pH響應(yīng)性磁靶向阿霉素復(fù)合納米載體的構(gòu)建與應(yīng)用研究
發(fā)布時(shí)間：2019-05-22 19:46
【摘要】：惡性腫瘤的發(fā)病率逐年上升,是嚴(yán)重威脅人類健康的重大疾病�；熓悄壳芭R床最常用的腫瘤治療手段之一。但由于一般化療藥物對(duì)腫瘤細(xì)胞和組織不具有選擇性,導(dǎo)致廣泛的毒副作用,嚴(yán)重影響了患者的生活質(zhì)量并限制了化療藥物的臨床應(yīng)用。因此,設(shè)計(jì)新型靶向腫瘤的藥物載體系統(tǒng),提高化療藥物體內(nèi)對(duì)腫瘤部位的靶向性,在治療過程中使化療藥物能夠在腫瘤部位靶向富集,有效提高腫瘤組織的藥物濃度,減小全身性的毒副作用,成為當(dāng)前腫瘤給藥系統(tǒng)研究的熱點(diǎn)。本研究中我們擬采用效果明確的磁靶向技術(shù)為靶向策略,根據(jù)腫瘤部位pH低于正常組織的生理特點(diǎn),設(shè)計(jì)合成能夠通過靜電作用有效結(jié)合化療藥物阿霉素(DOX)藥物分子且具有pH敏感釋放特性的高分子聚合物與磁性納米粒構(gòu)建形成阿霉素的腫瘤靶向性控釋復(fù)合納米給藥體系。以期在外磁場(chǎng)作用下,該化療藥物載體在體內(nèi)能夠定向富集于腫瘤病灶部位,在腫瘤組織較低pH的生理?xiàng)l件下有效釋放負(fù)載的化療藥物,增加藥物在腫瘤部位的濃度,降低化療藥物的全身毒性,從而達(dá)到更好的治療效果,提高患者的順應(yīng)性。在第一部分納米藥物載體的構(gòu)建、合成和表征中,我們首先合成了pH響應(yīng)性的聚合物載藥材料聚乙二醇-b-聚天冬氨酸(PEG-b-Pasp),反應(yīng)首先是由L-天冬氨酸-β-芐酯與無水四氫呋喃,在60℃和三光氣的環(huán)境中反應(yīng)制備得到天冬氨酸芐酯環(huán)內(nèi)酸酐,再與氨基聚乙二醇單甲醚發(fā)生開環(huán)聚合反應(yīng)得到聚乙二醇-b-聚天冬氨酸芐酯(PEG-b-PBLA),最后通過在OH-條件下水解去除PEG-b-PBLA的芐醇,經(jīng)過核磁共振和紅外吸收光譜表征表明成功合成了PEG-b-PAsp。然后利用水熱法合成了粒徑水合粒徑約140nm的四氧化三鐵(Fe_3O_4)磁性納米粒,為提高Fe_3O_4磁性納米粒在空氣中的穩(wěn)定性并降低其相互聚集,我們通過St?ber方法和溶膠凝膠過程在Fe_3O_4磁性納米粒表面包覆上一層厚度約10nm二氧化硅(SiO_2)層,最后通過酰胺化反應(yīng)將合成的PEG-b-PAsp與表面氨基化的SiO_2層化學(xué)交聯(lián),再加入鹽酸阿霉素溶液攪拌過夜進(jìn)行載藥,制備出Fe_3O_4@SiO_2@PEG-b-PAsp@DOX納米復(fù)合載體。經(jīng)對(duì)該納米復(fù)合載體的粒徑、Zeta電位、載藥量等的表征,結(jié)果表明制備得到的納米復(fù)合載體為球狀,粒徑較均一,約(197.7±1.5)nm,Zeta電位約為(-35.9±0.6)mv,DOX的載藥量約20.36%。在pH分別為5.5和7.4的緩沖溶液中的藥物釋放實(shí)驗(yàn)表明該納米復(fù)合載藥體系具有阿霉素pH敏感性釋放的特點(diǎn)。第二部分我們考察了載藥納米粒在體外磁場(chǎng)作用下的細(xì)胞靶向性,并考察了該納米復(fù)合載體對(duì)小鼠肺癌細(xì)胞LLC殺傷作用和載藥材料的初步安全性。熒光顯微鏡和生物透射電鏡觀察表明,載體材料能夠以內(nèi)吞的方式被腫瘤細(xì)胞有效攝取并聚集于腫瘤細(xì)胞中。在同一細(xì)胞培養(yǎng)體系中加入5μg·m L~(-1)的Fe_3O_4@SiO_2@PEG-b-PAsp@DOX載藥體系共培養(yǎng)2h后,利用流式細(xì)胞儀借助DOX的紅色熒光對(duì)載藥體系的體外靶向性進(jìn)行了定量檢測(cè),在其施加外界磁場(chǎng)一側(cè)的細(xì)胞中熒光強(qiáng)度(Xmean=98.65)顯著強(qiáng)于未施加外界磁場(chǎng)一側(cè)的細(xì)胞的熒光強(qiáng)度(Xmean=81.81),兩者之間存在顯著性差異(p0.05),表明該載藥體系在外界磁場(chǎng)下有較顯著的靶向性,而且在進(jìn)入腫瘤細(xì)胞后DOX能夠有效被釋放。在該載藥納米復(fù)合載體殺傷腫瘤細(xì)胞作用研究中發(fā)現(xiàn),載藥復(fù)合納米�？梢杂行У臍鸏LC細(xì)胞;通過CCK-8法測(cè)定結(jié)果計(jì)算出24h時(shí)游離DOX和載藥的納米復(fù)合載體的IC50值分別為0.46μg·m L~(-1)和0.89μg·m L~(-1),在48h時(shí)兩者的IC50分別為0.32μg·m L~(-1)和0.46μg·m L~(-1),可知隨著時(shí)間的延長(zhǎng)載藥納米復(fù)合載體殺傷腫瘤細(xì)胞能力逐漸接近游離DOX,這可能納米載藥體系中DOX的緩釋有關(guān)。我們還利用CCK-8法和流式細(xì)胞儀初步考察了空白載體的生物安全性,在空白載體濃度高達(dá)100μg·m L~(-1)時(shí),細(xì)胞與空白材料共培養(yǎng)48h后,三種不同的細(xì)胞(LLC細(xì)胞珠、人的肺癌細(xì)胞A549細(xì)胞株和成纖維細(xì)胞L929細(xì)胞株)存活率均在80%以上,而較低濃度的空白載體具有較好的生物安全性,幾乎不存在細(xì)胞毒性。流式檢測(cè)結(jié)果也說明,空白載體幾乎不會(huì)誘導(dǎo)腫瘤細(xì)胞的凋亡,而載藥后的復(fù)合納米材料可以有效誘導(dǎo)腫瘤細(xì)胞凋亡的發(fā)生,凋亡的比例隨載藥濃度的增加而增加,其作用與游離DOX對(duì)腫瘤細(xì)胞的作用一致。第三部分我們利用所建立的LLC細(xì)胞荷瘤小鼠模型研究了納米復(fù)合載藥體系在體內(nèi)的靶向性和抗腫瘤效果。通過在C57小鼠的右后腿外側(cè)皮下注射LLC細(xì)胞懸液建立荷瘤小鼠模型。在考察納米復(fù)合載藥體系的體內(nèi)靶向性實(shí)驗(yàn)中,荷瘤小鼠隨機(jī)分為施加和未施加外界磁場(chǎng)組,尾靜脈注射4mg·kg~(-1)的納米復(fù)合載藥體系溶液后,施加磁場(chǎng)組在腫瘤部位固定磁鐵4h,然后分別將各組腫瘤部位置于3.0 T磁共振成像儀中進(jìn)行T2加權(quán)成像檢測(cè),結(jié)果表明與對(duì)照相比施加磁場(chǎng)組腫瘤部位的鐵順磁性物質(zhì)富集明顯大于未施加磁場(chǎng)組,二者差別有統(tǒng)計(jì)學(xué)意義(p=0.0040.01),表明該納米復(fù)合載藥體系在小鼠體內(nèi)具有良好的磁靶向富集特性。在納米復(fù)合載藥體系體內(nèi)抗腫瘤效果研究中,我們將荷瘤小鼠分為生理鹽水組(S)、游離DOX組(FD)、未施加磁場(chǎng)組(P)、施加磁場(chǎng)組(MP)四組,通過記錄各組小鼠的生存率、腫瘤體積、體重的變化和肺轉(zhuǎn)移結(jié)節(jié)數(shù)考察納米復(fù)合載藥體系的抗腫瘤效果。在每組5只的荷瘤小鼠存活實(shí)驗(yàn)中,第36天各組的生存率分別為40%(S)、20%(FD)、80%(P)和100%(MP);腫瘤增長(zhǎng)曲線表明生理鹽水組和未施加磁場(chǎng)組小鼠腫瘤生長(zhǎng)稍快;而在小鼠體重生長(zhǎng)曲線中可以明顯看到只有游離DOX組小鼠的平均體重隨著治療的進(jìn)行呈下降趨勢(shì),結(jié)合小鼠存活實(shí)驗(yàn)和腫瘤增長(zhǎng)實(shí)驗(yàn)的結(jié)果,說明在該濃度下游離DOX直接給藥可能產(chǎn)生較大的系統(tǒng)毒性。通過對(duì)模型小鼠解剖的觀察,發(fā)現(xiàn)納米復(fù)合載藥體系可抑制模型小鼠腫瘤的肺部轉(zhuǎn)移,其機(jī)制有待于進(jìn)一步研究。本研究成功構(gòu)建的pH響應(yīng)性的磁靶向復(fù)合納米載藥體系能夠有效的負(fù)載DOX,并表現(xiàn)出顯著的藥物pH響應(yīng)釋放和磁靶向性,在體內(nèi)外均顯示出良好的抗腫瘤作用,有望在外磁場(chǎng)作用下靶向的到達(dá)腫瘤病灶部位,實(shí)現(xiàn)在腫瘤部位可控釋藥,減小抗腫瘤藥物化療副作用,為新型靶向抗腫瘤藥物傳遞系統(tǒng)的研究提供了有益的探索。
