CN102766215B - 一种具有协同靶向诊疗鼻咽癌功能的多肽和携带此多肽的纳米颗粒及其应用 - Google Patents
一种具有协同靶向诊疗鼻咽癌功能的多肽和携带此多肽的纳米颗粒及其应用 Download PDFInfo
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Abstract
本发明公开了一种具有协同靶向治疗鼻咽癌功能的多肽、具有协同靶向诊疗鼻咽癌功能的纳米颗粒及其应用,属于生物科学和药物载体领域。该多肽由具有靶向治疗鼻咽癌作用的多肽、连接序列肽以及具有α螺旋结构的鼻咽癌靶向治疗多肽以共价键的形式串连而成。该纳米颗粒是由具有协同靶向治疗鼻咽癌功能的多肽、磷脂、胆固醇脂或装载物组成。该多肽和纳米颗粒能够高效特异性地靶向鼻咽癌,并且极显著性地抑制鼻咽癌肿瘤的生长,可以应用于临床治疗。
Description
技术领域
本发明属于生物科学和药物载体领域,特别涉及一种具有协同靶向诊疗鼻咽癌功能的多肽和携带此多肽的纳米颗粒及其应用。
背景技术
鼻咽癌是来源于鼻咽上皮的高度恶性肿瘤,它极易侵犯颅底等重要结构,并能较早地发生颈部淋巴结转移和远处转移。由于鼻咽癌恶性程度高,发病部位比较特殊,使其手术治疗较难实施。因此,临床上的鼻咽癌治疗主要以放射治疗为主并配合全身化学药物治疗。然而,传统的放疗与化疗均具有较为严重的毒副作用,且放疗仅适用于肿瘤原发灶及其前哨淋巴结转移的治疗,而不适合远处转移灶的治疗。由于治疗手段的局限性,致使鼻咽癌总的五年生存率一直徘徊在60%左右。
单克隆抗体药物在肿瘤治疗方面已经展示了良好的临床应用前景。单克隆抗体与放射性核素、药物或毒素形成的偶联物,对肿瘤细胞具有靶向的特异性杀伤作用。此外,一些肿瘤标志物特异性的单克隆抗体本身也具有显著的肿瘤治疗作用,例如作用于肿瘤细胞的表皮生长因子HER-2/neu抗体Herceptin,它作为靶向药物治疗HER-2阳性转移乳腺癌已取得了很好的疗效。然而,单克隆抗体在实际临床应用中尚存在以下几个缺陷:临床研究的单抗药物多数使用小鼠制备,存在免疫原性问题;抗体分子量大,对肿瘤的穿透力低,使得大体积实体肿瘤的治疗效果仍不十分理想;肿瘤治疗所需的抗体量很大,产品纯度要求高,因此生产成本极高;由于肿瘤的异质性,使用单克隆抗体单一地通过抑制或杀死表达某种受体的肿瘤细胞,并不代表着肿瘤的治愈。由此可知,治疗高恶性度的鼻咽癌,单纯使 用单克隆抗体作为靶向分子,很难获得理想的效果。
多肽作为肿瘤标志物分子的特异性配体,一直是研究者们关注的热点。相对于单克隆抗体,多肽具有尺寸小、组织穿透性好、低免疫原性和造价低等优点,可以很大程度上克服抗体制剂的缺陷。然而,相对较弱的肿瘤亲和力和短的半衰期,限制了靶向肽在生物活体内的应用。基于纳米技术的多价策略,可明显延长靶向肽的体内有效循环时间,并大大提高其与特异受体结合的亲合力,从而达到显著增强多肽的生物学效应的目的。
为此,我们使用前期工作中发明的一种具有多价效应和纳米尺寸效应的多肽荧光探针的构建方法,制备了基于四聚体远红荧光蛋白的八价多肽纳米荧光探针。通过此方法可快速准确地筛选与鉴定多肽的肿瘤靶向性及其抗肿瘤生物学效应。然而,由于远红色荧光蛋白为外源蛋白,其免疫原性限制了它的临床使用。因此,迫切需要发展一种能有效运输靶向肽的纳米载体,而又不影响其靶向性与治疗效果。
