本文選題：絲裂霉素　切入點：地塞米松磷酸鈉　出處：《南方醫(yī)科大學(xué)》2012年碩士論文

【摘要】：研究背景 喉氣管狹窄(laryngo tracheal stenosis,LTS)最常見的病因是機械性外傷和醫(yī)源性損傷,機械性外傷包括喉氣管外傷后的軟骨骨折或者氣道挫裂和移位變形,醫(yī)源性損傷包括氣管插管、氣管切開、喉部放療及喉部手術(shù)等因素。喉氣管狹窄以聲門下狹窄(SGS,subglottic stenosis)和氣管狹窄(TS,tracheal stenosis)最常見,目前治療方法包括手術(shù)治療、激光治療、支架擴張及藥物治療等。常用的手術(shù)方法包括氣管重建術(shù)、環(huán)狀軟骨切除術(shù)、激光手術(shù)包括C02激光、Nd:YAG激光等方法。對于預(yù)防喉氣管狹窄手術(shù)后再狹窄及喉氣管惡性腫瘤阻塞需要支架的支撐,但是目前可行的支架都不能順應(yīng)氣道的解剖結(jié)構(gòu)而導(dǎo)致氣道的損傷,對喉氣管粘膜刺激引發(fā)的咳嗽,支架移位、脫落,支架上下端部位肉芽的生長及有可能拔管后再次發(fā)生喉氣管狄窄等一些常見并發(fā)癥尚未得到滿意的解決。對于良性的喉氣管狹窄,半年至1年后拔出支撐管后還有因纖維組織增生而再次狹窄的可能,肉芽組織的形成是喉狹窄支架置入最常見的并發(fā)癥。近年來絲裂霉素C(mitomycin C,MMC)抗腫瘤、抗瘢痕形成、減少肉芽組織增生和防止組織粘連的作用得到了公認(rèn),被廣泛應(yīng)用于臨床相關(guān)治療中。 MMC最早發(fā)現(xiàn)于1956年,是從頭狀鏈霉菌培養(yǎng)液中分離提取的一種廣譜抗腫瘤抗后素。作為一種廣譜抗腫瘤藥物,MMC被用作系統(tǒng)化療藥,應(yīng)用于乳腺、肺、胰腺及結(jié)腸直腸癌的治療中。MMC具有抗腫瘤和抑制增殖的雙重作用,作為一種烷化劑,其主要作用機制是與DNA的雙螺旋形成交聯(lián),破壞DNA的結(jié)構(gòu)和功能,抑制增殖期DNA的復(fù)制,對增殖期中的細(xì)胞均有殺傷作用,同時也作用于靜止期的細(xì)胞,因而可用來阻止手術(shù)區(qū)的血管再生和瘢痕形成。研究表明,MMC在體內(nèi)和體外均能抑制成纖維細(xì)胞增生,從而減少各種細(xì)胞外基質(zhì)成分合成。MMC可使體外培養(yǎng)的成纖維細(xì)胞中cyclin D1的表達(dá)下調(diào),caspase-3的表達(dá)上調(diào)。cyclin D1是細(xì)胞周期中G1期的關(guān)鍵調(diào)控蛋白,其下調(diào)將阻止細(xì)胞由G1期進(jìn)入S期,從而抑制細(xì)胞增殖。caspase-3被稱為死亡蛋白酶,其上調(diào)將激活凋亡級聯(lián)反應(yīng),使細(xì)胞進(jìn)入不可逆的凋亡過程,誘導(dǎo)細(xì)胞凋亡。MMC可能通過上述途徑抑制細(xì)胞增殖,誘導(dǎo)細(xì)胞凋亡,使成纖維細(xì)胞減少,預(yù)防瘢痕產(chǎn)生。在預(yù)防聲帶術(shù)后的粘連及氣管手術(shù)后的狹窄中,絲裂霉素可能也通過這些途徑發(fā)揮作用。 局部應(yīng)用絲裂霉素聯(lián)合氣道置入支架治療是一種有前景的方法。在耳鼻咽喉頭頸外科中,絲裂霉素C對預(yù)防喉粘連和鼻腔粘連有一定療效,但所有研究均是一次性用藥,把含有絲裂霉素C的棉片在創(chuàng)面敷貼4-5分鐘,不能完全解決粘連問題。國外報道用聚乳酸聚乙醇酸(Poly L-lactide-co-glycolide, PLGA)納米微�？梢宰鳛閯游锖聿康木徛屗庉d體,該實驗中將載有德克薩斯紅葡聚糖、肝細(xì)胞生長因子及牛血清白蛋白的PLGA納米微粒注射到小鼠聲帶,體外實驗中載有這三種不同物質(zhì)的PLGA均可釋放12d-14d天以上,紅葡聚糖在體內(nèi)持續(xù)釋放達(dá)1周,肝細(xì)胞生長因子在體外仍可以減少TGF-β誘導(dǎo)3T3型成纖維細(xì)胞中膠原的生長,說明了PLGA載藥納米微�？梢蚤L期釋放藥物并且可以保持藥物的生物活性。 聚乳酸凝膠為可注射用生物降解性材料,其生物組織相容性好。聚乳酸凝膠在冷藏條件下為液態(tài),常溫下為膠體狀,可攜帶藥物,在喉氣管疾病應(yīng)用方而,可作為良好的注射用藥物緩釋載體。溫敏型聚乳酸凝膠注射到體內(nèi)后,在體溫作用下原位凝固,可將其作為藥物釋放載體,把所需劑量的藥物與聚乳酸凝膠混合后注射到患病部位,可迅速形成凝膠。