【摘要】：背景目前腫瘤仍然是威脅人類健康的重要疾病,其中前列腺癌在老年男性中為高發(fā)的致死性腫瘤疾病之一,其早期診斷和治療對患者的預(yù)后至為重要。在前列腺癌診斷方面,除了常用的物理檢查和實(shí)驗(yàn)室檢查外,影像學(xué)方法在早期發(fā)現(xiàn)腫瘤中也扮演著越來越重要的作用。特別是近年來多種新技術(shù)應(yīng)用在醫(yī)學(xué)成像領(lǐng)域,使得多角度評價腫瘤生物學(xué)行為和患者預(yù)后成為可能。但是,多數(shù)基于解剖結(jié)構(gòu)的成像技術(shù)在發(fā)現(xiàn)腫瘤病灶時,患者往往多處于中晚期。而在前列腺癌的治療方面,手術(shù)治療、放射治療和藥物治療適合不同適應(yīng)癥的患者,其中化療作為早期的輔助治療及晚期的重要治療方式,發(fā)揮著重要的作用。但是,化療藥物由于其具有較強(qiáng)的副作用,如全身毒性反應(yīng),因此如何提高化療藥物對病灶的靶向性一直是腫瘤治療急需解決的問題。超聲造影技術(shù)是一種通過靜脈注射超聲造影劑,進(jìn)而實(shí)現(xiàn)增強(qiáng)組織對比度的方法。隨著對超聲造影劑認(rèn)識地不斷深入,研究者們開發(fā)了多種不同種類的超聲造影劑。超聲納米泡是一種粒徑在1000nm以下的聲學(xué)造影劑,能夠突破傳統(tǒng)微米級超聲造影劑單純血池顯像的局限,可以用于血管外顯像。而通過在納米泡上搭載針對病灶的特異性配體,特別是針對腫瘤細(xì)胞的特異性配體,能夠利用腫瘤內(nèi)皮細(xì)胞間隙較大、缺乏基底膜及淋巴循環(huán)不良的穿透和滯留增強(qiáng)效應(yīng)(EPR效應(yīng))進(jìn)入組織間隙進(jìn)一步與腫瘤細(xì)胞結(jié)合產(chǎn)生特異性的超聲增強(qiáng)信號,實(shí)現(xiàn)從分子水平診斷腫瘤的目的。前列腺特異性膜抗原(prostate specific membrane antigen,PSMA)是一種特異性表達(dá)于前列腺癌細(xì)胞表面的膜蛋白,特別是在雄激素非依賴型前列腺癌和死亡率極高的轉(zhuǎn)移性前列腺癌組織中呈高表達(dá)。我們的前期分別將針對PSMA的單克隆抗體、納米抗體與脂質(zhì)納米泡相連,成功構(gòu)建和制備了針對前列腺癌的靶向納米泡,并進(jìn)一步研究證實(shí),與非靶向納米泡相對比,靶向納米泡能在體外與前列腺癌細(xì)胞特異性結(jié)合,在體內(nèi)超聲顯像實(shí)驗(yàn)中表現(xiàn)為腫瘤顯像時間延長、峰值強(qiáng)度增高等特異性顯像特征。但是,與已經(jīng)開發(fā)出的多種針對PSMA的配體分子(單克隆抗體、工程化抗體、小分子結(jié)合物及我們課題組前期研究的納米抗體等)不同,分子量更小的適體分子是一種能夠與其他物質(zhì)進(jìn)行結(jié)合的核苷酸或者脫氧核苷酸序列,以其作為靶向納米泡的配基分子,既能夠避免像單克隆抗體、工程化抗體產(chǎn)生的免疫原性,又能避免生產(chǎn)過程中接觸到的生物活性物質(zhì),保證了其無毒、安全的特點(diǎn)。因此,將A10-3.2適體作為配基搭載在脂質(zhì)納米泡上構(gòu)建出粒徑小、性能穩(wěn)定、安全性好的針對前列腺癌的靶向納米泡將是我們需要進(jìn)一步深入研究的內(nèi)容。超聲技術(shù)同時在腫瘤的治療中發(fā)揮著重要的作用,如高強(qiáng)度聚焦超聲在臨床上用于治療子宮肌瘤取得良好的效果。但是在治療體內(nèi)深部腫瘤時,需要考慮到超聲能量對聲通道上組織的熱損傷及其腫瘤周圍神經(jīng)的破壞。而低強(qiáng)度超聲下聯(lián)合超聲微泡產(chǎn)生的超聲微泡靶向破壞技術(shù),相對來說較為安全,能夠在需要作用的靶部位應(yīng)用超聲定點(diǎn)破壞超聲造影劑,從而促進(jìn)輻照區(qū)域組織對藥物的吸收,該技術(shù)目前已經(jīng)在多個疾病領(lǐng)域(包括心血管、眼和腫瘤等相關(guān)疾病)中進(jìn)行了較為廣泛的研究探索。相比于微米尺寸的超聲造影劑,粒徑更小的納米泡具有更強(qiáng)的穿透能力、更好的穩(wěn)定性能等特點(diǎn),但是超聲輻照下納米泡破裂能否產(chǎn)生空化效應(yīng)促進(jìn)阿霉素(Doxorubin,DOX)抑制前列腺癌生長仍需進(jìn)一步研究和闡述�；谏鲜鲅芯窟M(jìn)展和我們前期的研究基礎(chǔ),本將分別從兩部分進(jìn)行基于納米泡的前列腺癌超聲靶向診斷及治療的實(shí)驗(yàn)研究,首先將A10-3.2適體作為配基搭載在脂質(zhì)納米泡上,構(gòu)建出粒徑小、安全性好、性能穩(wěn)定的靶向納米泡,研究其在PSMA陽性表達(dá)的前列腺癌中靶向顯像的能力和效果;其次進(jìn)一步探索納米泡在低強(qiáng)度超聲爆破技術(shù)下輔助廣譜、經(jīng)典的化療藥物-DOX抑制前列腺癌的效果。目的1.研究納米泡的超聲顯像能力及其在腫瘤組織中的穿透力,同時制備攜載針對PSMA的適體A10-3.2的靶向超聲納米泡,并研究其在診斷前列腺癌中的顯像效果,為前列腺癌的靶向超聲分子顯像提供一種穿透力強(qiáng)、安全、高效的靶向造影劑,也為攜載適體的靶向超聲納米泡的相關(guān)研究提供方法。2.在基于納米泡的前列腺癌靶向超聲分子顯像的基礎(chǔ)上,進(jìn)一步探討化療藥物DOX在低強(qiáng)度超聲靶向破壞納米泡技術(shù)下對前列腺癌生長的抑制作用及其潛在機(jī)制,為超聲輻照下納米泡破裂促進(jìn)阿霉素抑制前列腺癌提供詳實(shí)的研究基礎(chǔ),也為靶向納米泡真正實(shí)現(xiàn)腫瘤診療一體化功能奠定實(shí)驗(yàn)基礎(chǔ)。方法1.以PSMA適體A10-3.2為導(dǎo)向的脂質(zhì)納米泡在前列腺癌診斷中的研究(1)將一定比例的脂質(zhì)材料在水合液中進(jìn)行機(jī)械震蕩,并采用離心漂浮法分離超聲納米泡,在動物體內(nèi)觀察納米泡注射前后彩色血流信號的變化情況。在光鏡及共聚焦顯微鏡下觀察生理鹽水灌注后,納米泡在腫瘤組織及心臟組織中的分布情況。(2)化學(xué)法合成氟化的適體A10-3.2,通過細(xì)胞免疫熒光及流式細(xì)胞技術(shù)驗(yàn)證適體對PSMA陽性表達(dá)細(xì)胞的特異性。