[Abstract]:The incidence of malignant tumor is increasing year by year, which is a serious disease which is a serious threat to human health. Chemotherapy is one of the most common methods for the treatment of cancer. But because the general chemotherapy drugs do not have the selectivity to the tumor cells and the tissues, the invention leads to a wide toxic and side effect, and the quality of the life of the patients is seriously affected and the clinical application of the chemotherapy medicine is limited. therefore, the novel drug carrier system for targeting the tumor is designed, the targeting property of the tumor part in the chemotherapy medicine body is improved, the chemotherapy medicine can be targeted and enriched at the tumor part in the treatment course, the drug concentration of the tumor tissue is effectively improved, the systemic toxic and side effect is reduced, And is a hot spot for the research of the current tumor drug delivery system. In the study, we intend to use the magnetic targeting technology with definite effect as the targeting strategy, and according to the physiological characteristics of the tumor site, the pH is lower than that of the normal tissue, In that design and synthesis, the adriamycin (DOX) drug molecule and the high-molecular polymer with the pH-sensitive release characteristic and the magnetic nano-particle can be effectively combined with the chemotherapeutic drug adriamycin (DOX) drug molecule to form the adriamycin-based tumor-targeted controlled-release composite nano-drug delivery system. so as to effectively release the loaded chemotherapy drug under the physiological condition of lower pH of the tumor tissue, increase the concentration of the drug at the tumor site and reduce the systemic toxicity of the chemotherapeutic drug, So as to achieve better treatment effect and improve the compliance of the patient. In the construction, synthesis and characterization of the first part of the nano-drug carrier, we first synthesized the pH-responsive polymer drug-carrying material, polyethylene glycol-b-polyaspartic acid (PEG-b-Pasp), and the reaction is first carried out by the L-aspartic acid-1-phthalate and the anhydrous four-hydrogen peroxide, reacting in an environment of 60 DEG C and triphosgene to obtain an aspartic ester ring-b-polyaspartic acid ester (PEG-b-PBLA) in an open-loop polymerization reaction with the amino-polyethylene glycol monomethyl ether, and finally, performing hydrolysis to remove the polyoxyalkylene of the PEG-b-PBLA under the OH-condition, The results showed that PEG-b-PASP was successfully synthesized by nuclear magnetic resonance and infrared absorption spectrum. then the ferroferric oxide (Fe _ 3O _ 4) magnetic nano-particles with a particle size of