這種原位形成的水凝膠可以和周圍組織牢固的結(jié)合,可控制在特定部位形成凝膠,在病灶處精確地釋放包裹的藥物,有效地控制了凝膠中藥物的釋放范圍,減輕全身的不良反應(yīng)。 地塞米松磷酸鈉(Dexamethasone sodium phosphate, DSP)為糖皮質(zhì)激素類用藥,具有明顯抗炎作用,其對各種原因(物理、化學(xué)、生物、免疫等)引起炎癥都有很強的抗炎作用,減輕炎癥早期的滲出、水腫、毛細(xì)血管擴張、白細(xì)胞浸潤及吞噬反應(yīng)。在炎癥后期可抑制毛細(xì)血管和纖維母細(xì)胞的增生,延緩肉芽組織生成,防止粘連及瘢痕形成。其價格便宜,局部用藥不良反應(yīng)少,可抑制纖維組織增生,本實驗將聚乳酸凝膠作為MMC、DSP的緩釋載體并用于喉氣管外壁纖維組織增生的動物模型,研究其對氣管纖維組織增生的抑制作用,為未來研究PLGA支架涂層藥物緩釋載體對喉氣管狹窄的治療提供實驗基礎(chǔ)。 目的 探討載MMC與DSP的聚乳酸凝膠在體內(nèi)外的緩釋情況及對氣管纖維組織增生的抑制作用。 方法 在體外緩釋實驗中,將聚乳酸凝膠加入雙蒸水,于4℃冰箱中放置24h以上,直至完全溶解得到澄明溶液,攪拌下加入MMC、DSP攪拌10min。37℃水浴放置5min,制成原位凝膠。取1mg/ml的MMC聚乳酸凝膠1ml及2mg/ml的DSP聚乳酸凝膠1ml分別置于10mlPH為7.4PBS中,在37℃恒溫?fù)u床中,以120r/min的速度持續(xù)搖蕩。分別于1、4、6、8、12h,1、3、5、7、14、21、28、35d取出樣本200μl并加入等量的新鮮PBS溶液。各樣本通過0.45μm微孔濾膜過濾,測定釋放介質(zhì)中MMC及DSP的含量,藥物的累積濃度通過紫外分光光度法測定。通過觀察各時間點留取的浸出液分別測出在365nm及242nm處的紫外分光光度值,實驗重復(fù)3次。 在體內(nèi)緩釋試驗中,通過喉氣管外壁損傷建立纖維組織增生的動物模型。將42只新西蘭大白兔按照完全隨機的方法分成7組后進(jìn)行氣管外壁刮傷,將0.2ml載有不同的藥物劑量的聚乳酸凝膠與明膠海綿混勻后置于損傷后的氣管外壁,并用半圓形的硅膠管固定。實驗組包括載MMC組3組(0.1mg,0.21ng,0.4mg).載藥DSP組3組(1mg,2mg,3mg)和空白對照組1組。分別于術(shù)后1、3、7、10、14、21d從O.4mgMMC組耳緣靜脈抽血1ml,用質(zhì)譜方法測量動物體內(nèi)藥物釋放濃度。術(shù)后1、7、14d從耳緣靜脈抽血1.5ml測定血常規(guī)觀察白細(xì)胞計數(shù)。術(shù)后4周通過空氣栓塞處死動物后取氣管外壁標(biāo)本,標(biāo)本經(jīng)過福爾馬林固定,石蠟切片,HE染色,光學(xué)顯微鏡下觀察纖維組織增生厚度。 統(tǒng)計學(xué)方法：實驗數(shù)據(jù)通過SPSS13.0統(tǒng)計軟件進(jìn)行分析,采用單因素方差分析(One-Way ANOVA),組間比較采用LSD(Least-significant Difference),P0.05表示差異有統(tǒng)計學(xué)意義。 結(jié)果 藥物體外實驗發(fā)現(xiàn)1mgMMC緩釋時間可達(dá)35天以上,2mgDSP緩釋時間可達(dá)28天以上,DSP早期釋放相對較快,6hDSP累積釋放濃度達(dá)(31.51±2.31)%,28d時累積釋放濃度達(dá)(92.01±1.76)%,以后釋放逐漸緩慢,逐漸趨于平衡。MMC在21d之前釋放較緩慢,累積釋放濃度達(dá)(32.05±1.81)%,35d時累積釋放濃度達(dá)(84.28±3.06)%。 在動物體內(nèi)兩種藥物凝膠在術(shù)后4周尚未完全降解,各組氣管外壁纖維組織增生厚度如下：空白組：0.82±0.29mm；0.1mgMMC組：0.65±0.16mm； O.2mgMMC組：O.49±0.24mm；0.4mgMMC組：O.17±0.09mm；1mgDSP組：0-31±O.33mm；2mgDSP組：0.18±0.13mm:3mgDSP組：0.14±0.13mm。通過One-Way ANOVA LSD檢驗,兩種藥物各劑量組(除0.1mgMMC組外)與對照組比較,纖維組織增生厚度差異具有統(tǒng)計學(xué)意義(F=9.482,P=0.000),說明藥物(除0.1mgMMC組外)對氣管壁纖維組織增生有明顯抑制作用；在MMC凝膠不同劑量組中,0.4mgMMC組與其他劑量組纖維組織增生厚度差異均有統(tǒng)計學(xué)意義(F=11.973,P=0.001),0.4mgMMC纖維組織增生的平均厚度最小,說明0.4mg MMC為動物體內(nèi)抑制纖維組織增生效果最好的最低劑量；在DSP不同劑量組中,總體差異無顯著統(tǒng)計學(xué)意義(F=0.988,P=0.395),1mgDSP為動物體內(nèi)最大程度抑制氣管瘢痕形成的合適劑量；0.4mg MMC與DSP各組間抑制纖維組織增生的程度差異均無統(tǒng)計學(xué)意義(F=0.893,P=0.462)。