本文選題：納米炭 + 直腸癌�。� 參考：《南方醫(yī)科大學》2017年博士論文

【摘要】：直腸癌是目前人類最高發(fā)的惡性腫瘤之一,手術(shù)治療一直是最有效的治療手段。根據(jù)目前的TNM腫瘤分期標準,術(shù)后準確的區(qū)域淋巴結(jié)轉(zhuǎn)移情況對于患者病理分期及后期治療和隨訪計劃指定有著重要的重要指導(dǎo)意義。為了得到準確的區(qū)域淋巴結(jié)評價,目前美國的NCCN指南要求在結(jié)直腸癌術(shù)后標本中必須獲取12-14枚淋巴結(jié)。還有一些研究認為從手術(shù)標本中獲取更多的淋巴結(jié)對于術(shù)后準確的區(qū)域淋巴結(jié)轉(zhuǎn)移及預(yù)后評估更有利。新輔助放化療后進行根治性直腸前切除是目前NCCN指南推薦的局部進展期直腸癌的標準治療方案。大量的研究表明這種方案可以增加術(shù)中腫瘤切除率及保留肛門括約肌的比例,也可以降低術(shù)后局部復(fù)發(fā)率。然而目前大量的研究證明新輔助放化療后直腸癌手術(shù)標本中獲取的淋巴結(jié)術(shù)后會顯著減少。雖然針對新輔助放化療后這一類患者來說,從標本中獲取淋巴結(jié)數(shù)目減少對于患者預(yù)后評價的影響還有爭議,但也有一些觀察性研究表明,在這一類患者中,區(qū)域淋巴結(jié)陽性患者的標本淋巴結(jié)獲取數(shù)量明顯多于區(qū)域淋巴結(jié)陰性患者。這就預(yù)示著提高這一類患者術(shù)后標本中淋巴結(jié)檢出數(shù)目,有可能可以提高癌轉(zhuǎn)移淋巴結(jié)的發(fā)現(xiàn)率,從而獲得更加準確的區(qū)域淋巴結(jié)轉(zhuǎn)移情況,以指導(dǎo)術(shù)后治療及隨訪計劃的制定,為患者帶來更大的獲益。在之前的研究中,我們發(fā)現(xiàn)腫瘤周圍粘膜下注射納米炭混選注射液可以提高胃腸癌手術(shù)標本中淋巴結(jié)獲取數(shù)目,而不增加手術(shù)時間和標本處理時間。為了進一步評價新輔助放化療后直腸癌患者術(shù)后標本中淋巴結(jié)獲取數(shù)目和陽性癌轉(zhuǎn)移淋巴結(jié)發(fā)現(xiàn)率之間的關(guān)系,并且評價納米炭混懸注射液在提高該類患者淋巴結(jié)檢出數(shù)目中的作用,我們從2013年8月開始對新輔助放化療直腸癌患者運用了這項技術(shù)。雖然納米炭等淋巴結(jié)示蹤劑可以特異性識別淋巴結(jié),顯著術(shù)者術(shù)中、術(shù)后標本淋巴結(jié)的識別能力。但目前臨床上使用所有淋巴結(jié)示蹤劑均不具備腫瘤特異性,無法再術(shù)中實時辨別轉(zhuǎn)移淋巴結(jié)。這使得淋巴結(jié)示蹤劑的使用受到了很大的限制。因此,我們計劃合成新型的納米材料,預(yù)期使其既要有特異性的淋巴結(jié)示蹤功能,也要可以卸載可特異性識別腫瘤細胞的熒光材料,以達到術(shù)中實時辨認癌轉(zhuǎn)移淋巴結(jié)的作用。為達到此目的,我們設(shè)計了結(jié)合氧化鐵納米簇和葡聚糖的新型可攜載納米淋巴結(jié)示蹤材料(DIONs)。該納米材料的大小限制在100-200nm之間,這使得它可以像納米炭一樣通過淋巴管內(nèi)皮細胞之間的間隙進入淋巴管而特異性進入淋巴結(jié)中,使淋巴結(jié)顯現(xiàn)出鐵離子的黑褐色。并且因為在納米簇上修飾合成了葡聚糖,而使納米簇具有大量的羥基結(jié)構(gòu)。這些羥基結(jié)構(gòu)可以通過共軛效應(yīng)鏈接可以識別腫瘤細胞的熒光藥物。在特異性進入淋巴結(jié)后,在癌轉(zhuǎn)移淋巴結(jié)的酸性環(huán)境下大量釋放藥物,產(chǎn)生遠大于正常的自體熒光,以達到鑒別癌轉(zhuǎn)移淋巴結(jié)的作用。本研究就在于研究合成的DIONs的方法及其淋巴結(jié)示蹤效果和生物安全性,為后期鏈接腫瘤特異性熒光藥物做基礎(chǔ)。第一部分術(shù)前粘膜下注射納米炭對于提高新輔助直腸癌患者淋巴結(jié)病理分期的作用研究目的分析新輔助放化療后直腸癌患者淋巴結(jié)檢出數(shù)目和淋巴結(jié)病理分期之間的關(guān)系。并評價納米炭混選注射液在提高新輔助放化療后直腸癌患者淋巴結(jié)檢出數(shù)目及準確淋巴結(jié)病理分期的作用。方法 從2008年9月到2014年7月,152名連續(xù)的局部進展期直腸癌患者接受新輔助放化療后根治性切除手術(shù),其中45例患者術(shù)前經(jīng)肛行納米炭混懸液腫瘤周圍粘膜下注射。分析所有患者術(shù)后淋巴結(jié)檢出數(shù)目和癌轉(zhuǎn)移淋巴結(jié)發(fā)現(xiàn)率之間的關(guān)系,并分析注射納米炭患者和未注射納米炭患者之間淋巴結(jié)檢出數(shù)目和淋巴結(jié)病理分期之間的關(guān)系。結(jié)果 在淋巴結(jié)檢出1-5枚的患者中,術(shù)后淋巴結(jié)陽性比例8.6%,明顯低于淋巴結(jié)檢出數(shù)目17-44枚的37.8%。多因素分析顯示淋巴結(jié)檢出數(shù)目是淋巴結(jié)癌轉(zhuǎn)移發(fā)現(xiàn)率的獨立危險因素(p=0.036)。納米炭組患者術(shù)后淋巴結(jié)檢出數(shù)目明顯高于對照組患者(21.1 vs 8.0,p = 0.000)。對照組術(shù)后淋巴結(jié)陽性患者比率明顯少于納米炭組(19.6%vs 35.6%,p = 0.037)。在納米炭組中發(fā)現(xiàn)的58枚癌轉(zhuǎn)移淋巴結(jié)中,45枚(77.6%)被黑染。在37枚小于5mm的癌轉(zhuǎn)移淋巴結(jié)中33枚(89.2%)被黑染。結(jié)論 使用納米炭等淋巴結(jié)示蹤劑可以提高新輔助放化療后直腸癌患者術(shù)后淋巴結(jié)檢出數(shù)目,并且得到更加準確的淋巴結(jié)病理分期。第二部分葡聚糖修飾納米氧化鐵分散液的制備及淋巴結(jié)示蹤的作用和生物安全性研究目的本研究的目的在于制備和表征可攜載藥物的葡聚糖修飾納米氧化鐵分散液(DIONs),評價其淋巴結(jié)示蹤功能及生物安全性。方法我們利用三價鐵、二價鐵與右旋糖干經(jīng)化學共沉淀得到DIONs并表征其理化性質(zhì)。將合成的DIONs于大鼠胃壁漿膜下注射,觀察DIONs的區(qū)域淋巴結(jié)示蹤功能。并通過DIONs與人淋巴細胞共培養(yǎng)及CCK-8法評價其體外細胞生物安全性。通過觀察大鼠注射后三個月內(nèi)不同時期肝腎功能及腹腔情況,了解DIONs的體內(nèi)生物安全性。通過DIONs攜載Cy5熒光以及對示蹤大鼠的解剖,了解DIONs在心、腦、肝、肺、腎等重要器官的代謝情況。結(jié)果我們合成的DIONs流體動力學直徑為165nm,可將氧化鐵納米簇離子包裹起來,形成穩(wěn)定納米結(jié)構(gòu);有很好的水溶性、磁性和穩(wěn)定性,而且本身為深棕色。其合適的大小、穩(wěn)定性及黑褐色使得經(jīng)過胃壁漿膜下注射后淋巴結(jié)特異性好,6小時后區(qū)域淋巴結(jié)開始染色,24小時染色時間最佳,48小時后逐漸褪色但仍可清晰辨認,得到良好的區(qū)域淋巴結(jié)示蹤效果。通過DIONs與人淋巴細胞共培養(yǎng)及CCK-8法檢測,可見其有良好的體外細胞生物安全性。通過長時間(漿膜下注射4天至3個月)對大鼠血液學及組織病理學觀察,DIONs具有良好的生物安全性及相容性。通過DIONs攜載Cy5熒光以及對示蹤大鼠的解剖,了解DIONs僅存在于注射胃壁局部及淋巴結(jié)中,并不進入心、腦、肝、肺、腎等重要器官,具有良好的淋巴結(jié)特異性,不會對重要器官造成損傷。結(jié)論我們成功合成了一種新型的可攜載的具有淋巴結(jié)示蹤功能的納米材料DIONs。它具有良好的生物安全性及相容性,并且淋巴結(jié)示蹤效果明顯。為下一步利用該納米材料攜載藥物進行淋巴結(jié)腫瘤特異性示蹤及癌轉(zhuǎn)移淋巴結(jié)的藥物治療奠定了基礎(chǔ)。