隨后,通過酰胺反應(yīng)將A10-3.2適體連接到納米泡表面構(gòu)建靶向納米泡,采用凝膠電泳及免疫熒光驗(yàn)證納米泡的靶向性。(3)檢測靶向納米泡與非靶向納米泡的大小及體外超聲顯像情況,溶血實(shí)驗(yàn)驗(yàn)證靶向納米泡的安全性。在細(xì)胞水平,通過流式細(xì)胞技術(shù)和體外結(jié)合實(shí)驗(yàn)觀察靶向納米泡與細(xì)胞的結(jié)合能力。(4)構(gòu)建C4-2和PC-3前列腺癌移植瘤裸鼠模型,觀察靶向納米泡和非靶向納米泡的超聲造影參數(shù)(達(dá)峰時間、峰值強(qiáng)度、減半時間及1/2峰值強(qiáng)度曲線下面積)的變化情況,以及通過活體熒光顯像觀察靶向納米泡在荷瘤小鼠中的分布情況。2.脂質(zhì)納米泡在超聲靶向破壞技術(shù)下輔助阿霉素抑制前列腺癌生長的實(shí)驗(yàn)研究(1)在動物PC-3前列腺癌移植瘤中通過超聲造影觀察納米泡在不同強(qiáng)度的超聲功率(1W/cm2、1.75W/cm2和2.5W/cm2)下,超聲輻照的腫瘤區(qū)域納米泡的破壞情況,從而確定超聲參數(shù),包括超聲功率、輻照時間和輻照模式。(2)將荷PC-3前列腺癌的裸鼠分為阿霉素組(DOX)、阿霉素加納米泡組(DOX+NB)、阿霉素加超聲組(DOX+US)、超聲輻照下阿霉素加納米泡組(DOX+NB+US)共四組。于處理后6小時處死裸鼠,取心、肝、脾、肺、腎和移植瘤組織勻漿后取上清,通過各自組織的阿霉素標(biāo)準(zhǔn)定量曲線中計算各組藥物含量。(3)將PC-3前列腺癌細(xì)胞分為DOX、DOX+NB、DOX+US和DOX+NB+US共四組,進(jìn)行分別干預(yù),采用CCK-8法測定細(xì)胞生存率。在上述荷瘤裸鼠動物分組基礎(chǔ)上增加生理鹽水組(Control)共5組。超聲參數(shù)保持不變,治療每隔1天處理1次,共處理9次,并監(jiān)測裸鼠體重、腫瘤體積變化情況。對治療結(jié)束的裸鼠心肌和腫瘤組織進(jìn)行HE染色和TUNEL染色分析凋亡情況。(4)按照Control、NB、US和NB+US對PC-3細(xì)胞和移植瘤進(jìn)行分組處理,通過掃描電鏡觀察細(xì)胞表面形態(tài),透射電鏡觀察眶后靜脈注射硝酸鑭電子示蹤劑后的各組腫瘤內(nèi)電子示蹤劑分布情況。結(jié)果1.以PSMA適體A10-3.2為導(dǎo)向的脂質(zhì)納米泡在前列腺癌診斷中的研究(1)注射納米泡后,動物腹部血流信號顯示更為敏感清晰;光鏡和激光共聚焦技術(shù)均發(fā)現(xiàn)納米泡能夠進(jìn)入腫瘤血管間隙,而不能進(jìn)入心肌組織間隙。(2)免疫組化技術(shù)和流式細(xì)胞技術(shù)證實(shí)適體分子A10-3.2對PSMA陽性表達(dá)的細(xì)胞具有良好的特異性。凝膠電泳和免疫熒光技術(shù)證實(shí)靶向納米泡構(gòu)建成功,溶血實(shí)驗(yàn)表明靶向納米泡對紅細(xì)胞沒有明顯的溶血作用。(3)非靶向納米泡和靶向納米泡的粒徑分別為(519.4±74.6)nm和(576.6±40.2)nm,兩者體外顯像效果沒有明顯差別(P0.05),靶向納米泡能夠與PSMA陽性表達(dá)的C4-2細(xì)胞發(fā)生特異性結(jié)合,而與PSMA陰性表達(dá)的PC-3細(xì)胞不能結(jié)合。(4)通過在PSMA陽性表達(dá)的動物移植瘤中比較靶向納米泡和非靶向納米泡的超聲造影指標(biāo),發(fā)現(xiàn)達(dá)峰時間沒有顯著差異(P0.05),而峰值強(qiáng)度、減半時間和1/2峰值強(qiáng)度下曲線面積存在明顯差異[分別為(19.48±2.59)vs(16.86±2.64)d B,(862.53±143.83)vs(347.69±74.86)s和(1978.60±370.21)vs(795.60±115.41)d B·s,P0.05];PSMA陰性表達(dá)的動物移植瘤中兩種納米泡的四種造影指標(biāo)均無明顯差異(P0.05)。同時,小動物活體熒光顯像表明靶向納米泡在C4-2移植瘤中具有一定的聚集能力。2.脂質(zhì)納米泡在超聲靶向破壞技術(shù)下輔助阿霉素抑制前列腺癌生長的實(shí)驗(yàn)研究(1)用于治療得到的納米泡粒徑為(485.7+33.0)nm,多分散系數(shù)為0.026。確定在1W/cm2超聲功率下、100Hz的間歇脈沖及手動調(diào)節(jié)下“5s-on-5s-off”的輻照模式,能夠在15min內(nèi)有效地破壞腫瘤輻照區(qū)域內(nèi)的納米泡且不會產(chǎn)生明顯的熱效應(yīng)。(2)藥物分布情況測定時,阿霉素在DOX+NB+US組[(43.71±5.03)ng/g]的移植瘤中分布最多,其次為DOX+US組[(36.91±5.72)ng/g];而心肌組織中藥物含量與此相反,在DOX+NB+US組[(13.49±3.14)ng/g]中分布最少。(3)在治療效果評價的觀察中,發(fā)現(xiàn)相比于Control組,DOX+NB+US組的前列腺癌細(xì)胞生存率[(43.16±2.47)%]和移植瘤體積[(68.16±14.00)mm3]明顯受到抑制,超聲造影治療前后的強(qiáng)度變化及病理切片的亦證實(shí)DOX+NB+US組壞死情況最為明顯。(4)在掃描電鏡觀察中,發(fā)現(xiàn)NB+US組前列腺癌細(xì)胞上出現(xiàn)較多孔洞,且細(xì)胞表面的褶皺明顯增多;而透射電鏡亦證實(shí)NB+US組有更多的硝酸鑭顆粒進(jìn)入移植瘤的實(shí)質(zhì)細(xì)胞和組織間隙內(nèi)。結(jié)論1.納米泡具有良好的超聲顯像效果,能夠利用腫瘤的EPR效應(yīng)進(jìn)入腫瘤組織間隙,為實(shí)現(xiàn)腫瘤實(shí)質(zhì)細(xì)胞的靶向超聲顯像奠定了造影劑方面的基礎(chǔ)。2.攜載針對PSMA的適體A10-3.2的靶向納米泡能在體外與PSMA陽性表達(dá)的前列腺癌細(xì)胞靶向結(jié)合,能使PSMA陽性表達(dá)的前列腺癌移植瘤具有特征性超聲分子顯像特征,為腫瘤的靶向超聲分子診斷提供了一種新的超聲造影劑和方法。3.超聲輻照下納米泡靶向破壞技術(shù)是一種能有效促進(jìn)藥物作用特定部位的方法,能夠有效增加化療藥物在腫瘤區(qū)域的含量,減少化療藥物副作用,并發(fā)揮有效抑制前列腺癌生長的作用,其背后的潛在機(jī)制可能與納米泡能穿過腫瘤血管、進(jìn)入腫瘤組織間隙內(nèi),在腫瘤細(xì)胞周圍近距離發(fā)生超聲空化效應(yīng)相關(guān)。