其中0.4mgMMC組,從第1-21天動物體內(nèi)MMC血漿中平均濃度為(0.16±0.12)ng/ml,在第7天釋放濃度達(dá)到高峰,第10天以后藥物釋放逐漸趨于平衡。術(shù)后1、7、14d抽血觀察白細(xì)胞計數(shù),白細(xì)胞計數(shù)分別為(9.03±1.57)×109/L、(9.85±1.63)×109/L、(10.17±3.11)×109/L,通過One-Way ANOVA LSD檢驗發(fā)現(xiàn)3組白細(xì)胞計數(shù)差別無顯著性統(tǒng)計學(xué)意義(P0.05),說明載有MMC的聚乳酸凝膠對動物的骨髓無明顯抑制作用。結(jié)論 MMC及DSP聚乳酸凝膠在動物體內(nèi)及體外釋放時間均可長達(dá)4周以上。在新西蘭大白兔體內(nèi)MMC抑制纖維增生的最合適劑量為0.4mg,DSP最合適劑量為1mg、MMC、DSP聚乳酸凝膠均可作為預(yù)防纖維組織增生的臨床用藥。本研究結(jié)果為未來研究生物可降解聚乳酸聚乙醇酸(Poly L-lactide-co-glycolide, PLGA)涂層藥物緩釋載體支架對喉氣管狹窄的治療提供實驗基礎(chǔ)。
[Abstract]:Research background
Laryngotracheal stenosis (laryngo tracheal stenosis, LTS) is the most common cause of mechanical trauma and iatrogenic injury, including mechanical traumatic laryngotracheal injuries after cartilage fracture or airway laceration and displacement, iatrogenic injury including tracheal intubation, incision of trachea, larynx and laryngeal surgery radiotherapy and other factors. The throat in order to tracheal stenosis subglottic stenosis (SGS, subglottic, stenosis) and tracheal stenosis (TS, tracheal stenosis) is the most common current treatment methods include surgery, laser therapy, stent expansion and drug therapy. Surgery commonly used methods include tracheal reconstruction, cricoidectomy, laser surgery including C02 laser, Nd:YAG laser method for the prevention of laryngotracheal stenosis and restenosis after surgery of laryngeal and tracheal malignant tumor obstruction need support, but at present the feasible bracket can not adapt to the anatomic structure of airway and lead to airway The damage of cough, laryngeal and tracheal mucosa irritation caused by stent migration, fall off, the lower part of the bracket granulation growth, may occur again after extubation, laryngeal and tracheal narrow common complications has not been satisfactorily solved. For laryngotracheal benign stricture, half