about 140 nm are synthesized by a hydrothermal method, so that the stability of the Fe _ 3O _ 4 magnetic nano-particles in the air is improved, in that sol-gel process, a layer of silicon dioxide (SiO _ 2) with a thickness of about 10 nm is coat on the surface of the Fe _ 3O _ 4 magnetic nano-particle by a St-ber method and a sol-gel process, The Fe_3O_4@SiO_2 @ PEG-b-PAsp@DOX nano composite carrier is prepared. The results of the characterization of the particle size, Zeta potential and drug-carrying amount of the nano-composite carrier show that the prepared nano-composite carrier is spherical, the particle size is uniform, about (197.7-1.5) nm, the Zeta potential is about (-35.9-0.6) mv, and the loading amount of DOX is about 20.36%. The drug release experiment in the buffer solution with pH of 5.5 and 7.4 shows that the nano-composite drug-carrying system has the characteristics of the adriamycin pH-sensitive release. In the second part, we investigated the cell targeting of the drug-loaded nanoparticles under the action of the in vitro magnetic field, and examined the anti-killing effect of the nano-composite carrier on the mouse lung cancer cell LLC and the initial safety of the drug-loaded material. The observation of the fluorescence microscope and the transmission electron microscope shows that the carrier material can be taken up by the tumor cells and accumulated in the tumor cells in a manner that the carrier material can be swallowed. In the same cell culture system,5. mu. g. m L-(-1) of the Fe_3O_4@SiO_2 @ PEG-b-PAsp@DOX drug-carrying system was co-cultured for 2 h, and the in vitro targeting of the drug-carrying system was quantitatively detected by flow cytometry using the red fluorescence of DOX. The fluorescence intensity (Xmean = 98.65) in the cells on the side of which the external magnetic field was applied was significantly stronger than that of the cells without the external magnetic field (Xmean = 81.81), and there was a significant difference between the two (p0.05), indicating that the drug-carrying system had significant targeting at the external magnetic field. And DOX can be effectively released after entering the tumor cells. in that study of the effect of the drug-loaded nano-composite carrier on the tumor cell, the drug-loaded composite nanoparticle can effectively kill the LLC cell, and the IC50 value of the free DOX and the drug-loaded nano composite carrier at 24 h is 0.46. mu. g 路 m L-(-1) and 0.89. m The IC50 of the two was 0.32 & mu; g 路 m-L ~ (-1) and 0.46. m u.g 路 m-L ~ (-1) respectively at 48 h, and it was found that the ability of the drug-loaded nano-composite carrier to kill the tumor cells gradually approaches the free DOX over time, which may be related to the slow release of DOX in the nano-drug-loaded system. We also used CCK-8 method and flow cytometer to study the biological safety of blank carrier, and when the concentration of blank carrier was as high as 100 & mu; g 路 m L ~ (-1), the cells were co-cultured with blank material for 48 h, and three different cells (LLC cell beads, The survival rate of the human lung cancer cell A549 cell line and the fibroblast cell line L929 cell line is more than 80%, and the lower concentration blank carrier