本文選題：卟啉 + ~(131)I�。� 參考：《中國工程物理研究院》2014年博士論文

【摘要】：國際癌癥研究機(jī)構(gòu)報(bào)道癌癥在2012年造成820萬人死亡,并且未來20年,估計(jì)每年癌癥病例將由目前的1400萬上升到2200萬,嚴(yán)重影響了人類的生存和發(fā)展。如果早期發(fā)現(xiàn),通過手術(shù)和放射治療,大部分癌癥都可以治愈。但是,臨床發(fā)現(xiàn)的病例大多已是中晚期,無法進(jìn)行手術(shù)治療,放療和化療會(huì)引起厭食、脫發(fā)等較大的毒副作用,治療過程中給病人帶來了極大的痛苦,因此,需要開發(fā)新的治療方法。近年來,光動(dòng)力治療以適用性好、毒性小和無耐藥性等優(yōu)勢,引起了廣泛關(guān)注。卟啉化合物具有良好的親腫瘤性和光動(dòng)力性質(zhì),且易與核素結(jié)合,因此,可以很好地將光動(dòng)力治療和核素治療結(jié)合在一起,在癌癥治療領(lǐng)域具有廣闊的應(yīng)用前景。 本論文合成了五種帶不同取代基的卟啉化合物,考察了其作為光動(dòng)力治療光敏劑的抗菌性能和細(xì)胞毒性；選用131I對(duì)光動(dòng)力性質(zhì)優(yōu)良的卟啉化合物進(jìn)行標(biāo)記,研究了制備條件對(duì)標(biāo)記率的影響,得到了高放化純度的標(biāo)記物；考察了標(biāo)記物的體內(nèi)外性質(zhì),對(duì)其抗腫瘤性能進(jìn)行了初步評(píng)價(jià)。具體內(nèi)容如下： (1)設(shè)計(jì)合成了五種不同取代基(-H、-NO2、-NH2、-OH、-OCH3)的卟啉化合物TPP、TPPNO2、TPPNH2、TPPOH和TPPOCH3,一種金屬卟啉CuTPPOCH3,兩種富勒烯-卟啉化合物C60-TPPOCH3和C60-TPPOH,并通過紅外(IR)、核磁共振氫譜(1HNMR)、質(zhì)譜(MS)和紫外-可見光譜(UV-Vis)對(duì)化合物進(jìn)行表征。 (2)采用平板菌落計(jì)數(shù)法考察了卟啉化合物TPP、TPPNO2、TPPNH2、TPPOH、 TPPOCH3和CuTPPOCH3在不同濃度和光照條件下,對(duì)大腸桿菌和金黃色葡萄球菌的細(xì)菌毒性。結(jié)果表明：化合物的暗毒性低,細(xì)菌毒性具有明顯的光照和濃度依賴性,并與光照能量密度和濃度呈正相關(guān)關(guān)系；TPPOH在光照條件下具有較強(qiáng)的細(xì)菌毒性；當(dāng)TPPOCH3的卟吩環(huán)中心絡(luò)合順磁性金屬離子銅后,細(xì)菌毒性明顯下降；化合物對(duì)金黃色葡萄球菌的抑制效果明顯優(yōu)于大腸桿菌。 (3)考察了卟啉化合物TPP、TPPNO2、TPPNH2、TPPOH和TPPOCH3對(duì)人肝癌細(xì)胞HepG2、SMMC-7721和人正常肝細(xì)胞HL-7702存活率的影響。結(jié)果表明：化合物的暗毒性低,細(xì)胞毒性具有明顯的光照和濃度依賴性,并與光照能量密度和濃度呈正相關(guān)的關(guān)系；TPPOH的光毒性較高；各化合物對(duì)三種細(xì)胞的毒性差異不顯著。 (4)采用密度泛函理論(B3LYP)優(yōu)化了化合物TPPNH2和TPPOH及其碘標(biāo)記物的分子結(jié)構(gòu),計(jì)算了Mulliken電荷分布和能量,從理論上預(yù)測了碘標(biāo)記TPPNH2和TPPOH的最可幾位點(diǎn)。 (5)以氯胺T為氧化劑,對(duì)TPPOH和TPPNH2進(jìn)行131I標(biāo)記,研究了制備條件對(duì)標(biāo)記率的影響,得到了高放化純度的標(biāo)記物。優(yōu)化條件為：a)13II-TPPOH:pH為5.5,TPPOH濃度2mg/mL,氯胺T濃度0.25mg/mL,反應(yīng)溫度20℃,反應(yīng)時(shí)間15min,標(biāo)記率98%; b)131I-TPPNH2:pH為1.5, TPPNH2濃度2mg/mL,氯胺T濃度3mg/mL,反應(yīng)溫度95℃,反應(yīng)時(shí)間40min,標(biāo)記率96%。兩種標(biāo)記物體內(nèi)穩(wěn)定性好,血液清除較快,對(duì)肝臟和肺有較高的親和性,肝臟是主要代謝途徑,腫瘤中有良好的積累和滯留性質(zhì),表明131I-TPPOH和131I-TPPNH2對(duì)腫瘤的治療有潛在價(jià)值。 (6)初步評(píng)價(jià)了131I-TPPOH和131I-TPPNH2的抗腫瘤性能,結(jié)果表明：在131I的核素治療和卟啉的光動(dòng)力治療雙重作用下,131I-TPPOH和131I-TPPNH2都具有較好的抗腫瘤性能,但131I-TPPOH的抗腫瘤性能更優(yōu)且毒性小,有望成為一種具有雙重功效的腫瘤治療藥物。
[Abstract]:The International Cancer Research Institute reported that cancer killed 8 million 200 thousand people in 2012, and in the next 20 years, it is estimated that cancer cases will rise from 14 million to 22 million a year, seriously affecting human survival and development. If early detection, most cancers can be cured by surgery and radiation treatment. However, the clinical cases are large. Most of them are middle and late stage, unable to perform surgical treatment, radiotherapy and chemotherapy will cause anorexia, hair loss and other major toxic and side effects, and bring great pain to the patients during the treatment. Therefore, new treatment methods need to be developed. In recent years, photodynamic therapy has attracted wide attention, with the advantages of good applicability, small toxicity and no drug resistance. The compound has good ONCOPHILIC and photodynamic properties, and is easy to combine with nuclides. Therefore, the combination of photodynamic therapy and nuclide therapy can be well combined, and it has a broad application prospect in the field of cancer treatment.