[Abstract]:Background Nowadays, cancer is still an important disease threatening human health. Prostate cancer is one of the most common fatal cancer diseases in elderly men. Early diagnosis and treatment of prostate cancer is very important to the prognosis of patients. Tumors are also playing an increasingly important role. Especially in recent years, many new techniques have been applied in the field of medical imaging, making it possible to evaluate tumor biological behavior and prognosis from multiple perspectives. Surgical treatment, radiotherapy and drug therapy are suitable for patients with different indications. Chemotherapy, as an important adjuvant therapy in the early and late stages, plays an important role. Targeting has always been an urgent problem in tumor therapy. Contrast-enhanced ultrasound (CEUS) is a method to enhance tissue contrast by intravenous injection of CEUS. With the deepening understanding of CEUS, researchers have developed a variety of CEUS agents. Ultrasound nanobubbles are a kind of ultrasound contrast agents with a diameter of 1000 nm. The following ultrasound contrast agents can break through the limitation of traditional micron-scale ultrasound contrast agent blood pool imaging and can be used for vascular imaging. Poor circulatory penetration and retention enhancement effect (EPR effect) enters the tissue gap and further binds with tumor cells to produce specific enhanced ultrasound signals for molecular diagnosis of cancer. prostate specific membrane antigen (PSMA) is a specific expression on prostate cancer cell surface. Facial membrane proteins are highly expressed, especially in androgen-independent prostate cancer and metastatic prostate cancer with high mortality. We successfully constructed and prepared targeted nanobubbles for prostate cancer by linking monoclonal antibodies against PSMA and nanoantibodies to lipid nanobubbles, respectively, in our previous studies. In contrast to non-targeted nanobubbles, targeted nanobubbles can specifically bind to prostate cancer cells in vitro and exhibit specific imaging characteristics in vivo, such as prolonged tumor imaging time and increased peak intensity. Different from small molecular conjugates and nano-antibodies previously studied by our team, aptamers with smaller molecular weights are nucleotide or deoxynucleotide sequences that can bind to other substances and serve as ligand molecules for targeting nanobubbles, thus avoiding immunogenicity such as monoclonal antibodies and engineered antibodies. Therefore, using aptamer A10-3.2 as ligand to construct lipid nanobubbles with