has better biological safety, and has little cytotoxicity. The results of the flow test also show that the blank carrier can hardly induce the apoptosis of the tumor cells, and the compound nano-materials after the loading can effectively induce the apoptosis of the tumor cells, and the proportion of the apoptosis is increased with the increase of the concentration of the drug carrier, and the effect is consistent with the effect of the free DOX on the tumor cells. In the third part, we study the targeting and anti-tumor effect of the nano-composite drug-loaded system in vivo using the established model of LLC cell-bearing mice. The tumor-bearing mouse model was established by subcutaneous injection of the LLC cell suspension on the right hind leg of the C57 mouse. in the in vivo targeting experiment of the nano composite drug-carrying system, the tumor-bearing mice were randomly divided into the nano-composite drug-carrying system solution applied and not applied to the external magnetic field group and the tail vein injection of 4 mg/ kg to (-1), and the magnetic field group is applied to the tumor part to fix the magnet 4h, Then, the tumor sites of each group were placed in a 3.0T magnetic resonance imager for T2-weighted imaging, and the results showed that the concentration of the iron paramagnetic substance in the tumor part of the magnetic field group was significantly higher than that of the non-applied magnetic field group compared with the control group (p = 0.0040.01). It is shown that the nano-composite drug-loaded system has good magnetic targeting and enrichment characteristics in mice. in that study of the anti-tumor effect of the nano composite drug-loaded system, the tumor-bearing mice are divided into a normal saline group (S), a free DOX group (FD), an unapplied magnetic field group (P), a magnetic field group (MP) group, The anti-tumor effect of the nano-composite drug-loaded system was investigated by the change of body weight and the number of lung metastases. The survival rate of tumor-bearing mice in each group was 40% (S),20% (FD),80% (P) and 100% (MP), respectively. In the mouse body weight growth curve, the average body weight of only free DOX group mice was seen to decrease with the treatment, and combined with the results of the mouse survival experiment and the tumor growth experiment, it was shown that the free DOX direct administration at this concentration could result in a greater systemic toxicity. Through the observation of the model mouse, it is found that the nano-composite drug-loading system can inhibit the lung metastasis of the model mouse tumor, and its mechanism is to be further studied. The successfully constructed pH-responsive magnetic-targeting composite nano-drug-loading system is capable of effectively loading DOX, and shows remarkable drug pH response release and magnetic targeting, and has good anti-tumor effect in vivo. Can be targeted at the site of the tumor focus under the action of the external magnetic field, realize the controlled release medicine at the tumor site, reduce the side effect of the anti-tumor drug chemotherapy, and provide a beneficial exploration for the research of a novel targeting anti-tumor drug delivery system.
