本發(fā)明涉及藥物領(lǐng)域,特別是涉及一種石金錢龜多肽混合物在制備抗腫瘤藥物領(lǐng)域的應(yīng)用以及包括該石金錢龜多肽混合物的抗腫瘤藥物。
背景技術(shù):
癌癥仍在嚴(yán)重危害著人類生命和健康,全球癌癥病例仍在持續(xù)增加,很大程度上是由人口老齡化、世界人口增長(zhǎng)和致癌行為習(xí)慣增加等所致,特別是發(fā)展中國(guó)家的吸煙行為。報(bào)道提到,中國(guó)2015年新增430萬(wàn)癌癥病例,癌癥的死亡病例超過(guò)280萬(wàn),有專家預(yù)計(jì),中國(guó)每年的癌癥新發(fā)病例總數(shù)到2020年將達(dá)到400萬(wàn)左右,每年病例總數(shù)將達(dá)到600萬(wàn)。肺癌仍然是男性最常見(jiàn)癌癥,占癌癥總發(fā)病率的17%和死亡率的14%。乳腺癌是女性中最常被診斷出的腫瘤,是女性癌癥的首要死因,占癌癥總病例的23%和死亡病例的14%。發(fā)展中國(guó)家的癌癥存活期相對(duì)較短,主要原因是癌癥診出時(shí)間偏晚和治療手段有限。
癌癥主要的治療手段包括手術(shù)治療、化療及放療。化學(xué)藥物治療是腫瘤治療的主要手段之一,傳統(tǒng)化療的療效與病人對(duì)藥物的敏感程度、耐受程度和藥物毒性反應(yīng)等相關(guān),多數(shù)化療藥物屬于細(xì)胞毒類抗腫瘤藥,具有擇性差、毒性大和易產(chǎn)生腫瘤多藥耐藥等缺陷,傳統(tǒng)化療用藥已經(jīng)難以滿足臨床的需要。
由于腫瘤細(xì)胞有其特殊的生長(zhǎng)模式,如無(wú)限增殖、生長(zhǎng)信號(hào)可進(jìn)行自我調(diào)節(jié),對(duì)外界生長(zhǎng)抑制信號(hào)敏感性較差,以及具有極強(qiáng)的抗細(xì)胞凋亡能力,可以自主調(diào)控供給營(yíng)養(yǎng)血管的生成和免疫逃逸等特性,使一般的抗腫瘤藥物很難達(dá)到較好的殺死腫瘤細(xì)胞的功效。而肽類對(duì)腫瘤具有較好的親和力和較強(qiáng)的特異性以及以肽為基礎(chǔ)的治療,與其它小分子化學(xué)藥物及抗體相比,由于他們體積微小,因此更容易滲透到組織中,再者就是多肽類具有低毒性等優(yōu)點(diǎn),還可以增加對(duì)腫瘤治療的敏感度,因此成為近年來(lái)抗腫瘤治療新型抗癌方法研究的熱點(diǎn)之一。雖然多肽類化合物具有一定的活性,尤其是在抗腫瘤方面,但2015版藥典收錄的多肽藥物僅有20多種,且皆是國(guó)外的已過(guò)專利保護(hù)期或未在我國(guó)申請(qǐng)專利的藥物,而抗腫瘤肽僅有一種(醋酸奧曲肽),因此開(kāi)發(fā)出具有自主知識(shí)產(chǎn)權(quán)的抗腫瘤多肽藥物也成為多肽研發(fā)的一個(gè)熱點(diǎn)。
技術(shù)實(shí)現(xiàn)要素:
基于此,有必要提供一種石金錢龜多肽混合物在制備抗腫瘤藥物領(lǐng)域的應(yīng)用以及包括該石金錢龜多肽混合物的抗腫瘤藥物。
一種石金錢龜多肽混合物在制備抗腫瘤藥物領(lǐng)域的應(yīng)用。
在一個(gè)實(shí)施例中,所述石金錢龜多肽混合物的平均分子質(zhì)量為2000~3000。
在一個(gè)實(shí)施例中,所述石金錢龜多肽混合物包括1470條肽段和313個(gè)蛋白質(zhì)。