small size, stable performance and good safety will be the content of further research. Surgery also plays an important role in the treatment of tumors, such as high intensity focused ultrasound (HIFU) in the clinical treatment of uterine fibroids achieved good results. But in the treatment of deep tumors in vivo, we need to take into account the ultrasound energy on the sound channel tissue thermal damage and the destruction of the tumor peripheral nerves. Targeted destruction of ultrasound microbubbles produced by ultrasound microbubbles is relatively safe and can be used to destroy ultrasound contrast agents at targeted sites where they are needed, thus promoting the absorption of drugs by irradiated tissue. This technology has been compared in a number of disease areas (including cardiovascular, eye and tumor related diseases). Compared with micron-sized ultrasound contrast agents, the smaller size nanobubbles have stronger penetration ability and better stability. However, whether the cavitation effect of nanobubbles rupture under ultrasound irradiation can promote doxorubin (DOX) inhibiting prostate cancer growth still needs further study and elaboration. In this study, we will carry out ultrasound targeted diagnosis and treatment of prostate cancer based on nanobubbles in two parts. Firstly, aptamer A10-3.2 was loaded on lipid nanobubbles as ligand to construct targeted nanobubbles with small particle size, good safety and stable performance, and its PSMA-positive was studied. Objective 1. To study the ultrasound imaging ability of nanobubbles and their penetrating power in tumor tissues, and to prepare PSMA-loaded nanobubbles for PSMA. Targeted ultrasound nanobubbles of body A10-3.2 were used to study the imaging effect of targeted ultrasound nanobubbles in the diagnosis of prostate cancer. It provides a high-penetrating, safe and efficient targeted contrast agent for targeted ultrasound molecular imaging of prostate cancer. It also provides a method for the study of targeted ultrasound nanobubbles carrying aptamers. 2. Targeting prostate cancer based on nanobubbles. On the basis of ultrasound molecular imaging, the inhibitory effect of chemotherapy drug DOX on the growth of prostate cancer and its potential mechanism under low intensity ultrasound targeted destruction of nanobubbles were further explored, which provided a detailed research basis for promoting the inhibition of prostate cancer by adriamycin by nanobubbles rupture under ultrasound irradiation, and also provided a real tumor targeting nanobubbles. Methods 1. Lipid nanobubbles directed by PSMA aptamer A10-3.2 were used in the diagnosis of prostate cancer. (1) Lipid nanobubbles were separated by centrifugal floatation and mechanical vibration in the hydrate