In this paper, five porphyrin compounds with different substituents were synthesized, and the antibacterial properties and cytotoxicity of the photosensitizers were investigated. 131I was used to mark the porphyrin compounds with good photodynamic properties, and the effects of the preparation conditions on the labeling rate were studied. Its properties in vivo and in vitro were preliminarily evaluated for its anti-tumor properties.
(1) the porphyrin compounds of five different substituents (-H, -NO2, -NH2, -OH, -OCH3), TPP, TPPNO2, TPPNH2, TPPOH and TPPOCH3, a metalloporphyrin CuTPPOCH3, two kinds of fulleren-porphyrin compounds, are designed, and the compounds are entered by IR, nuclear magnetic resonance hydrogen spectrum, mass spectrometry and ultraviolet visible spectrum. Characterization.
(2) the bacterial toxicity of porphyrin compounds TPP, TPPNO2, TPPNH2, TPPOH, TPPOCH3 and CuTPPOCH3 on Escherichia coli and Staphylococcus aureus under different concentrations and illumination conditions were investigated by the plate colony counting method. The results showed that the dark toxicity of the compounds was low, the toxicity of the compounds had obvious light and concentration dependence, and the light energy was associated with the light energy. There is a positive correlation between density and concentration; TPPOH has strong bacterial toxicity under light conditions. When the porphyrin ring in TPPOCH3 is complex with paramagnetic metal ions copper, the toxicity of bacteria is obviously decreased, and the inhibitory effect of the compound on Staphylococcus aureus is obviously better than that of Escherichia coli.
(3) the effects of porphyrin compounds TPP, TPPNO2, TPPNH2, TPPOH and TPPOCH3 on the survival rate of HL-7702 in human hepatocellular carcinoma cells, HepG2, SMMC-7721 and human normal hepatocytes were investigated. The results showed that the dark toxicity of the compounds was low, the cytotoxicity had obvious light and concentration dependence, and the relationship with light energy density and concentration was positively correlated; TPPOH The toxicity of the compounds to three kinds of cells was not significant.
(4) the molecular structure of TPPNH2 and TPPOH and their iodine markers were optimized by density functional theory (B3LYP), and the charge distribution and energy of Mulliken were calculated. The most possible loci of iodine labeled TPPNH2 and TPPOH were predicted theoretically.
(5) with chloramine T as an oxidant, TPPOH and TPPNH2 were labeled with 131I, and the effect of preparation conditions on the labeling rate was studied, and the marker of high degree of purity was obtained. The optimization conditions were as follows: a) 13II-TPPOH:pH was 5.5, TPPOH concentration 2mg/mL, chloramine T concentration 0.25mg/mL, reaction temperature 20 C, reaction time 15min, labeling rate 98%, b) 1.5, The concentration of H2 is 2mg/mL, the concentration of chloramine T is 3mg/mL, the reaction temperature is 95, the reaction time is 40min, the labeling rate 96%. is stable, the blood scavenging is faster, the liver and lung have higher affinity, the liver is the main metabolic pathway, the tumor has good accumulation and retention properties, which indicates that 131I-TPPOH and 131I-TPPNH2 have potential for the treatment of tumor. In value.
(6) the anti-tumor properties of 131I-TPPOH and 131I-TPPNH2 were evaluated preliminarily. The results showed that both 131I-TPPOH and 131I-TPPNH2 had good anti-tumor performance under the dual effects of 131I and porphyrin photodynamic therapy, but 131I-TPPOH had better anti-tumor performance and less toxicity. It was expected to be a dual efficacy tumor treatment. Medications.