【學(xué)位授予單位】：河北北方學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R943
本文編號(hào)：2483203
[Abstract]:The incidence of malignant tumor is increasing year by year, which is a serious disease which is a serious threat to human health. Chemotherapy is one of the most common methods for the treatment of cancer. But because the general chemotherapy drugs do not have the selectivity to the tumor cells and the tissues, the invention leads to a wide toxic and side effect, and the quality of the life of the patients is seriously affected and the clinical application of the chemotherapy medicine is limited. therefore, the novel drug carrier system for targeting the tumor is designed, the targeting property of the tumor part in the chemotherapy medicine body is improved, the chemotherapy medicine can be targeted and enriched at the tumor part in the treatment course, the drug concentration of the tumor tissue is effectively improved, the systemic toxic and side effect is reduced, And is a hot spot for the research of the current tumor drug delivery system. In the study, we intend to use the magnetic targeting technology with definite effect as the targeting strategy, and according to the physiological characteristics of the tumor site, the pH is lower than that of the normal tissue, In that design and synthesis, the adriamycin (DOX) drug molecule and the high-molecular polymer with the pH-sensitive release characteristic and the magnetic nano-particle can be effectively combined with the chemotherapeutic drug adriamycin (DOX) drug molecule to form the adriamycin-based tumor-targeted controlled-release composite nano-drug delivery system. so as to effectively release the loaded chemotherapy drug under the physiological condition of lower pH of the tumor tissue, increase the concentration of the drug at the tumor site and reduce the systemic toxicity of the chemotherapeutic drug, So as to achieve better treatment effect and improve the compliance of the patient. In the construction, synthesis and characterization of the first part of the nano-drug carrier, we first synthesized the pH-responsive polymer drug-carrying material, polyethylene glycol-b-polyaspartic acid (PEG-b-Pasp), and the reaction is first carried out by the L-aspartic acid-1-phthalate and the anhydrous four-hydrogen peroxide, reacting in an environment of 60 DEG C and triphosgene to obtain an aspartic ester ring-b-polyaspartic acid ester (PEG-b-PBLA) in an open-loop polymerization reaction with the amino-polyethylene glycol monomethyl ether, and finally, performing hydrolysis to remove the polyoxyalkylene of the PEG-b-PBLA under the OH-condition, The results showed that PEG-b-PASP was successfully synthesized by nuclear magnetic resonance and infrared absorption spectrum. then the ferroferric oxide (Fe _ 3O _ 4) magnetic nano-particles with a particle size of about 140 nm are synthesized by a hydrothermal method, so that the stability of the Fe _ 3O _ 4 magnetic nano-particles in the air is improved, in that sol-gel process, a layer of silicon dioxide (SiO _ 2) with a thickness of about 10 nm is coat on the surface of the Fe _ 3O _ 4 magnetic nano-particle by a St-ber method and a sol-gel process, The Fe_3O_4@SiO_2 @ PEG-b-PAsp@DOX nano composite carrier is prepared. The results of the characterization of the particle size, Zeta potential and drug-carrying amount of the nano-composite carrier show that the prepared nano-composite carrier is spherical, the particle size is uniform, about (197.7-1.5) nm, the Zeta potential is about (-35.9-0.6) mv, and the loading amount of DOX is about 20.36%. The drug release experiment in the buffer solution with pH of 5.5 and 7.4 shows that the nano-composite drug-carrying system has the characteristics of the adriamycin pH-sensitive release. In the second part, we investigated the cell targeting of the drug-loaded nanoparticles under the action of the in vitro magnetic field, and examined the anti-killing effect of the nano-composite carrier on the mouse lung cancer cell LLC and the initial safety of the drug-loaded material. The observation of the fluorescence microscope and the transmission electron microscope shows that the carrier material can be taken up by the tumor cells and accumulated in the tumor cells in a manner that the carrier material can be swallowed. In the same cell culture system,5. mu. g. m L-(-1) of the Fe_3O_4@SiO_2 @ PEG-b-PAsp@DOX drug-carrying system was co-cultured for 2 h, and the in vitro targeting of the drug-carrying system was quantitatively detected by flow cytometry using the red fluorescence of DOX. The fluorescence intensity (Xmean = 98.65) in the cells on the side of which the external magnetic field was applied was significantly