solution. The color hemodynamics before and after injection of nanobubbles were observed in vivo. (2) Fluorinated aptamer A10-3.2 was synthesized by chemical method, and the specificity of aptamer to PSMA-positive cells was verified by immunofluorescence and flow cytometry. Afterwards, the amide reaction was performed. The targeted nanobubbles were constructed by attaching aptamer A10-3.2 to the surface of nanobubbles. The targeting of nanobubbles was verified by gel electrophoresis and immunofluorescence. (3) The size of targeted nanobubbles and non-targeted nanobubbles and ultrasound imaging in vitro were detected, and the safety of targeted nanobubbles was verified by hemolysis test. The binding ability of targeted nanobubbles to cells was observed by external binding experiment. (4) The nude mice models of prostate cancer transplanted with C4-2 and PC-3 were constructed to observe the changes of contrast-enhanced ultrasound parameters (peak time, peak intensity, halving time and area under 1/2 peak intensity curve) of targeted nanobubbles and non-targeted nanobubbles, as well as in vivo fluorescence imaging. Objective To observe the distribution of targeted nanobubbles in tumor-bearing mice.2.Lipid nanobubbles assisted doxorubicin in inhibiting the growth of prostate cancer by ultrasound-targeted destruction technique(1)Contrast-enhanced ultrasound was used to observe the effect of nanobubbles on the growth of prostate cancer in animal PC-3 prostate cancer xenografts under different ultrasound power(1W/cm 2,1.75W/cm 2 and 2.5W/cm 2). (2) Nude mice bearing PC-3 prostate cancer were divided into four groups: doxorubicin group (DOX), doxorubicin plus nanobubbles group (DOX+NB), doxorubicin plus ultrasound group (DOX+US), doxorubicin plus nanobubbles group (DOX+NB+US) and doxorubicin plus nanobubbles group (DOX+NB+US). After 6 hours of treatment, the nude mice were sacrificed, the heart, liver, spleen, lung, kidney and transplanted tumor tissues were taken out, and the supernatant of each group was calculated by the standard quantitative curve of adriamycin. (3) PC-3 prostate cancer cells were divided into four groups: DOX, DOX+NB, DOX+US and DOX+NB+US. The cell survival rate was determined by CCK-8 method. On the basis of the above-mentioned grouping of tumor-bearing nude mice, 5 groups were added to the normal saline group (Control). Ultrasound parameters remained unchanged, treatment was given once every other day for 9 times, and the changes of body weight and tumor volume were monitored. PC-3 cells and transplanted tumor were grouped by NB, US and NB+US. The cell surface morphology was observed by scanning electron microscopy. The distribution of electron tracers in tumor was observed by transmission electron microscopy after