在一個(gè)實(shí)施例中,所述石金錢龜多肽混合物包括具有抗腫瘤活性的7個(gè)功能性蛋白:Ras-相關(guān)蛋白、T復(fù)合蛋白-1亞基δ、GTP結(jié)合蛋白、熱休克蛋白90、Ctr轉(zhuǎn)運(yùn)蛋白、熱休克同源蛋白71和肌動(dòng)蛋白4。
在一個(gè)實(shí)施例中,所述石金錢龜多肽混合物通過(guò)如下方法制得:
按照質(zhì)量比為1:5~10將石金錢龜肉糜與超純水混合,在溫度為40℃~50℃的范圍內(nèi),調(diào)節(jié)pH為7~8,加入中性蛋白酶并充分反應(yīng),得到反應(yīng)液;
對(duì)所述反應(yīng)液進(jìn)行滅酶處理后,離心除去沉淀并保留上清液,對(duì)所述上清液進(jìn)行冷凍干燥,得到所述石金錢龜多肽混合物。
在一個(gè)實(shí)施例中,所述調(diào)節(jié)pH為7~8的操作為:采用NaOH調(diào)節(jié)pH為7~8。
在一個(gè)實(shí)施例中,所述滅酶處理為:80℃~90℃熱處理5min~10min。
在一個(gè)實(shí)施例中,所述離心為:6000r/min~10000r/min離心10min~20min。
在一個(gè)實(shí)施例中,所述抗腫瘤藥物為抗乳腺癌藥物。
一種抗腫瘤藥物,包括石金錢龜多肽混合物。
石金錢龜多肽混合物具有良好的抗腫瘤的作用,經(jīng)過(guò)試驗(yàn)驗(yàn)證,石金錢龜多肽混合物可明顯抑制乳腺癌細(xì)胞MDA-MB-231和MCF-7的增殖,可阻滯MDA-MB-231的G2-M期、可阻滯MCF-7的S期,并可明顯抑制乳腺癌細(xì)胞MCF-7在BALB/c-Nude裸鼠體內(nèi)的增殖。因此,石金錢龜多肽混合物在制備抗腫瘤藥物領(lǐng)域具有良好的應(yīng)用前景。
附圖說(shuō)明
圖1a~圖1j為石金錢龜多肽混合物抑制腫瘤細(xì)胞MDA-MB-231、HeLa、SGC-7901、COLO-320、MCF-7、Hep-G2、PC-3、K562、A-375和A-549的增殖的測(cè)定圖;
圖2a為石金錢龜多肽混合物對(duì)乳腺癌細(xì)胞MDA-MB-231的細(xì)胞周期影響測(cè)定對(duì)比圖;
圖2b為石金錢龜多肽混合物對(duì)乳腺癌細(xì)胞MDA-MB-231的細(xì)胞周期影響測(cè)定柱狀圖;
圖3a為石金錢龜多肽混合物對(duì)乳腺癌細(xì)胞MCF-7的細(xì)胞周期影響測(cè)定對(duì)比圖;
圖3b為石金錢龜多肽混合物對(duì)乳腺癌細(xì)胞MCF-7的細(xì)胞周期影響測(cè)定柱狀圖;
圖4a為石金錢龜多肽混合物對(duì)MCF-7細(xì)胞瘤在裸鼠體內(nèi)生長(zhǎng)狀況影響的測(cè)定對(duì)比圖;
圖4b為石金錢龜多肽混合物對(duì)MCF-7細(xì)胞瘤在裸鼠體內(nèi)生長(zhǎng)狀況影響的體積測(cè)定對(duì)比圖;
圖4c為石金錢龜多肽混合物對(duì)MCF-7細(xì)胞瘤在裸鼠體內(nèi)生長(zhǎng)狀況影響的瘤重測(cè)定對(duì)比圖。
具體實(shí)施方式
為使本發(fā)明的上述目的、特征和優(yōu)點(diǎn)能夠更加明顯易懂,下面結(jié)合具體實(shí)施例對(duì)本發(fā)明的具體實(shí)施方式做詳細(xì)的說(shuō)明。在下面的描述中闡述了很多具體細(xì)節(jié)以便于充分理解本發(fā)明。但是本發(fā)明能夠以很多不同于在此描述的其它方式來(lái)實(shí)施,本領(lǐng)域技術(shù)人員可以在不違背本發(fā)明內(nèi)涵的情況下做類似改進(jìn),因此本發(fā)明不受下面公開(kāi)的具體實(shí)施的限制。