a year to 1 years after pulling out and supporting tube because of the hyperplasia of fibrous tissue and re stenosis may, the formation of granulation tissue is the most common complication of laryngeal stenosis stent implantation. In recent years, mitomycin C (mitomycin C MMC) anti tumor, anti scar formation, reduce the proliferation of granulation tissue and prevent tissue adhesion has been recognized and has been widely applied in clinical treatment.
MMC was first discovered in 1956, is from Streptomyces caespitosus cultivating a broad-spectrum extraction liquid anti tumor and anti vasopressin. As a broad-spectrum anticancer drug, MMC was used as the system used in chemotherapy, breast, lung, pancreatic and colorectal cancer.MMC treatment has double antitumor effect and inhibited the proliferation of and as an alkylating agent, its main mechanism is the double helix and the formation of DNA crosslinking, damage to the structure and function of DNA, inhibit the proliferation of DNA replication, killing of proliferating cells in the important role, but also in quiescent cells, and thus can be used to prevent angiogenesis and scar the formation. The results show that MMC can inhibit the proliferation of fibroblasts in vivo and in vitro, thus reducing the various components of extracellular matrix synthesis of.MMC can make the in vitro expression of fibroblast in cyclin D1 down regulated the expression of Caspase-3. .cyclin D1 is the cell cycle in G1 phase of the key regulatory protein, its downregulation will prevent cells from G1 phase to S phase, thus inhibiting the proliferation of.Caspase-3 cells is called death protease, its increase will activate the apoptotic cascade, the cells into the irreversible process of apoptosis, cell apoptosis induced by.MMC may inhibit cell proliferation by the pathway, induce cell apoptosis, fibroblasts decreased, prevent scar stenosis. In tracheal surgery to prevent adhesions and vocal cords postoperatively, MMC can through these pathways play a role.