intravenous injection of lanthanum nitrate. (2) Immunohistochemistry and flow cytometry demonstrated that aptamer A10-3.2 had good specificity for PSMA positive cells. Gel electrophoresis and immunofluorescence techniques confirmed that the targeted nanobubbles were successfully constructed. Hemolysis experiments showed that the targeted nanobubbles had no obvious hemolysis effect on red blood cells. (3) The diameter of non-targeted nanobubbles and targeted nanobubbles were (519.4 (74.6) nm and (576.6 (40.2) nm, respectively. Bubbles can specifically bind to C4-2 cells which are PSMA-positive, but not to PC-3 cells which are PSMA-negative. (4) By comparing the target nanobubbles and non-target nanobubbles in PSMA-positive animal transplanted tumors, we found that there was no significant difference in peak time (P 0.05), peak strength, halving time and non-target nanobubbles. There were significant differences in the area of curves under 1/2 peak intensity [19.48 (+ 2.59) vs (16.86 (+ 2.64) D B, (862.53 (+ 143.83) vs (347.69 (+ 74.86) s) and (1978.60 (+ 370.21) vs (795.60 (+ 115.41) D B (+) s, P 0.05)]; there were no significant differences in the four angiographic indices of the two kinds of nanobubbles in PSMA-negative animals (P 0.05). Fluorescence imaging showed that the targeted nanobubbles had a certain aggregation ability in C4-2 transplanted tumor. 2. Lipid nanobubbles assisted doxorubicin to inhibit the growth of prostate cancer by ultrasound targeted destructive technology (1) The diameter of the nanobubbles was (485.7 + 33.0) nm, and the polydispersity coefficient was 0.026. (2) When the drug distribution was determined, doxorubicin was most distributed in the transplanted tumors of DOX+NB+US group [(43.71+5.03) ng/g], followed by DOX+US group [(36.91+5.72)]. (3) Compared with the control group, the survival rate of prostate cancer cells in the DOX+NB+US group [(43.16+2.47)%] and the volume of transplanted tumor [(68.16+14.00) mm3] were significantly inhibited before contrast-enhanced ultrasound treatment. The changes of intensity and pathological section after transplantation also confirmed that the necrosis was most obvious in DOX+NB+US group. (4) In scanning electron microscopy, more holes were found in prostate cancer cells of NB+US group, and the wrinkles on the cell surface were significantly increased. Transmission electron microscopy also confirmed that more lanthanum nitrate particles entered the transplanted tumor cells and tissues in NB+US group. Conclusion1. Nanobubbles have a good ultrasound imaging effect, can use the EPR effect of tumor into the tumor tissue gap, to achieve tumour. 2.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R737.25;R445.1

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