發(fā)布時間：2018-06-21 23:50

  本文選題：腦膠質(zhì)瘤 + 化療�。� 參考：《復(fù)旦大學(xué)》2014年碩士論文

【摘要】：腦膠質(zhì)瘤是中樞神經(jīng)系統(tǒng)最為常見的腫瘤,占腦部腫瘤發(fā)病數(shù)40%左右。腦膠質(zhì)瘤多生長在腦部重要部分,比如中央溝區(qū)、丘腦及腦干等區(qū)域,因此于術(shù)難度大,而目.腦膠質(zhì)瘤侵潤性高,瘤體細(xì)胞生長速度快,通過手術(shù)無法將腫瘤組織完全清除。化療是目前治療神經(jīng)上皮腫瘤和改善預(yù)后的重要手段之一。然而化療藥物對腦膠質(zhì)瘤患者的體內(nèi)療效卻不甚理想。其主要原因可以歸結(jié)為以下幾個方面：(1)化療藥物無選擇性,組織分布廣泛,對腫瘤組織無靶向作用,毒副作用大；(2)由膠質(zhì)瘤新生血管內(nèi)皮細(xì)胞和膠質(zhì)瘤細(xì)胞所組成的血瘤屏障(blood-brain tumor barrier, BBTB)的存在極大的限制了化療藥物向膠質(zhì)瘤部位的的遞送；(3)腦膠質(zhì)瘤屬于實體腫瘤,化療藥物對腦膠質(zhì)瘤的穿透性差；(4)細(xì)胞外基質(zhì)(ECM)是腦膠質(zhì)瘤的重要組成部分,占腦膠質(zhì)瘤微環(huán)境的80%以上,細(xì)胞外基質(zhì)在膠質(zhì)瘤體的形態(tài)維持、膠質(zhì)瘤細(xì)胞的分化和增殖起到重要作用,但目前針對腦膠質(zhì)瘤細(xì)胞外基質(zhì)的治療手段卻鮮見報道。因此,構(gòu)建高效主動靶向、增加腫瘤穿透和以細(xì)胞外基質(zhì)為靶點的遞藥策略有望提高腦膠質(zhì)瘤的化療效果,具有較高研究價值和臨床意義。針對腦膠質(zhì)瘤的生理和病理學(xué)特征,本課題采用不同的靶向策略以期增加化療藥物對腦膠質(zhì)瘤的治療效果。本文第一部分設(shè)計了CGKRK多肽修飾的納米遞藥系統(tǒng),其能同時靶向膠質(zhì)瘤新生血管內(nèi)皮細(xì)胞和膠質(zhì)瘤細(xì)胞,增加化療藥物在腦膠質(zhì)瘤部位的蓄積；第二部分構(gòu)建了腫瘤滲透促進多肽tLyp-1修飾的納米遞藥系統(tǒng),在靶向BBTB的同時,增加了化療藥物在血管以及腫瘤實體的穿透能力；第三部分設(shè)計了內(nèi)化型多肽F3修飾的納米遞藥系統(tǒng)聯(lián)合腫瘤滲透多肽tLyp-1共給藥策略,進一步提高化療藥物在腫瘤部位的蓄積以及穿透；第四部分以腫瘤細(xì)胞外基質(zhì)和腫瘤新生血管為靶點,構(gòu)建了CGKRK和ATWLPPR雙重修飾的雙級靶向系統(tǒng),使其能同時靶向腫瘤微環(huán)境和新生血管,提高治療效果。本文第一部分設(shè)計了CGKRK多肽修飾的雙重靶向遞藥系統(tǒng)。CGKRK多肽的受體是硫酸乙酰肝素,該受體高表達(dá)于膠質(zhì)瘤新生血管內(nèi)皮細(xì)胞和膠質(zhì)瘤細(xì)胞表面,而在正常組織細(xì)胞中不表達(dá),具有很強的特異性。因此以CGKRK多肽修飾的納米遞藥系統(tǒng)可以雙重靶向于腫瘤新生血管和膠質(zhì)瘤細(xì)胞,增加化療藥物在腫瘤部位的蓄積。這部分研究中首先通過開環(huán)聚合法合成納米材料聚乙二醇聚己內(nèi)酯(MPEG-PCL)和馬來酰亞胺聚乙二醇聚己內(nèi)酯(Maleimide-PEG-PCL)并采用乳化溶媒蒸發(fā)法制備包載PTX的納米粒(NP-PTX),利用馬來酰亞胺基和巰基的特異性反應(yīng)構(gòu)建CGKRK修飾的載紫杉醇納米粒(CGKRK-NP-PTX)。制得的CGKRK-NP-PTX大小均勻,形態(tài)圓整,平均粒徑為117 nm, Zeta電位為-15.7 mV。細(xì)胞攝取結(jié)果顯示,與普通納米粒相比,CGKRK修飾的納米粒顯著增加了HUVEC細(xì)胞和U87MG細(xì)胞的攝取,且在這兩種細(xì)胞上的攝取為濃度、時間和溫度依賴。攝取抑制實驗顯示,CGKRK-NP在HUVEC細(xì)胞上的內(nèi)吞需要能量,通過細(xì)胞膜穴樣凹陷和脂筏介導(dǎo)的兩種內(nèi)吞途徑入胞,并且內(nèi)吞過程有微管蛋白的參與；在U87MG細(xì)胞上的內(nèi)吞需要能量,通過細(xì)胞膜穴樣凹陷和脂筏介導(dǎo)的兩種內(nèi)吞途徑入胞,并且內(nèi)吞過程有高爾基體的參與。U87MG腫瘤球滲透實驗和生長抑制實驗表明CGKRK修飾的納米遞藥系統(tǒng)在增加腫瘤球穿透能力的同時顯著抑制了腫瘤球的生長。體外誘導(dǎo)凋亡實驗和毒性實驗顯示,經(jīng)過CGKRK多肽修飾后,載PTX納米粒的體外誘導(dǎo)HUVEC細(xì)胞和U87MG細(xì)胞凋亡的能力以及毒性都有顯著性增高。小動物活體成像和腦組織的冰凍切片結(jié)果顯不,CGKRK肽修飾的納米粒在腫瘤部位的熒光強度明顯高于未修飾的納米粒,表明CGKRK肽的修飾顯著提高了納米粒透過腫瘤血管的能力,增加了腫瘤部位的蓄積。荷皮下U87MG的裸鼠腫瘤抑制實驗顯示,在給藥后,經(jīng)過CGKRK多肽修飾的載PTX納米粒的抗實體瘤生長能力最強。本文第二部分構(gòu)建了腫瘤滲透促進多肽tLyp-1修飾的納米遞藥系統(tǒng),tLyp-1多肽的受體是腫瘤新生血管和腫瘤細(xì)胞上均高表達(dá)的神經(jīng)纖毛蛋白Neuropilin-1(NRP-1)蛋白,NRP-1蛋白是血管上的轉(zhuǎn)膜蛋白,能介導(dǎo)腫瘤血管內(nèi)外的物質(zhì)運輸。本部分將tLyp-1多肽修飾在納米粒表面,以期靶向腫瘤新生血管和腫瘤細(xì)胞的同時,增加納米粒從血管中的滲透以及腫瘤穿透。用乳化溶媒蒸發(fā)法制備包載PTX的PEG-PLA納米粒(NP-PTX),并通過馬來酰亞胺基團和巰基的特異性反應(yīng)將tLyp-1多肽共價結(jié)合到納米粒表面。制備的tLyp-1-NP-PTX粒徑在111nm左右,Zeta電位-24.3 mV. HUVEC細(xì)胞和C6細(xì)胞定性定量結(jié)果顯示, HUVEC細(xì)胞和C6細(xì)胞對tLyp-1-NP的攝取呈現(xiàn)時間、濃度和溫度依賴性,且顯著高于未修飾NP組。攝取抑制實驗結(jié)果表明tLyp-1-NP的內(nèi)吞需要能量,在HUVEC上的攝取主要通過陷穴小泡和脂筏介導(dǎo)的兩種內(nèi)吞途徑入胞,并且內(nèi)吞過程有高爾基體和酸性溶酶體參與,在C6細(xì)胞上的攝取主要通過脂筏介導(dǎo)的,并且由高爾基體參與。通過C6細(xì)胞毒和細(xì)胞凋亡等實驗表明tLyp-1肽修飾的納米粒顯著增大了PTX對膠質(zhì)瘤細(xì)胞的抑制作用。體外C6細(xì)胞三維腫瘤球模型評價結(jié)果表明tLyp-1肽的修飾顯著增強了納米粒對實體腫瘤的滲透能力和抑制能力。通過荷C6原位瘤小鼠的體內(nèi)實驗評價tLyp-1修飾的納米遞藥系統(tǒng)的膠質(zhì)瘤體內(nèi)靶向性。