顯變化。與PEI-SS-OA載藥系統(tǒng)相比,PEI-NH-OA載藥系統(tǒng)粒徑更小,陽(yáng)離子特性更強(qiáng),具有更好的穩(wěn)定性。4.PEI-NH-OA/LOR-2501傳遞系統(tǒng)的建立和評(píng)價(jià)本文同時(shí)建立了PEI-NH-OA/LOR-2501傳遞系統(tǒng),對(duì)PEI-NH-OA的轉(zhuǎn)染效率進(jìn)行了評(píng)價(jià)。以粒徑和zeta電位為指標(biāo),得到了最佳的N/P為6:1。此時(shí),PEI-NH-OA與LOR-2501已完全結(jié)合,形成納米復(fù)合物�？鼓[瘤實(shí)驗(yàn)顯示復(fù)合物對(duì)He La和A549細(xì)胞的抑制率分別為46.2%和41.5%。通過(guò)流式細(xì)胞計(jì)數(shù)和激光共聚焦顯微鏡觀察發(fā)現(xiàn),復(fù)合物能夠大量地進(jìn)入到He La和A549腫瘤細(xì)胞內(nèi)。實(shí)時(shí)熒光定量PCR測(cè)定R1 m RNA結(jié)果顯示,PEI-NH-OA作為載體時(shí),在He La和A549細(xì)胞中對(duì)R1 m RNA的下調(diào)效率分別為37.7%和34.5%,而PEI組僅為20%左右。Western-blot測(cè)定R1蛋白結(jié)果顯示,R1蛋白的下調(diào)率分別為50.1%和46.3%�？梢�(jiàn)PEI-NH-OA能夠高效地將LOR-2501轉(zhuǎn)染進(jìn)入細(xì)胞,與PEI-SS-OA相比穩(wěn)定性較高且粒徑較小,后期實(shí)驗(yàn)中選擇對(duì)其進(jìn)行進(jìn)一步修飾。5.FA/PEI-NH-OA/LOR-2501傳遞系統(tǒng)的建立和評(píng)價(jià)本文在PEI-NH-OA/LOR-2501復(fù)合物基礎(chǔ)上,進(jìn)一步將葉酸(Folic acid,FA)與上述復(fù)合物通過(guò)靜電吸附作用結(jié)合,得到FA/PEI-NH-OA/LOR-2501傳遞系統(tǒng)。FA/PEI-NH-OA/LOR-2501復(fù)合物在最佳比例時(shí)粒徑為159.0±1.1 nm,zeta電位值為-12.2±1.3 m V,加入FA后的PEI-NH-OA載體仍能夠與LOR-2501緊密結(jié)合。FA/PEI-NH-OA載體無(wú)明顯毒性,細(xì)胞活力均在80%以上。體外細(xì)胞抗腫瘤評(píng)價(jià)實(shí)驗(yàn)中,對(duì)He La和A549細(xì)胞的抑制率分別達(dá)到55.6%和53.7%。流式細(xì)胞計(jì)數(shù)檢測(cè)轉(zhuǎn)染效率結(jié)果顯示,復(fù)合物在葉酸受體高表達(dá)(FR+)的He La細(xì)胞中和葉酸受體低表達(dá)(FR-)的A549細(xì)胞中,平均熒光強(qiáng)度是FA修飾前的2倍以上,在KB細(xì)胞(FR+)和SK-HEP-1細(xì)胞(FR-)中同樣出現(xiàn)此現(xiàn)象。激光共聚焦顯微鏡觀察結(jié)果顯示復(fù)合物能夠大量地進(jìn)入到腫瘤細(xì)胞中。R1 m RNA測(cè)定結(jié)果顯示,在He La和A549細(xì)胞中,R1 m RNA下調(diào)效率分別為51.7%和45.7%。Western-blot測(cè)定R1蛋白結(jié)果顯示,R1蛋白下調(diào)效率分別達(dá)到72.0%和68.9%,與未修飾的載體相比大幅提高。6.FA/PEI-NH-OA/LOR-2501傳遞系統(tǒng)內(nèi)化機(jī)制的初步研究首先考察了游離FA對(duì)FA/PEI-NH-OA/LOR-2501納米復(fù)合物進(jìn)入腫瘤細(xì)胞過(guò)程的影響。結(jié)果顯示,加入濃度為0.01、0.1、1 mmol/L的游離FA組與未加入游離FA組相比,無(wú)論在He La、KB細(xì)胞(FR+)還是A549、SK-HEP-1細(xì)胞(FR-)中,并沒(méi)有對(duì)復(fù)合物的攝取情況有一定的影響。同時(shí)考察了三種內(nèi)吞途徑抑制劑蔗糖、細(xì)胞松弛素D和制霉菌素對(duì)復(fù)合物內(nèi)吞過(guò)程的影響。結(jié)果顯示,復(fù)合物可能主要是通過(guò)網(wǎng)格蛋白介導(dǎo)的內(nèi)吞途徑進(jìn)入到細(xì)胞中的。使用三種內(nèi)化途徑特異性染料標(biāo)記細(xì)胞后,采用激光共聚焦顯微鏡觀察復(fù)合物的攝取情況,結(jié)果進(jìn)一步驗(yàn)證了復(fù)合物主要是通過(guò)網(wǎng)格蛋白介導(dǎo)的內(nèi)吞途徑進(jìn)入到腫瘤細(xì)胞的。綜上所述,本文中制備的疏水改性的PEI及其FA修飾的載藥系統(tǒng)具有低毒高效的特點(diǎn),FA/PEI-NH-OA載藥系統(tǒng)的轉(zhuǎn)染效率與腫瘤細(xì)胞表面的FR表達(dá)量無(wú)關(guān),在多種腫瘤細(xì)胞系中均具有較高的轉(zhuǎn)染效率,有望成為安全高效的AS-ODN類藥物載體。
[Abstract]:In the field of cancer treatment, antisense oligodeoxynucleotides (Antisense oligonucleotide, AS-ODN) drugs and related therapies have attracted more and more attention. Although AS-ODN drugs have entered the clinical stage, there are still poor stability, weak transmembrane ability and easy to be degraded by nucleoacid,.LOR-2501 is a kind of 20 bases. AS-ODN, because it is complementary to the m RNA coding region of the Ribonucleotide reductase, RNR, R1, and has a certain anti-tumor activity. A great deal of research is focused on the development and application of AS-ODN drug carriers. The special "proton sponge effect", after PEI loading drugs, can absorb protons through a large number of amino groups, resulting in the osmotic swelling of the lysosome. When the drug is released to the cytoplasm and.PEI as a AS-ODN carrier after rupture, the high molecular weight PEI (25K Da) transfection efficiency is relatively high but the toxicity is larger, while the low molecular weight PEI (800 Da) is less