鼻咽癌是由环境因素与宿主遗传基因等因素共同参与的多步骤交互作用而逐步形成的复杂性疾病。放疗和辅助化疗综合治疗的临床研究表明,鼻咽癌是一种对化疗相对敏感的肿瘤,多种抗癌药物单用或联合使用均有一定的疗效。以顺铂和5-氟尿嘧啶(5-FU)等为主要的水溶性化疗药物能显著改善患者的预后。但是不管单独给药还是联合给药方案,静脉给药的顺铂和5-FU都具有半衰期短、缺乏选择性的缺点,从而增加了其毒副作用。姜黄素(Curcumin)和紫杉醇是两种具有代表性的抗癌中药。姜黄素是从草本植物姜黄根茎中提取的一种酚性色素,有着广泛的药理作用,众多研究证实,姜黄素可以抑制多种肿瘤细胞的生长。还可以增强肿瘤微环境NK细胞的招募,从而提高机体的免疫力。紫杉醇从1992年美国FDA批准首次进入临床用于治疗卵巢癌以来,也被应用于晚期鼻咽癌的治疗。研究发现,紫杉醇也具有增强肿瘤微环境NK细胞的招募和激活树突细胞的抗原提呈能力,从而提高机体对肿瘤的免疫。由于姜黄素与紫杉醇 都为脂溶性药物,被动运输方式很难直接被肿瘤组织细胞摄取,且有很强的静脉毒副作用,导致其目前临床应用效果欠佳。目前,针对鼻咽癌靶向治疗的纳米药物在国内还是一片空白。
纳米载体是将成像对比剂和药物靶向运输到肿瘤,实现肿瘤特异性成像诊断与靶向治疗的有效手段。已有研究者发明了一种仿高密度脂蛋白的多肽-脂质纳米颗粒(专利号:(WO/2009073984),它是利用具有α螺旋结构的功能多肽R4F与磷脂和胆固醇脂相互作用而形成的,其粒径小于30nm。这种纳米颗粒主要是基于多肽的功能靶向B型清道夫受体(SR-B1)高表达的细胞。然而,由于机体正常的组织细胞(如肝细胞)也高表达SR-B1,故此纳米颗粒在肿瘤与正常组织之间分布的对比度不太理想,在运输化疗药物的时候可能具有潜在的毒副作用。此外,该专利中的纳米颗粒本身仅做为靶向运输的工作,而其本身并未涉及到肿瘤治疗之功效。
综上所述,发展一种携带具有协同靶向与治疗功能的多肽的超小粒径(<40nm)纳米颗粒,并同时装载有成像对比剂和化疗药物分子,用于鼻咽癌的高特异性同步诊断与治疗,将会成为极具临床应用潜力的鼻咽癌靶向纳米药物。
发明内容
本发明的目的是为解决上述问题而提供了一种具有靶向治疗鼻咽癌作用的多肽(LTVSPWYLTVSPWY)和一种具有协同靶向与治疗鼻咽癌功能和控制脂质纳米颗粒尺寸功能的多肽(简称为dtTPNPC),以及携带dtTPNPC多肽的纳米颗粒(简称为dtDTNPNPC),并展示了其应用。上述多肽和纳米颗粒能够高效特异性地靶向鼻咽癌,并且显著性地抑制鼻咽癌肿瘤的生长,可以应用于临床治疗。
本发明所采用的技术方案是:
将一种具有靶向治疗鼻咽癌作用的多肽,与另一种具有α螺旋结构 的鼻咽癌靶向治疗多肽(该α螺旋多肽具有靶向治疗鼻咽癌作用并能与磷脂相互作用形成α螺旋结构的多肽),通过连接多肽以共价键的形式串连。它同时具有协同靶向与治疗鼻咽癌的功能和控制脂质纳米颗粒尺寸的功能。
一种具有协同靶向诊疗鼻咽癌功能的多肽的氨基酸序列为FAEKFKEAVKDYFAKFWDGSGLTVSPWYLTVSPWY。
优选地,所述具有靶向治疗鼻咽癌作用的多肽的氨基酸序列为LTVSPWYLTVSPWY。
一种具有协同靶向诊疗鼻咽癌功能的纳米颗粒,所述纳米颗粒由三部分物质组成:1)多肽:同时具有协同靶向治疗鼻咽癌的功能和控制脂质纳米颗粒尺寸的功能;2)磷脂和胆固醇脂:组成纳米颗粒的壳和维持稳定的球形纳米结构;3)装载物:成像对比剂、药物分子或者两者的结合,成像对比剂为胆固醇脂修饰的荧光染料分子(DiR-BOA和Fluo-BOA)、药物分子为紫杉醇、姜黄素。