【學(xué)位授予單位】：中國工程物理研究院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 樊衛(wèi),許光普,曾宗淵,劉楓;~(89)Sr和~(153)Sm-EDTMP治療鼻咽癌多發(fā)性骨轉(zhuǎn)移瘤療效的比較[J];癌癥;2000年06期

2 王捷，區(qū)慶嘉，，周修靜，呂斌，蔣寧一，江容堅(jiān)，周經(jīng)興，陳健宇，顏文機(jī);用膠體Cr~（32）PO＿4—碘油混懸液行肝動(dòng)脈栓塞并放射治療原發(fā)性肝癌的臨床觀察[J];癌癥;1995年06期

3 尤長宣,羅榮城,張鳴江;~(89)SrCl_2和/或骨膦治療多發(fā)性骨轉(zhuǎn)移癌的臨床研究[J];第一軍醫(yī)大學(xué)學(xué)報(bào);2001年07期

4 謝騰峰,王德軍,王瑛,李鐵津,汪進(jìn);四甲基-四乙基鈀卟啉的表面光伏特性研究[J];高等學(xué)�；瘜W(xué)學(xué)報(bào);1999年06期

5 宋正恩;陜多亮;楊建東;盧小泉;;β-甲酰基四苯基卟啉的一鍋法合成與光譜表征[J];光譜實(shí)驗(yàn)室;2010年02期

6 項(xiàng)景德,萬衛(wèi)星,葉萬忠,沈國平,范益軍,孫瑞輝;~(89)SrCl_2治療轉(zhuǎn)移性骨腫瘤疼痛的初步臨床觀察[J];核技術(shù);2001年05期

7 童沈陽;;高靈敏光度試劑——水溶性卟啉衍生物在分析化學(xué)中的應(yīng)用[J];化學(xué)試劑;1979年03期

8 楊玉青;宋宏濤;宋虎;蒲滿飛;;中位-四[二-(3,4-羧甲氧基)苯基]卟啉及其結(jié)合Re=O的初步研究[J];計(jì)算機(jī)與應(yīng)用化學(xué);2011年02期

9 周小娟;馬海琳;;頭頸部惡性腫瘤的分子靶向治療進(jìn)展[J];現(xiàn)代腫瘤醫(yī)學(xué);2008年01期

10 章穎;肖欣;鄧鵬星;黃齊茂;潘志權(quán);陳彰評(píng);;1-萘酚的β-取代金屬卟啉的合成及其抗菌活性[J];武漢工程大學(xué)學(xué)報(bào);2008年04期

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