toxic but less toxic but less toxic. The transfection efficiency is also relatively low, so how to improve the efficiency of PEI transfection and reduce its toxicity through the modification of PEI and targeting ligand modification has become a hot topic. The main contents of this paper include the following parts: the synthesis of 1.PEI-SS-OA and the establishment of the drug loading system, based on the PEI, were synthesized. A polymer containing two sulfur bonds (S-S) is hydrophobic modified (named PEI-SS-OA) using Oleylamine (OA). At the same time, the PEI-SS-OA drug delivery system is prepared by ethanol injection. The prepared PEI-SS-OA drug loading system has a certain buffer capacity and can effectively release its own drug after entering the cell. The particle size of the optimal preparation was 201 + 5.9 nm, the zeta potential value was 43.5 + 0.9 m V.PEI-SS-OA for He La and A549 cells, and the cell viability was above 90%. In 30 days, the particle size of the PEI-SS-OA carrier system increased slightly and the zeta potential value had no obvious change, and the.2.PEI-SS-OA/ LOR-2501 transmission system was established and evaluated for the preparation and evaluation of the.2.PEI-SS-OA/ LOR-2501 transmission system. The transfection efficiency of the PEI-SS-OA carrier was evaluated. In this paper, a kind of AS-ODN drug LOR-2501 was selected and the PEI-SS-OA/LOR-2501 transmission system was established. The optimum nitrogen and phosphorus ratio (N/P) was obtained by using the particle size and zeta potential as the index. At this time, PEI-SS-OA and LOR-2501 had been completely combined, and the addition of reducing agent could promote the release of LOR-2501. In the in vitro cell evaluation experiment, the results of MTT anti tumor experiment and flow cytometry assay showed that the prepared PEI-SS-OA vector could transfect LOR-2501 into He La and A549 cells and inhibit the growth of tumor cells. The laser confocal microscope observed that the PEI-SS-OA/LOR-2501 complex could enter into large quantities. The results of R1 m RNA measured by real time fluorescence quantitative PCR showed that the decrease efficiency of R1 m RNA in He La and A549 cells was 40.8% and 43.6% respectively. On the basis of PEI, a polymer containing amide bond (N-H) was synthesized on the basis of PEI. The hydrophobic modification (named PEI-NH-OA) was carried out with oil acyl (OA). The PEI-NH-OA drug delivery system.PEI-NH-OA was prepared by ethanol injection. The optimal preparation conditions were obtained. The particle size is 102 + 3.9 nm, the zeta potential value is 54.5 + 3.1 m V.PEI-NH-OA and the toxicity of He La and A549 cells is more than 90%. In the 30 days, the particle size and zeta potential of the PEI-NH-OA loading system are not obviously changed. The particle size of the PEI-NH-OA drug system is smaller and the cation characteristics are more than that of the PEI-SS-OA drug system. The establishment and evaluation of.4.PEI-NH-OA/LOR-2501 transmission system with better stability was established and the PEI-NH-OA/LOR-2501 transfer system was established at the same time, and the transfection efficiency of PEI-NH-OA was evaluated. The optimum N/P was 6:1. at the time of N/P as the index of particle size and zeta potential, and PEI-NH-OA and LOR-2501 have been fully combined to form