本发明具有以下优点:
1)理化特性优良:利用动态激光光散射方法测得纳米颗粒的平均粒径为14.6nm左右。纳米颗粒的粒径均一、分散性好、无聚集现象。
2)生物相容性好:制备该纳米颗粒所使用的原料为磷脂、胆固醇脂和具有协同靶向与治疗鼻咽癌功能的多肽等材料,这些原材料都已用于临床试验,具有良好的生物相容性。
3)制备工艺简单,便于规模化生产。
4)靶向效果好:在细胞水平,本发明的纳米颗粒dtDTNPNPC,相对应肝癌、Hela等很多癌细胞,它能更容易被鼻咽癌(如5-8F细胞、SUNE-1细胞和HONE-1细胞等)摄取;在体水平,本发明的dtDTNPNPC纳米颗粒在尾静脉注射鼻咽癌5-8F荷瘤裸鼠12h后,选择性地靶向和蓄积到肿瘤部位。
5)治疗效果好:在细胞水平,本发明的纳米颗粒与鼻咽癌5-8F细胞孵育1h后,能显著性地诱导细胞死亡;在活体动物实验中,本发明的纳米颗粒由于协同靶向效应和实体瘤的EPR效应(enhanced permeability and retention effect),使其在鼻咽癌组织中的蓄积能力和被鼻咽癌细胞摄取的能力大大提高,从而对肿瘤的生长具有很好的抑制效果。
6)毒副作用低:动物实验研究结果显示,本发明的dtDTNPNPC纳米颗粒在鼻咽癌5-8F细胞皮下接种于裸鼠后的第三天,开始隔天尾静脉注射直至第14天,相对于PBS对照组,体重没有发生明显的变化。
7)功能可扩展:本发明的纳米颗粒除了可以更换不同肿瘤靶向治疗多肽用以针对不同的肿瘤进行靶向治疗外,还可以在其核心装载用于疾病诊疗的染料分子(DiR-BOA)和脂溶性药物分子(如紫杉醇和姜黄素等),实现肿瘤协同靶向治疗与免疫治疗功效的完美结合。
附图说明
下面结合附图和实施方式对本发明做进一步详细的说明。
图1为实施例1中Octa-FNP荧光纳米探针对不同肿瘤细胞孵育3h后激光共聚焦成像结果;
图2为实施例1中Octa-FNP荧光纳米探针对不同肿瘤细胞孵育3h后FACS流式定量结果;
图3为实施例2中FPLC系统纯化2个合成单位核心装载0.4μmol荧光染料DiR-BOA的dtDTNPNPC纳米颗粒[描述为:0.4μmol(DiR-BOA)dtDTNPNPC]时的双波段吸收-洗脱体积曲线图;
图4为实施例2中FPLC系统纯化2个合成单位的0.45μmol(DiR-BOA)dtDTNPNPC纳米颗粒时的双波段吸收-洗脱体积曲线图;
图5为实施例2中FPLC系统纯化2个合成单位0.5μmol(DiR-BOA)dtDTNPNPC纳米颗粒时的双波段吸收-洗脱体积曲线图;
图6为实施例2中FPLC系统纯化1个合成单位核心装载0.1μmol胆固醇酯的dtDTNPNPC纳米颗粒时的双波段吸收-洗脱体积曲线图;
图7为实施例2中动态激光光散射(DLS)系统测量dtDTNPNPC纳米颗粒的纳米粒径分布图;
图8为实施例2中圆二色谱仪对dtDTNPNPC纳米颗粒中多肽α螺旋结构的测定曲线;
图9为实施例3中(DiR-BOA)dtDTNPNPC纳米颗粒与5-8F-mRFP和肺癌细胞LLC分别孵育1h后的激光共聚焦成像结果;
图10为实施例3中(DiR-BOA)dtDTNPNPC纳米颗粒与鼻咽癌5-8F细胞孵育1h后流式细胞仪检测的直方图;
图11为实施例3中(DiR-BOA)dtDTNPNPC纳米颗粒与鼻咽癌5-8F细胞孵育1h后,细胞摄取量的荧光定量结果。
图12为实施例3中(DiR-BOA)dtDTNPNPC纳米颗粒与鼻咽癌5-8F细胞孵育1h后,用Annexin V-FITC/PI凋亡试剂鉴定细胞的死亡方式的激光共聚焦成像结果;