本發(fā)明公開(kāi)了一種石金錢龜多肽混合物在制備抗腫瘤藥物領(lǐng)域的應(yīng)用。
優(yōu)選的,石金錢龜多肽混合物的平均分子質(zhì)量為2000~3000。
優(yōu)選的,石金錢龜多肽混合物包括1470條肽段和313個(gè)蛋白質(zhì)。
優(yōu)選的,石金錢龜多肽混合物包括Ras-相關(guān)蛋白(Rab)、T復(fù)合蛋白-1亞基δ(TCP-1)、GTP結(jié)合蛋白(SAR1b)、熱休克蛋白90(HSP90a)、Ctr轉(zhuǎn)運(yùn)蛋白(ATOX1)、熱休克同源蛋白71(71KDa)和肌動(dòng)蛋白4。
Ras-相關(guān)蛋白(Rab)、T復(fù)合蛋白-1亞基δ(TCP-1)、GTP結(jié)合蛋白(SAR1b)、熱休克蛋白90(HSP90a)、Ctr轉(zhuǎn)運(yùn)蛋白(ATOX1)、熱休克同源蛋白71(71KDa)和肌動(dòng)蛋白4均具有抗腫瘤活性。
Ras-相關(guān)蛋白(Rab)的序列如SEQ ID No.1所示,T復(fù)合蛋白-1亞基δ(TCP-1)的序列如SEQ ID No.2所示,GTP結(jié)合蛋白(SAR1b)的序列如SEQ ID No.3所示,熱休克蛋白90(HSP90a)的序列如SEQ ID No.4所示,Ctr轉(zhuǎn)運(yùn)蛋白(ATOX1)的序列如SEQ ID No.5所示,熱休克同源蛋白71(71KDa)的序列如SEQ ID No.6所示,肌動(dòng)蛋白4的序列如SEQ ID No.7所示。
具體的,石金錢龜多肽混合物通過(guò)如下方法制得:
按照質(zhì)量比為1:5~10將石金錢龜肉糜與超純水混合,在溫度為40℃~50℃的范圍內(nèi),調(diào)節(jié)pH為7~8,加入中性蛋白酶并充分反應(yīng)(中性蛋白酶的加入量為37313.43U/g,反應(yīng)時(shí)間優(yōu)選為10h),得到反應(yīng)液;
對(duì)反應(yīng)液進(jìn)行滅酶處理后,離心除去沉淀并保留上清液,對(duì)上清液進(jìn)行冷凍干燥,得到石金錢龜多肽混合物。
制得的石金錢龜多肽混合物經(jīng)過(guò)檢測(cè),包括Ras-相關(guān)蛋白(Rab)、T復(fù)合蛋白-1亞基δ(TCP-1)、GTP結(jié)合蛋白(SAR1b)、熱休克蛋白90(HSP90a)、Ctr轉(zhuǎn)運(yùn)蛋白(ATOX1)、熱休克同源蛋白71(71KDa)和肌動(dòng)蛋白4。
超純水是指將水中的導(dǎo)電介質(zhì)幾乎全部去除,又將水中不離解的膠體物質(zhì)、氣體和有機(jī)物均去除至很低程度的水。一般來(lái)說(shuō),超純水為電阻率大于18MΩ×cm的水。
優(yōu)選的,調(diào)節(jié)pH為7~8的操作為:采用NaOH調(diào)節(jié)pH為7~8。
優(yōu)選的,滅酶處理為:80℃~90℃熱處理5min~10min。
更優(yōu)選的,滅酶處理為:85℃熱處理10min。
優(yōu)選的,離心為:6000r/min~10000r/min離心10min~20min。
更優(yōu)選的,離心為:8000r/min離心30min。
優(yōu)選的,抗腫瘤藥物為抗乳腺癌藥物。
本發(fā)明還公開(kāi)了一種抗腫瘤藥物,包括上述石金錢龜多肽混合物。