stronger than that of the cells without the external magnetic field (Xmean = 81.81), and there was a significant difference between the two (p0.05), indicating that the drug-carrying system had significant targeting at the external magnetic field. And DOX can be effectively released after entering the tumor cells. in that study of the effect of the drug-loaded nano-composite carrier on the tumor cell, the drug-loaded composite nanoparticle can effectively kill the LLC cell, and the IC50 value of the free DOX and the drug-loaded nano composite carrier at 24 h is 0.46. mu. g 路 m L-(-1) and 0.89. m The IC50 of the two was 0.32 & mu; g 路 m-L ~ (-1) and 0.46. m u.g 路 m-L ~ (-1) respectively at 48 h, and it was found that the ability of the drug-loaded nano-composite carrier to kill the tumor cells gradually approaches the free DOX over time, which may be related to the slow release of DOX in the nano-drug-loaded system. We also used CCK-8 method and flow cytometer to study the biological safety of blank carrier, and when the concentration of blank carrier was as high as 100 & mu; g 路 m L ~ (-1), the cells were co-cultured with blank material for 48 h, and three different cells (LLC cell beads, The survival rate of the human lung cancer cell A549 cell line and the fibroblast cell line L929 cell line is more than 80%, and the lower concentration blank carrier has better biological safety, and has little cytotoxicity. The results of the flow test also show that the blank carrier can hardly induce the apoptosis of the tumor cells, and the compound nano-materials after the loading can effectively induce the apoptosis of the tumor cells, and the proportion of the apoptosis is increased with the increase of the concentration of the drug carrier, and the effect is consistent with the effect of the free DOX on the tumor cells. In the third part, we study the targeting and anti-tumor effect of the nano-composite drug-loaded system in vivo using the established model of LLC cell-bearing mice. The tumor-bearing mouse model was established by subcutaneous injection of the LLC cell suspension on the right hind leg of the C57 mouse. in the in vivo targeting experiment of the nano composite drug-carrying system, the tumor-bearing mice were randomly divided into the nano-composite drug-carrying system solution applied and not applied to the external magnetic field group and the tail vein injection of 4 mg/ kg to (-1), and the magnetic field group is applied to the tumor part to fix the magnet 4h, Then, the tumor sites of each group were placed in a 3.0T magnetic resonance imager for T2-weighted imaging, and the results showed that the concentration of the iron paramagnetic substance in the tumor part of the magnetic field group was significantly higher than that of the non-applied magnetic field group compared with the control group (p = 0.0040.01). It is shown that the nano-composite drug-loaded system has good magnetic targeting and enrichment characteristics in mice. in that study of the anti-tumor effect of the nano composite drug-loaded system, the tumor-bearing mice are divided into a normal saline group (S), a free DOX group (FD), an unapplied magnetic field group (P), a magnetic field group (MP) group, The anti-tumor effect of the nano-composite drug-loaded system was investigated by the change of body weight and the number of lung metastases. The survival rate of tumor-bearing mice in each group was 40% (S),20% (FD),80% (P) and 100% (MP), respectively. In the mouse body weight growth curve, the average body weight of only free DOX group mice was seen to decrease with the treatment, and combined with the results of the mouse survival experiment and the tumor growth experiment, it was shown that the free DOX direct administration at this concentration could result in a greater systemic toxicity. Through the observation of the model mouse, it is found that the nano-composite drug-loading system can inhibit the lung metastasis of the model mouse tumor, and its mechanism is to be further studied. The successfully constructed pH-responsive magnetic-targeting composite nano-drug-loading system is capable of effectively loading DOX, and shows remarkable drug pH response release and magnetic targeting, and has good anti-tumor effect in vivo. Can be targeted at the site of the tumor focus under the action of the external magnetic field, realize the controlled release medicine at the tumor site, reduce the side effect of the anti-tumor drug chemotherapy, and provide a beneficial exploration for the research of a novel targeting anti-tumor drug delivery system.
【學(xué)位授予單位】：河北北方學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R943
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