[Abstract]:Rectal cancer is one of the highest malignant tumors in human being. Surgical treatment has always been the most effective treatment. According to the current standard of TNM tumor staging, accurate regional lymph node metastasis after operation has important guiding significance for the patient's pathological staging, later treatment and follow-up plan. The NCCN guidelines in the United States now require 12-14 lymph nodes in the specimens after colorectal surgery. Some studies suggest that obtaining more lymph nodes from the surgical specimen is more favorable for accurate postoperative regional lymph node metastasis and prognostic evaluation. A standard treatment for locally advanced rectal cancer recommended by the NCCN guide is currently recommended. A large number of studies have shown that this scheme can increase the rate of intraoperative tumor resection and the retention of the anal sphincter, and also reduce the local recurrence rate. However, a large number of studies have proved that the new adjuvant chemoradiotherapy has been proved to be a new type of rectal cancer. There is a significant decrease in postoperatively. Although there is a dispute over the impact of the reduction of the number of lymph nodes on the prognosis of the patients after neoadjuvant chemoradiotherapy, there are some observational studies showing that in this type of patients, the number of lymph nodes in the regional lymph node positive patients is significantly more than that in the area. This is an indication that the number of lymph nodes detected in the specimen after surgery in this class may improve the detection rate of metastatic lymph nodes, and thus obtain more accurate regional lymph node metastases to guide postoperative treatment and follow-up planning and to bring greater benefits to patients. In the study, we found that the number of lymph nodes in the surgical specimens of gastric cancer could be improved by the injection of nano carbon mixed injection by Submucous injection of the tumor around the tumor, without increasing the time of operation and the time of treatment. In order to evaluate the number of lymph node acquisition and the positive metastatic lymph node in the postoperative specimens of rectal cancer after neoadjuvant radiotherapy and chemotherapy The relationship between the present rate and the evaluation of Carbon Nanoparticles Suspension Injection's role in improving the number of lymph node detection in this type of patients, we have been using this technique since August 2013 for neoadjuvant radiotherapy and chemotherapy for rectal cancer patients. Although nano carbon and other lymph node tracers can specifically identify lymph nodes, significant surgical procedures, and postoperative specimens have been used. But the use