石金錢龜多肽混合物具有良好的抗腫瘤的作用,經(jīng)過(guò)試驗(yàn)驗(yàn)證,石金錢龜多肽混合物可明顯抑制乳腺癌細(xì)胞MDA-MB-231和MCF-7的增殖,可阻滯MDA-MB-231的G2-M期、可阻滯MCF-7的S期,并可明顯抑制乳腺癌細(xì)胞MCF-7在BALB/c-Nude裸鼠體內(nèi)的增殖。因此,石金錢龜多肽混合物在制備抗腫瘤藥物領(lǐng)域具有良好的應(yīng)用前景。
以下為具體實(shí)施例。
具體實(shí)施例中采用藥物和儀器均為本領(lǐng)域常規(guī)選擇。
實(shí)施例1、石金錢龜多肽混合物的制備
將10g石金錢龜肉糜與80g超純水混合,在溫度為45℃、pH為7.5的條件下,加入中性蛋白酶(25000U,37313.43U/g)并充分反應(yīng)10h,得到反應(yīng)液。
對(duì)反應(yīng)液在85℃滅酶處理10min,8000r/min離心30min,除去沉淀并保留上清液,對(duì)上清液進(jìn)行冷凍干燥,得到粗產(chǎn)物,即石金錢龜多肽混合物
將得到的石金錢龜多肽(GDP)混合物稀釋成原始濃度1g/mL,4℃保存?zhèn)溆谩?/p>
實(shí)施例2、石金錢龜多肽混合物的抗腫瘤性能測(cè)定
1、石金錢龜多肽抑制腫瘤細(xì)胞增殖的測(cè)定
取對(duì)數(shù)生長(zhǎng)期的腫瘤細(xì)胞株制成一定濃度的細(xì)胞懸液,接種至96孔板,每孔接種5000個(gè)細(xì)胞(100μL),置于5%CO2,37℃培養(yǎng)箱中,培養(yǎng)24h后棄掉原培養(yǎng)基,并用PBS洗一遍,然后分別加入不同濃度的石金錢龜多肽混合物溶液,每個(gè)濃度設(shè)3個(gè)平行孔,同時(shí)設(shè)加PBS的對(duì)照組,置5%CO2,37℃培養(yǎng)箱,孵育24h后,倒掉原培養(yǎng)基,加PBS洗2遍,然后每孔加10μL MTT溶液,放培養(yǎng)箱孵育4h后,吸去MTT溶液,然后每孔加100μL DMSO溶液,避光充分震蕩后置酶聯(lián)免疫檢測(cè)儀在570nm波長(zhǎng)下測(cè)吸光度,計(jì)算細(xì)胞存活率。
實(shí)驗(yàn)過(guò)程中用到的腫瘤細(xì)胞株包括:MDA-MB-231、HeLa、SGC-7901、COLO-320、MCF-7、Hep-G2、PC-3、K562、A-375和A-549(均購(gòu)買于ATCC細(xì)胞庫(kù)),實(shí)驗(yàn)結(jié)果如圖1a~圖1j所示。
由圖1a~圖1j可以看出,石金錢龜多肽混合物對(duì)MCF-7和MDA-MB-231的增殖具有明顯抑制作用。
2、石金錢龜多肽對(duì)腫瘤細(xì)胞細(xì)胞周期的影響
取對(duì)數(shù)生長(zhǎng)期的乳腺癌細(xì)胞MCF-7和MDA-MB-231制成一定濃度的細(xì)胞懸液(1×106個(gè)/mL),加入24孔(0.2mL/孔)培養(yǎng)板置于5%CO2,37℃培養(yǎng)箱中,24h后加入不同稀釋度的石金錢龜多肽,每個(gè)濃度設(shè)3個(gè)復(fù)孔,繼續(xù)培養(yǎng)24h。用PBS液洗2次,用預(yù)冷的75%乙醇固定過(guò)夜,加入碘化丙啶染料,4℃避光染色50min,400目尼龍網(wǎng)過(guò)濾,用流式細(xì)胞儀檢測(cè)乳腺癌細(xì)胞的細(xì)胞周期分布情況。試驗(yàn)結(jié)果如圖2a、圖2b、圖3a和圖3b所示。
由圖2a、圖2b、圖3a和圖3b可以看出,石金錢龜多肽混合物對(duì)MCF-7和MDA-MB-231的細(xì)胞周期具有抑制作用,石金錢龜多肽混合物可阻滯MDA-MB-231細(xì)胞的G2-M期、可阻滯MCF-7細(xì)胞的S期。