图13为实施例3中(DiR-BOA)dtDTNPNPC纳米颗粒与鼻咽癌5-8F肿瘤孵育1h后,用流式细胞仪和Annexin V-FITC/PI凋亡试剂定量检测细胞的死亡数量和鉴定死亡方式的结果;
图14为实施例4中尾静脉注射2.5nmol(DiR-BOA)dtDTNPNPC纳米颗粒后,分别于3h、6h、12h、24h、48h、72h和96h后进行整体荧光成像的结果;
图15为实施例4中尾静脉注射2.5nmol(DiR-BOA)dtDTNPNPC纳米颗粒24h后各脏器的整体荧光成像结果;
图16为实施例5中在裸鼠皮下接种5-8F或LLC肿瘤细胞,第三天后隔天尾静脉注射2.5nmol(DiR-BOA)dtDTNPNPC纳米颗粒或PBS直至14天,肿瘤体积变化的曲线图;
图17为实施例5中在裸鼠皮下接种5-8F或LLC肿瘤细胞,第三天后隔天尾静脉注射2.5nmol(DiR-BOA)dtDTNPNPC纳米颗粒或PBS直至14天,实验组与对照组荷瘤裸鼠体重变化的曲线图。
图18为实施例7中鼻咽癌5-8F细胞与装载有姜黄素(curcumin)的dtDTNPNPC,游离姜黄素孵育1h后的细胞激光共聚焦成像结果。
具体实施方式
实施例1
本实施实例中我们使用前期工作中发明的一种具有多价效应和纳米尺寸效应的多肽荧光探针的构建方法,制备了基于四聚体远红荧光蛋白的多肽八价纳米荧光探针。为了对多肽LTVSPWYLTVSPWY的肿瘤靶向性进行筛选与鉴定,我们利用该探针对不同类型的肿瘤细胞系进行检验与筛选。结果如图1所示,多肽LTVSPWYLTVSPWY不仅对鼻咽癌细胞有很好的靶向性,而且能有效地诱导肿瘤细胞的死亡。图2为Octa-FNP荧光纳米探针对不同肿瘤细胞孵育3h后FACS流式定量结果,可以很明显看到,相对应肝癌和宫颈癌等很多癌细胞,基于LTVSPWYLTVSPWY多肽的八价纳米荧光探针更容易被鼻咽癌(如5-8F细胞、SUNE-1细胞和HONE-1细胞等)摄取。
实施例2
本实施例中,我们将具有鼻咽癌特异性靶向与治疗功能的两种多肽LTVSPWYLTVSPWY和FAEKFKEAVKDYFAKFWD通过GSG序列相连,形成一条具有协同靶向与治疗鼻咽癌功能的新型多肽(简称为dtTPNPC,a dual-targeted therapeutic peptide for Nasopharyngeal carcinoma)。其完整氨基酸序列为序列表中SEQ ID NO.1所述。
利用dtTPNPC制备的具有协同靶向诊疗鼻咽癌功能的纳米颗粒(简称 dtDTNPNPC,a dual-targeted diagnostic and therapeutic nanoparticle for Nasopharyngeal carcinoma),其步骤为:
1)将3μmol DMPC
(1,2-dimyristoyl-sn-glycero-3-phosphocholine)、0.225μmolDiR-BOA(或0.1μmol Cholesteryl oleate,简称C.O)的氯仿溶液在玻璃试管中充分混合,并用封口膜将试管口封死;
2)在稳定的氮气流中将试管内的氯仿吹干,使步骤1)中的混合物能够在试管底部形成一层薄膜;
3)将试管放入真空干燥器中真空干燥1h;
4)向试管中加入1ml的磷酸缓冲液,利用涡旋震荡仪稍稍振荡;
5)将试管在48°C水浴中超声30-60min,以溶液变澄清为准;