小動物活體成像和腦組織的冰凍切片結(jié)果顯示,tLyp-1肽的修飾顯著提高了納米粒穿過腫瘤血管的能力和在膠質(zhì)瘤部位的蓄積。原位膠質(zhì)瘤裸鼠的生存時間考察結(jié)果顯示,tLyp-1-NP-PTX組的平均生存時間為37天,顯著高于Saline組(18天) (p0.001,), Taxol組(23天)(p0.001), NP-PTX組(28天)(p0.01),表明載PTX納米粒經(jīng)tLyp-1肽修飾后具有更強的抗腦膠質(zhì)瘤作用。本文第三部分以內(nèi)化型多肽F3修飾納米遞藥系統(tǒng)聯(lián)合腫瘤滲透促進多肽tLyp-1構(gòu)建共給藥納米遞釋系統(tǒng)。F3肽的受體是腫瘤新生血管和腫瘤細(xì)胞上高表達(dá)的核仁素,且核仁素不在正常細(xì)胞表面,隨著腫瘤細(xì)胞的惡化程度增加而表達(dá)量增加,是腫瘤靶向給藥的理想靶點。tLyp-1是一種具有碳端規(guī)則((R/K)XX(R/K))的多肽,可以特異性靶向NRP-1受體,激活一種特殊的血管運輸系統(tǒng),同時增加組織滲透。本部分研究將F3肽修飾的PEG-PLA納米粒聯(lián)合tLyp-1肽共同注射構(gòu)建共給藥系統(tǒng),以克服BTB的阻礙作用,進一步增加納米粒透過膠質(zhì)瘤血管的能力和在腫瘤部位的蓄積。制得F3-NP粒徑在125 nm左右,zeta電位為-13.3 mV,并通過透射電鏡和表面元素分析對其表征。以C6細(xì)胞為模型,細(xì)胞攝取實驗結(jié)果表明與未修飾的NP相比,F3-NP可以通過筏介導(dǎo)內(nèi)吞以及能量依賴的直接轉(zhuǎn)運途徑極大地提高細(xì)胞攝取量,并且是高爾基體參與的過程。體外C6細(xì)胞三維腫瘤球模型評價結(jié)果表明F3肽的修飾顯著增強了納米粒對實體腫瘤的滲透能力。小動物活體成像和腦組織的冰凍切片結(jié)果顯示,F3肽的修飾以及tLyp-1的共給藥策略顯著提高了納米粒穿過腫瘤血管的能力和在膠質(zhì)瘤部位的蓄積。原位膠質(zhì)瘤裸鼠的生存時間考察結(jié)果顯示,F3-NP-PTX+tLyp-1組的平均生存時間為42天,顯著高于Saline組(19天)(p0.001),Taxol組(24天)(p 0.001), NP-PTX組(28天)(p0.001),F3-NP組(32天)(p0.05)和F3-NP-PTX+tLyp-1組(32天)(p0.01),表明載紫杉醇納米粒經(jīng)F3肽修飾和tLyp-1多肽共給藥后具有更強的抗腦膠質(zhì)瘤作用。本文的第四個部分選取細(xì)胞外基質(zhì)和腫瘤新生血管為靶點,構(gòu)建了CGKRK多肽和ATWLPPR共修飾的雙級靶向系統(tǒng).CGKRK多肽的受體是硫酸乙酰肝素,而ATWLPPR多肽的受體是NRP-1。硫酸乙酰肝素是細(xì)胞外基質(zhì)的重要組成成分,與腫瘤的復(fù)發(fā)再生以及轉(zhuǎn)移具有很大關(guān)系。采用半胱氨酸基團將ATWLPPR多肽和CGKRK多肽相連接,形成ATWLPPRCCGKRK (AC)多肽,通過馬來酰亞胺基團的特異性反應(yīng)制得AC-NP,粒徑在123 nm左右,zeta電位為-11.4 mV,透射電鏡顯示形態(tài)圓整,大小均一。HUVEC細(xì)胞和U87MG細(xì)胞模型評價結(jié)果顯示經(jīng)過AC聯(lián)合肽修飾的納米粒攝取顯著增加,載PTX對U87MG細(xì)胞的誘導(dǎo)凋亡能力和毒性顯著提高。AC-NP在HUVEC上的攝取是能量依賴的,由陷穴小泡和脂筏共同介導(dǎo)的內(nèi)吞,并有酸性溶酶體的參與；AC-NP在U87MG上的攝取是能量依賴的,由陷穴小泡和脂筏共同介導(dǎo)的,有微管蛋白、高爾基體和酸性溶酶體的參與。體外U87MG細(xì)胞三維腫瘤球模型評價結(jié)果表明AC肽的修飾顯著增強了納米粒對實體腫瘤的滲透能力和生長抑制能力。小動物活體成像和腦組織的冰凍切片結(jié)果顯示,AC肽修飾的納米粒在腦膠質(zhì)瘤部位的熒光強度明顯高于未修飾的納米粒以及ATWLPPR多肽和CGKRK多肽單修飾的納米粒,顯著.提高了納米粒透過腫瘤血管的能力,增加了膠質(zhì)瘤部位的蓄積。同時體內(nèi)抗腦膠質(zhì)瘤實驗顯示AC-NP-PTX組的平均生存時間為51天,顯著高于Saline組(22天)(p0.001),Taxol組(29天)(p0.001),NP-PTX組(31天)(p0.001),ATWLPPR-NP-PTX組(41.5天)(p0.01)和CGKRK-NP-PTX組(42天)(p0.01),表明ATWLPPR多肽和CGKRK多肽雙重修飾顯著性提高了荷U87MG原位瘤裸鼠的中位生存期。綜上所述,本研究針對腦膠質(zhì)瘤的生理和病理學(xué)特征,設(shè)計了具有膠質(zhì)瘤新生血管和膠質(zhì)瘤細(xì)胞雙重靶向效果、提高腫瘤穿透效率和靶向細(xì)胞外基質(zhì)的遞藥系統(tǒng),為腦膠質(zhì)瘤的靶向化療提供了實驗和理論依據(jù),具有一定參考價值。
[Abstract]:Glioma is the most common tumor in the central nervous system, accounting for about 40% of the brain tumors. The brain glioma grows in important parts of the brain, such as the central sulcus, thalamus and brain stem, so it is difficult, but the brain glioma has high invasion, the growth rate of the tumor cells is fast, and the tumor can not be completely organized through surgery. Chemotherapy is one of the important means to treat the neuroepithelial tumor and improve the prognosis. However, the therapeutic effect of chemotherapeutic drugs on the patients with glioma is not ideal. The main reasons can be attributed to the following aspects: (1) there is no selective chemotherapy drug, extensive tissue distribution, no target effect on tumor tissue, and toxic and side effects. (2) the presence of blood-brain tumor barrier (BBTB), composed