3、石金錢龜多肽動(dòng)物實(shí)驗(yàn)測(cè)定
實(shí)驗(yàn)條件(實(shí)驗(yàn)動(dòng)物和飼養(yǎng)環(huán)境):40只雄性BALB/c-Nude裸鼠購(gòu)買于中山大學(xué)實(shí)驗(yàn)動(dòng)物中心,鼠齡4~5周,體重16~18g。接種腫瘤前先飼養(yǎng)觀察一周左右。將裸鼠飼養(yǎng)在暨南大學(xué)實(shí)驗(yàn)動(dòng)物中心,SPF級(jí)別,飼養(yǎng)條件受到嚴(yán)格控制,恒溫、恒溫,并且環(huán)境中無(wú)任何病原體。裸鼠飼料及飲水都經(jīng)過(guò)高溫滅菌。
分組:將40只裸鼠分為5組,接種MCF-7細(xì)胞。
準(zhǔn)備細(xì)胞:觀察裸鼠的一周時(shí)間里,取對(duì)數(shù)生長(zhǎng)期的MCF-7細(xì)胞,傳代于100mm的培養(yǎng)皿中,置于5%CO2,37℃培養(yǎng)箱中培養(yǎng),收集足夠多的乳腺癌細(xì)胞。
裸鼠異體移植瘤模型的建立:取對(duì)數(shù)生長(zhǎng)期的MCF-7細(xì)胞,消化(1000rpm×5min),PBS洗兩遍,吸盡PBS,轉(zhuǎn)移至15mL離心管中,收集MCF-7細(xì)胞,用稀釋好的高濃度基質(zhì)膠混勻細(xì)胞(PBS:基質(zhì)膠=2:1)。調(diào)整細(xì)胞的密度,使得裸鼠接種MCF-7細(xì)胞的密度為5×106個(gè)/只,MCF-7細(xì)胞的密度為6×106個(gè)/只,每只裸鼠接種0.2mL混有細(xì)胞的基質(zhì)膠。
給藥:接種完細(xì)胞約一周,待腫瘤長(zhǎng)至100mm3左右,將裸鼠隨機(jī)分為5組,陰性對(duì)照組,Control組,高劑量組,中劑量組和低劑量組,隔天給藥一次。每次給藥前先稱量裸鼠的體重并用游標(biāo)卡尺記錄裸鼠腫瘤的長(zhǎng)徑和短徑,共給藥15天。
處死:最后一次給藥結(jié)束24h內(nèi),斷頸法處死裸鼠,剝離其腫瘤進(jìn)行稱重,計(jì)算各組體內(nèi)腫瘤的抑制率。
結(jié)果處理:腫瘤體積(mm3)=1/2×(L×W2),L為腫瘤的長(zhǎng)徑,W為腫瘤的短徑。腫瘤抑制率(%)=(1-給藥組平均瘤重/陰性對(duì)照組平均瘤重)×100%。實(shí)驗(yàn)結(jié)果如圖4a、圖4b和圖4c所示。
由圖4a、圖4b和圖4c可以看出,石金錢龜多肽混合物可明顯抑制乳腺癌細(xì)胞MCF-7在BALB/c-Nude裸鼠體內(nèi)的增殖。
以上所述實(shí)施例的各技術(shù)特征可以進(jìn)行任意的組合,為使描述簡(jiǎn)潔,未對(duì)上述實(shí)施例中的各個(gè)技術(shù)特征所有可能的組合都進(jìn)行描述,然而,只要這些技術(shù)特征的組合不存在矛盾,都應(yīng)當(dāng)認(rèn)為是本說(shuō)明書(shū)記載的范圍。
以上所述實(shí)施例僅表達(dá)了本發(fā)明的幾種實(shí)施方式,其描述較為具體和詳細(xì),但并不能因此而理解為對(duì)發(fā)明專利范圍的限制。應(yīng)當(dāng)指出的是,對(duì)于本領(lǐng)域的普通技術(shù)人員來(lái)說(shuō),在不脫離本發(fā)明構(gòu)思的前提下,還可以做出若干變形和改進(jìn),這些都屬于本發(fā)明的保護(hù)范圍。因此,本發(fā)明專利的保護(hù)范圍應(yīng)以所附權(quán)利要求為準(zhǔn)。