nanocomposites. The antitumor experiment showed that the inhibitory rate of the complex on He La and A549 cells was 46.2% and 41.5%., respectively, by flow cytometry and laser confocal microscopy, and found that the complex was able to enter into He La and A549 tumor cells in large quantities. The down regulation efficiency of R1 m RNA in the cells was 37.7% and 34.5% respectively, while the PEI group was only 20%.Western-blot to determine R1 protein results, and the down regulation of R1 protein was 50.1% and 46.3%. visible PEI-NH-OA could efficiently transfect LOR-2501 into cells, which was more stable and smaller than PEI-SS-OA, and selected in the later experiment. On the basis of PEI-NH-OA/LOR-2501 complex, this paper further modifies the.5.FA/PEI-NH-OA/LOR-2501 transfer system and further combines the Folic acid (FA) with the above complex by electrostatic adsorption to obtain the FA/PEI-NH-OA/LOR-2501 transfer system.FA/PEI-NH-OA/LOR-2501 complex at the optimum proportion. The diameter was 159 + 1.1 nm and the value of zeta potential was -12.2 + 1.3 m V. The PEI-NH-OA carrier after adding FA was still able to combine with LOR-2501 without obvious toxicity, and the cell viability was above 80%. The inhibitory rate of He La and A549 cells was 55.6% and the flow cytometry was detected in the anti tumor evaluation experiment of the cells in vitro. The results showed that the average fluorescence intensity of the complex in He La cells with high expression of folate receptor (FR+) and the low expression of folate receptor (FR-) in A549 cells was more than 2 times more than before FA modification, and the same phenomenon appeared in KB cells (FR+) and SK-HEP-1 cells (FR-). The results of laser confocal microscopy showed that the complex could be a large amount. The results of.R1 m RNA assay in the tumor cells showed that in He La and A549 cells, the RNA downregulation efficiency of R1 m RNA was 51.7% and 45.7%.Western-blot showed R1 protein, and the downregulation efficiency of R1 protein was 72% and 68.9% respectively. The effect of free FA on the entry of FA/PEI-NH-OA/LOR-2501 nanocomposites into tumor cells was first investigated. The results showed that the free FA group with a concentration of 0.01,0.1,1 mmol/L was compared with that of the free FA group, no matter in He La, KB cell (FR+) or A549, and there was no one in the uptake of the complex. The effect of three endocytic pathway inhibitors, sucrose, cytosin D and nystatin on endocytosis, is also investigated. The results show that the complex may be mainly through the endocytic pathway mediated by the gridin. The laser copolymerization is used after three kinds of internalized pathway specific dye labeling cells. The results further verify that the complex is mainly through the endocytic pathway mediated by the gridin to enter the tumor cells. To sum up, the hydrophobic modified PEI and its FA modified carrier system have low toxicity and high efficiency, and the transfection efficiency of the FA/PEI-NH-OA drug delivery system The expression level of FR on tumor cells is independent, and has high transfection efficiency in a variety of tumor cell lines. It is expected to become a safe and efficient AS-ODN drug carrier.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R943

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