of glioma neovascular endothelial cells and glioma cells, greatly restricts the delivery of chemotherapeutic drugs to glioma sites; (3) glioma is a solid tumor, and the penetration of chemotherapeutic drugs to glioma is poor; (4) the extracellular matrix (ECM) is the brain. The important part of glioma accounts for more than 80% of the microenvironment of glioma. The extracellular matrix is maintained in the form of glioma, and the differentiation and proliferation of glioma cells play an important role. However, the treatment methods for the extracellular matrix of glioma are rarely reported. Therefore, the efficient and active target is constructed to increase the penetration of the tumor and to increase the penetration of the tumor. The delivery strategy of extracellular matrix as a target is expected to improve the therapeutic effect of brain glioma. It has high research value and clinical significance. In view of the physiological and pathological features of glioma, this subject uses different targeting strategies to increase the therapeutic effect of chemotherapeutic drugs on glioma. The first part of this paper is designed to modify the CGKRK polypeptide. The nano drug delivery system can target glioma neovascular endothelial cells and glioma cells at the same time, increase the accumulation of chemotherapeutic drugs in the brain glioma, and the second part constructs the nano delivery system of tumor infiltration promoting peptide tLyp-1 modification, and increases the penetration of chemotherapeutic drugs in blood vessels and tumor entities at the same time as target BBTB. The third part designed an internalized polypeptide F3 modified nano drug delivery system combined with tumor osmotic polypeptide tLyp-1 co delivery strategy to further improve the accumulation and penetration of chemotherapeutic drugs in the tumor site. The fourth part was targeted by the tumor extracellular matrix and tumor neovascularization, and the dual modification of CGKRK and ATWLPPR was constructed. The first part of this paper has designed the CGKRK peptide modified double targeting delivery system.CGKRK polypeptide, which is highly expressed in the neovascular endothelial cells of glioma and the surface of glioma cells, and in normal tissues. The CGKRK peptide modified nano drug delivery system can double target in neovascularization and glioma cells, and increase the accumulation of chemotherapeutic drugs at the tumor site. In this part, the nanomaterial polyethylene glycol polyhexyl (MPEG-PCL) and Malay were first synthesized by ring opening polymerization. The PTX nanoparticles (NP-PTX) were prepared by the emulsion solvent evaporation method, and the CGKRK modified paclitaxel nanoparticles (CGKRK-NP-PTX) were constructed by the specific reaction of maleimide and sulfhydryl groups. The CGKRK-NP-PTX size was uniform and the shape was round, and the average particle size was 117 nm, Zeta The uptake of -15.7 mV. cells showed that CGKRK modified nanoparticles significantly increased the uptake of HUVEC and U87MG cells compared