SEQUENCE LISTING
<110> 深圳凱聯(lián)龜業(yè)有限公司
<120> 石金錢龜多肽混合物的應(yīng)用以及抗腫瘤藥物
<160> 7
<170> PatentIn version 3.3
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Leu Val Pro Lys Arg Asp His Ala Leu Gln Asp Glu Gln Ser Lys Gln
660 665 670
Gln Ser Asn Glu His Leu Arg Arg Gln Phe Ala Ser Gln Ala Asn Ile
675 680 685
Val Gly Pro Trp Ile Gln Thr Lys Met Glu Glu Ile Gly Arg Ile Ser
690 695 700
Ile Glu Met Asn Gly Thr Leu Glu Asp Gln Leu Asn His Leu Lys Gln
705 710 715 720
Tyr Glu Gln Ser Ile Val Asp Tyr Lys Pro Asn Ile Asp Leu Leu Glu
725 730 735
Gln Gln His Gln Leu Ile Gln Glu Ala Leu Ile Phe Asp Asn Lys His
740 745 750
Thr Asn Tyr Thr Met Glu His Ile Arg Val Gly Trp Glu Gln Leu Leu
755 760 765
Thr Thr Ile Ala Arg Thr Ile Asn Glu Val Glu Asn Gln Ile Leu Thr
770 775 780
Arg Asp Ala Lys Gly Ile Ser Gln Glu Gln Met Gln Glu Phe Arg Ala
785 790 795 800
Ser Phe Asn His Phe Asp Lys Asp His Gly Gly Thr Leu Gly Pro Glu
805 810 815
Glu Phe Lys Ala Cys Leu Ile Ser Leu Gly Tyr Asp Val Glu Asn Asp
820 825 830
Arg Gln Gly Asp Ala Glu Phe Asn Arg Ile Met Ser Val Val Asp Pro
835 840 845
Asn Asn Ser Gly Ile Val Thr Phe Gln Ala Phe Ile Asp Phe Met Ser
850 855 860
Arg Glu Thr Thr Asp Thr Asp Thr Ala Asp Gln Val Ile Ala Ser Phe
865 870 875 880
Lys Val Leu Ala Gly Asp Lys Asn Tyr Ile Thr Ala Glu Glu Leu Arg
885 890 895
Arg Glu Leu Pro Pro Asp Gln Ala Glu Tyr Cys Ile Ala Arg Met Ala
900 905 910
Pro Tyr Gln Gly Pro Asp Ala Val Pro Gly Ala Leu Asp Tyr Lys Ser
915 920 925
Phe Ser Thr Ala Leu Tyr Gly Glu Ser Asp Leu
930 935