of all lymph node tracers in clinical use is not specific and can not identify the metastatic lymph nodes in real time. This makes the use of lymph node tracers very limited. Therefore, we plan to synthesize new nanomaterials, which are expected to have specific lymph node tracers. In order to achieve this goal, we designed a new portable carrying nano lymph node tracer (DIONs) with iron oxide nanoclusters and dextran. The size of the nanomaterial is limited to 100-200nm. This allows it to enter the lymph nodes through the space between the lymphatic endothelial cells, like the nano carbon, and specifically enter the lymph nodes, making the lymph nodes appear to be dark brown in the iron ions. And because the dextran is synthesized on the nanoclusters, and the nanoclusters have a large number of hydroxyl structures. These hydroxyl structures can be conjugated by conjugation. The effect links can identify the fluorescent drugs of the tumor cells. After the specific entry of the lymph nodes, a large number of drugs are released in the acid environment of the metastatic lymph nodes, producing far greater than normal autofluorescence to identify the role of the metastatic lymph nodes. This study is based on the study of the combined DIONs method and its lymph node tracing effect. Biological safety, which is the basis for late linking of tumor specific fluorescent drugs. Part 1 the role of submucosal injection of carbon nanoscale before operation to improve lymph node pathological staging of neoadjuvant rectal cancer patients: to analyze the relationship between the number of lymph node detection and the pathological staging of lymph nodes after neoadjuvant radiotherapy and chemotherapy. The effect of the valence nano carbon mixed injection on the number of lymph nodes and the accurate lymph node pathological staging of rectal cancer patients after neoadjuvant chemoradiotherapy. Methods from September 2008 to July 2014, 152 consecutive patients with locally advanced rectal cancer underwent radical resection after neoadjuvant radiotherapy and chemotherapy, of which 45 patients were treated by anus preoperatively. The relationship between the number of lymph nodes detected after operation and the rate of metastatic lymph node discovery in all patients was analyzed, and the relationship between the number of lymph node detection and the pathological staging of lymph nodes was analyzed. The results were found in 1-5 patients with lymph nodes. In the case of postoperative lymph node positive ratio of 8.6%, significantly lower than the number of lymph nodes detected by 17-44 37.8%. multivariate analysis, the number of lymph nodes detected is an independent risk factor for lymph node metastasis (p=0.036). The number of lymph nodes detected in the nanoscale group was significantly higher than that of the control group (21.1 vs 8, P = 0). The rate of posterior lymph node positive patients was significantly less than that in the nanoscale group (19.6%vs 35.6%, P = 0.037). Of the 58 metastatic lymph nodes found in the nanoscale group, 45 (77.6%) were black. 