with ordinary nanoparticles, and the uptake on these two cells was concentration, time and temperature dependence. The uptake inhibition experiment showed that the endocytosis of CGKRK-NP on HUVEC cells required energy through the cell membrane. The two endocytic pathways mediated by depression and lipid rafts enter the cell, and the endocytosis process is involved in microtubule protein; the endocytosis on U87MG cells requires energy, two endocytic pathways mediated by cell membrane cavern and lipid rafts, and the endocytosis process has a Golgi body involvement in the.U87MG tumor sphere penetration experiment and growth inhibition experiment. The CGKRK modified nano drug delivery system significantly inhibited the growth of tumor balls while increasing the penetration ability of tumor balls. In vitro induction of apoptosis and toxicity experiments showed that after the modification of CGKRK peptide, the ability to induce apoptosis of HUVEC cells and U87MG cells with PTX nanoparticles in vitro increased significantly. The results of imaging and brain tissue frozen section showed that the fluorescence intensity of CGKRK peptide modified nanoparticles at the tumor site was significantly higher than that of unmodified nanoparticles, indicating that the modification of CGKRK peptide significantly increased the capacity of nanoparticles through the tumor vessels and increased the accumulation of tumor sites. After that, the anti solid tumor growth ability of the loaded PTX nanoparticles modified by CGKRK polypeptide is the strongest. The second part of this paper has constructed the nano delivery system of tumor infiltration promoting peptide tLyp-1 modification. The receptor of tLyp-1 polypeptide is the high expression of the tumor cells and the high expression of the Neuropilin-1 (NRP-1) protein of the tumor cells, and the NRP-1 protein is a protein. The transmembrane protein on the vessel can mediate the transport of substances inside and outside the tumor. This part modifies the tLyp-1 peptide on the surface of the nanoparticles to target the neovascularization and tumor cells of the tumor, and increase the penetration of the nanoparticles from the blood vessels and the penetration of the tumor. The PTX PEG-PLA nanoparticles (NP-PTX) are prepared by the emulsification solvent evaporation method. The tLyp-1 polypeptide was covalently bound to the nanoparticles by the specific reaction of the maleimide group and the sulfhydryl group. The prepared tLyp-1-NP-PTX particle size was around 111nm, and the Zeta potential -24.3 mV. HUVEC cells and C6 cells qualitatively and quantitatively showed that HUVEC and C6 cells showed the time, concentration and temperature dependence of the concentration and temperature dependence. The uptake inhibition test results showed that the endocytosis of tLyp-1-NP needed energy, and the uptake on HUVEC was mainly through two endocytic pathways mediated by trapping vesicles and lipid rafts, and the endocytosis process was involved with Golgi and acid lysosomes, and the uptake of C6 cells was