The treatment of topical mitomycin combined airway stent implantation is a promising approach. In otorhinolaryngology head and neck surgery, mitomycin C for the prevention of laryngeal adhesion and adhesion of nasal cavity has certain curative effect, but all of them is a one-time medication, the cotton sheet containing mitomycin C in wound dressing for 4-5 minutes, can not completely solve the adhesion the problem with the foreign reports. PLGA (Poly L-lactide-co-glycolide PLGA) nanoparticles can be used as animal throat slow release carrier, the experiment with Texas red dextran, hepatocyte growth factor and bovine serum albumin PLGA nanoparticles injected into mice carrying the vocal cords, the in vitro experiments of three different substances PLGA can release more than 12d-14d days, red dextran in vivo sustained release up to 1 weeks, the hepatocyte growth factor in vitro could reduce the fibroblast induced 3T3 TGF- beta The growth of collagen in cells shows that PLGA nanoparticles can release drugs for a long time and keep the biological activity of the drug.
Polylactic acid gel as biodegradable material for injection and its biocompatibility. The polylactic acid gel under refrigerated conditions for liquid at room temperature for colloid, can carry drugs applied in laryngeal tracheal diseases, can be used as a good drug carrier injection. Wen Min type polylactic acid gel was injected into the in vivo, at body temperature in situ solidification, can be used as drug delivery carrier, the desired drug dosage and polylactic acid gel mixture was injected into the diseased part, can quickly form a gel. The in situ formed hydrogels can be firmly combined with the surrounding tissue, can control the formation of gel at a specific location, accurate drug the release of the parcel in lesions and effectively control the extent of drug delivery in the gel, reduce systemic adverse reactions.
Dexamethasone sodium phosphate (Dexamethasone sodium, phosphate, DSP) for glucocorticoid medication has significant anti-inflammatory effects, for various reasons (physical, chemical, biological, immunological etc.) cause inflammation have potent anti-inflammatory effects, reduce inflammatory exudation, early edema, capillary dilatation, leukocyte infiltration and phagocytosis. In the late inflammation can inhibit the proliferation of capillaries and fibroblasts, delaying the generation of granulation tissue, preventing adhesion and scar formation. It is cheap, less adverse reactions and local drug, can inhibit the proliferation of fibrous tissue, the polylactic acid gel as a carrier of DSP MMC, and the animal model for laryngotracheal wall fibrous tissue hyperplasia the study on the inhibition of tracheal fibroplasia, for the future research of PLGA stent coating drug carrier to provide the experimental basis for the treatment of laryngotracheal stenosis.
objective
To investigate the sustained release of polylactic acid gel containing MMC and DSP in vivo and in vitro and the inhibition of tracheal fibrous tissue proliferation.
Method
In vitro release experiment, the polylactic acid gel with double distilled water, placed in the refrigerator at the temperature of 4 24h or more, until completely dissolved by a clear solution, stirring MMC, DSP 10min.37 5min placed C water bath stirring, made of in situ gel. The 1mg/ml MMC 1ml and 2mg/ ml polylactic acid gel DSP polylactic acid gel 1ml 10mlPH were placed in 7.4PBS, 37 in constant temperature shaker, with the speed of 120r/min continuous swing. In 1,4,6,8,12h, the fresh PBS solution 1,3,5,7,14,21,28,35d take a sample of 200 L and adding the same amount of each sample. By 0.45 m microporous membrane filtration, determination of the release of MMC and DSP in the medium, the cumulative drug concentration by UV spectrophotometry. The leaching solution at each time point for the measured UV in 365nm and 242nm spectrophotometry, the experiment was repeated 3 times.