33 (89.2%) in the 37 lymph nodes less than 5mm were black. Conclusion the use of nano carbon and other lymph node tracers can improve the new adjuvant radiotherapy and chemotherapy. The number of lymph nodes detected in colorectal cancer patients and more accurate lymph node pathological staging. The preparation of second partial glucan modified iron oxide dispersions and the role of lymph node tracer and biosafety study aim to prepare and characterize the dispersions of dextran modified nano iron oxide, which can carry drugs. Liquid (DIONs), evaluation of its lymph node tracer function and biological safety. Methods we used trivalent iron, two iron and dextran to obtain DIONs and characterize its physicochemical properties. The synthetic DIONs was injected under the serous of the rat gastric wall, and the regional lymph node tracing function of DIONs was observed. And the co culture of human lymphocytes was co cultured with DIONs. CCK-8 method was used to evaluate the biological safety of the cells in vitro. By observing the liver and kidney function and the abdominal condition in different periods of three months after injection, the biological safety of DIONs was understood. The metabolism of the important organs such as the heart, brain, liver, lung and kidney was understood by carrying the Cy5 fluorescence and the anatomy of the traced rats by DIONs. The result was that we combined with the results of the metabolism of the important organs of the heart, brain, liver, lung and kidney. The DIONs fluid dynamic diameter is 165nm, which can wrap the iron oxide nanocluster ions and form a stable nanostructure. It has good water solubility, magnetism and stability, and itself is dark brown. The appropriate size, stability and black brown make the lymph node specificity better after subserous injection of the gastric wall and the regional lymph nodes 6 hours later. The 24 hour dyeing time was the best, the color fading gradually after 48 hours, but it could be discoloration gradually, but still can be clearly identified, and a good regional lymph node tracer effect was obtained. Through DIONs and human lymphocyte co culture and CCK-8 method, it can be found that it has a good biological safety in vitro. The hematology of rats through the long time interval (4 days to 3 months under the serous injection) And histopathological observation, DIONs has good biological safety and compatibility. Through carrying the Cy5 fluorescence with DIONs and the anatomy of the traced rats, it is understood that DIONs exists only in the local and lymph nodes of the gastric wall, and does not enter the important organs such as heart, brain, liver, lung and kidney. It has a good lymph node specificity and does not cause damage to important organs. Conclusion we have successfully synthesized a new portable DIONs. nanomaterial with lymph node tracer function. It has good biological safety and compatibility, and the lymph node tracer effect is obvious. The next step is to use the nano material to carry the drugs for lymph node tumor specific tracer and cancer metastasis lymph node. The treatment laid the foundation.

【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.37

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