mainly mediated by lipid rafts, and by Golgi. The effects of tLyp-1 peptide modified nanoparticles on the inhibitory effect of PTX on glioma cells were significantly increased by C6 cytotoxicity and cell apoptosis. The evaluation of three-dimensional tumor ball model of C6 cells in vitro showed that the modification of tLyp-1 peptide significantly enhanced the osmotic ability and inhibition ability of nanoparticles to solid tumors. By loading C6 in situ tumor In vivo experiments in mice evaluate the targeting of glioma in the tLyp-1 modified nano delivery system. The results of small animal living imaging and brain tissue section show that the modification of tLyp-1 peptide significantly improves the capacity of nanoparticles through the tumor vessels and accumulation in the site of glioma. The results of the survival time of the nude mice of the primary glioma The average survival time of group tLyp-1-NP-PTX was 37 days, significantly higher than that in group Saline (18 days) (p0.001,), group Taxol (23 days) and NP-PTX group (28 days) (P0.01), indicating that the PTX nanoparticles were modified with the tLyp-1 peptide to be more resistant to glioma. The third part of this article was the combination of the internalized polypeptide F3 modified nano delivery system and the tumor infiltration. The receptor of peptide tLyp-1 for the construction of the.F3 peptide of the co delivery system is a highly expressed nucleolus on the neovascularization and tumor cells of the tumor, and the nucleolus is not on the surface of the normal cell. With the increase of the tumor cell deterioration, the expression of the nucleolus is increased, which is an ideal target for targeting the tumor,.TLyp-1 is a kind of carbon end rule (R/ K) XX (R/K) peptide, which can specifically target NRP-1 receptor, activates a special vascular transport system and increases tissue permeability. This part studies the co injection system of F3 peptide modified PEG-PLA nanoparticles combined with tLyp-1 peptide to overcome BTB's hindrance and further increase the capacity of nanoparticles through the glioma vessels. The grain size of F3-NP was about 125 nm, and the zeta potential was -13.3 mV and characterized by transmission electron microscopy and surface element analysis. C6 cells were used as models. The results of cell uptake experiments showed that F3-NP could be greatly improved through raft mediated endocytosis and energy dependent direct transport, compared with unmodified NP. Cell uptake was the process of Golgi involvement. The evaluation of C6 cells in vitro showed that the modification of F3 peptide significantly enhanced the osmotic ability of the nanoparticles to solid tumors. The results of small animal living imaging and brain tissue frozen section showed that the modification of F3 peptide and the strategy of CO delivery of tLyp-1 increased significantly. The survival time of the nude mice in situ showed that the average survival time of the F3-NP-PTX+tLyp-1 group was 42 days, significantly higher than that in the Saline group (p0.001), Taxol (24 days) (P 0.001), NP-PTX group (28 days) (p0.001), F3-NP group (32 days) (P0.05) and F3-NP-PTX+tLyp-1 (P0.05) and F3-NP-PTX+tLyp-1. Group (32 days) (P0.01) (P0.01) showed that the paclitaxel nanoparticles had a stronger anti glioma effect after the F3 peptide modification and tLyp-1 polypeptide co administration. The fourth parts of this paper selected the extracellular matrix and tumor neovascularization as the target. The receptor of the CGKRK polypeptide and ATWLPPR modified double target system.CGKRK polypeptide was the liver sulfate acetyl liver. The receptor of ATWLPPR polypeptide is an important component of NRP-1. acetyl heparan sulfate, an important component of the extracellular matrix, which is closely related to the recurrence and metastasis of the tumor. Using the cysteine group, the ATWLPPR polypeptide and the CGKRK polypeptide are connected to form a ATWLPPRCCGKRK (AC) polypeptide, and the specific reaction of the maleimide group is made to produce AC. -NP, the particle size is about 123 nm, the zeta potential is -11.4 mV, the transmission electron microscope shows the shape round, the size of the.HUVEC cell and the U87MG cell model evaluation results show that the uptake of nanoparticles modified by AC combined peptide is significantly increased, and the ability to induce apoptosis and toxicity of U87MG cells is significantly increased by PTX, and the uptake of.AC-NP on HUVEC is energy dependent. The uptake of acupoint vesicles and lipid rafts co mediated endocytosis and the involvement of acid lysosomes; the uptake of AC-NP on U87MG is energy dependent, with the involvement of trapping vesicles and lipid rafts, with the involvement of microtubulin, Golgi bodies and acid lysosomes. The evaluation of the three dimensional tumor ball model in vitro shows that the modification of the AC peptide in vitro is significant. The results showed that the fluorescence intensity of AC peptide modified nanoparticles in brain glioma was significantly higher than that of unmodified nanoparticles as well as ATWLPPR polypeptide and CGKRK polypeptides modified nanoparticles. In vivo anti glioma experiments showed that the average survival time of AC-NP-PTX group was 51 days, significantly higher than group Saline (p0.001), group Taxol (29 days), NP-PTX group (31 days) (p0.001), ATWLPPR-NP-PTX group (41.5 days) (P0.01) and CGKRK-NP-PTX group (42 days) (P0.01). It shows that the double modification of ATWLPPR polypeptide and CGKRK polypeptide improves the median survival of nude mice bearing U87MG in situ tumor. To sum up, this study designed the dual targeting effect of glioma neovascularization and glioma cells to improve the penetration efficiency of tumor and target extracellular matrix against the physiological and pathological characteristics of glioma. Drug delivery system provides experimental and theoretical basis for targeted chemotherapy of glioma and has a certain reference value.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943;R96

【共引文獻(xiàn)】

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