In vivo release experiment, through the establishment of animal model of laryngeal and tracheal wall injury of fibrous tissue hyperplasia. 42 New Zealand white rabbits were randomly divided into 7 groups after the method of tracheal wall scraping 0.2ml containing different doses of polylactic acid gel and gelatin sponge after mixing in the injury of tracheal wall. The silicone tube and fixed with semicircular. The experimental group including MMC group 3 groups (0.1mg, 0.21ng, 0.4mg). The drug loaded DSP 3 groups (1mg, 2mg, 3mg) and blank control group. 1 groups respectively after 1,3,7,10,14,21d O.4mgMMC group from ear vein blood 1ml, release concentration by using mass spectrometry the measurement of animal drugs. Postoperative 1,7,14d were determined from the ear vein blood 1.5ml to observe blood white cell count at 4 weeks after operation by air embolism death animal after tracheal wall specimens were fixed in formalin, paraffin section, HE staining, optical display The thickness of fibrous tissue was observed under microscopes.
Statistical methods: the experimental data were analyzed by SPSS13.0 statistical software, and the single factor analysis of variance (One-Way ANOVA) was used. The comparison between groups was LSD (Least-significant Difference), P0.05 showed that the difference was statistically significant.
Result
In vitro experiments showed that the 1mgMMC release time up to 35 days, 2mgDSP release time up to 28 days, DSP early release is relatively fast, 6hDSP cumulative release concentration of (31.51 + 2.31)%, 28d cumulative release concentration of (92.01 + 1.76)%, after gradually slow, tending to balance.MMC before 21d slow release, the cumulative release concentration of (32.05 + 1.81)%, 35d cumulative release concentration of (84.28 + 3.06)%.
In two kinds of animal drug gel in 4 weeks after the operation has not been completely degraded, tracheal wall thickness of fibrous tissue hyperplasia were as follows: blank group: 0.82 + 0.29mm; group 0.1mgMMC: 0.65 + 0.16mm; group O.2mgMMC: O.49 + 0.24mm; group 0.4mgMMC: O.17 + 0.09mm; 1mgDSP group: 0-31 + O.33mm; group 2mgDSP: 0.18 group: 0.14 + 0.13mm:3mgDSP + 0.13mm. by One-Way ANOVA LSD test, two kinds of drugs in each dose group (except group 0.1mgMMC) compared with the control group, with statistically significant difference between the thickness of fibrous tissue hyperplasia (F=9.482, P=0.000), indicating that the drug (except 0.1mgMMC group) had significant inhibitory effects on proliferation of fibrous tissue in the tracheal wall; different doses of MMC gel group, 0.4mgMMC group and other groups of hyperplasia of fibrous tissue thickness differences were statistically significant (F=11.973, P=0.001), the average thickness of fibrous tissue proliferation in 0.4mgMMC's 0.4mg MMC. To inhibit the proliferation of fibrous tissue in vivo animal effect best in the lowest dose; different doses of DSP group, no significant difference (F=0.988, P=0.395), the appropriate dose of 1mgDSP was the animal maximum suppression of trachea scar formation; 0.4mg MMC and DSP were inhibited the proliferation of fibrous tissues showed no significant difference (the degree of F=0.893, P=0.462). In 0.4mgMMC group, from the 1-21 day average concentration of MMC in plasma for animal in vivo (0.16 + 0.12) ng/ml, on the seventh day release concentration reached the peak, tenth days after the drug release has gradually come to balance. Observe the white blood cell count blood 1,7,14d after operation, white blood cell count (9.03 + 1.57 respectively.) * 109/L (9.85 + 1.63) * 109/L (10.17 + 3.11) * 109/L One-Way ANOVA LSD, through the inspection found 3 groups of white blood cell count no significant difference statistically significant (P0.05), shows that MMC loaded polylactic acid gel There is no obvious inhibitory effect on the bone marrow of animals.
MMC and DSP polylactic acid gel in animal in vivo and in vitro release time can be up to more than 4 weeks. The most suitable dose of inhibitory fiber hyperplasia in New Zealand rabbits in MMC is 0.4mg, DSP is the most suitable dose of 1mg, MMC, DSP polylactic acid gel can be used as prevention of fibrous tissue hyperplasia clinical treatment. The results of this study for the future study of biodegradable polylactic acid polyglycolic acid (Poly, L-lactide-co-glycolide, PLGA) coating drug release carrier to provide the experimental basis of treatment of laryngotracheal stenosis.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R767.1

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