6)使用注射器向密封的试管中加入含有0.36μmol dtTPNPC多肽的PBS溶液,混匀后密封,4°C放置过夜;
7)次日,使用FPLC系统纯化,收集富含dtDTNPNPC纳米颗粒的溶液,并浓缩备用;
为了研究dtDTNPNPC纳米颗粒的肿瘤特异靶向能力,选择核心装载荧光染料DiR-BOA(一种经过胆固醇酯修饰的近红外荧光染料,激发和发射波长分别为748nm和780nm),使得纳米颗粒同时具有协同靶向诊断与治疗鼻咽癌的功能。我们通过调整荧光染料DiR-BOA与多肽和磷脂之间的配比,获得了合适粒径并有一定装载量的dtDTNPNPC纳米颗粒。FPLC纯化结果如图3至图4所示。图3为FPLC系统纯化2个合成单位0.4μmol(DiR-BOA)dtDTNPNPC纳米颗粒时的双波段吸收-洗脱体积曲线图,此合成比例在118min左右有非常多游离的多肽,并且荧光染料DiR-BOA的吸收峰值非常低,表明装载荧光染料DiR-BOA的效率非常低。将2个纳米颗粒合成单位核心装载的荧光染料DiR-BOA摩尔量调整为0.45μmol时,得到结果如图4所示。此合成比例,得到的纳米颗粒大部分都在55.52min 出峰,尽管在42.56min有一个极小的峰,但是相比较最佳纳米颗粒出峰的积分面积来说此比例是非常小的,而且几乎没有游离多肽。如果将2个纳米颗粒合成单位核心装载的荧光染料DiR-BOA量调整为0.5μmol时,如图5所示,纳米颗粒最佳出峰时间由原来的55.52min提前到50.08min,原来在42.56min时出小峰也变为在41.60min时出大峰了,且在118min时又出现了非常多的游离多肽。因此,此配比下所合成的纳米颗粒效率大大降低。由此,合成具有合适粒径的(DiR-BOA)dtDTNPNPC纳米颗粒,其各组分最佳配比为:6μmol DMPC、0.45μmol DiR-BOA,0.72μmol dtTPNPC多肽。
为了研究多肽协同靶向治疗鼻咽癌的功能,使用胆固醇酯替代近红外荧光染料DiR-BOA同样可以得到合适粒径的纳米颗粒。FPLC纯化结果如图6,得到的纳米颗粒出峰时间为59.60min,118min时仅有很少的游离多肽,这说明上述优化配比是适合胆固醇酯的。其原料配比为:3μmolDMPC、0.1μmol C.O、0.36μmol dtTPNPC多肽。
使用动态激光光散射(DLS)系统测量上述纯化的dtDTNPNPC纳米颗粒的粒径,结果如图7所示,平均粒径为14.60±1.64nm,且粒径均一、单分散性好。图8为圆二色谱仪对dtDTNPNPC纳米颗粒中多肽α螺旋结构的测定,结果表明合成的dtDTNPNPC纳米颗粒具有典型的α螺旋结构。
实施例3
实施例2中制备核心装载荧光染料DiR-BOA的dtDTNPNPC纳米颗粒,其肿瘤细胞的靶向性验证结果如图9所示。2μmol(DiR-BOA)dtDTNPNPC纳米颗粒与鼻咽癌细胞5-8F-mRFP和肺癌细胞LLC孵育1h后进行激光共聚焦成像。成像结果显示,(DiR-BOA)dtDTNPNPC纳米颗粒很容易被5-8F-mRFP细胞摄取,却不能被LLC细胞摄取,说明(DiR-BOA)dtDTNPNPC纳米颗粒具有鼻咽癌细胞的选择性靶向能力。为了定量测定鼻咽癌细胞摄 取(DiR-BOA)dtDTNPNPC纳米颗粒的能力,含8μmol多肽的(DiR-BOA)-dtDTNPNPC纳米颗粒与5-8F细胞孵育1h后,进行流式细胞仪检测。如图10和图11结果所示,相比对照组来说,(DiR-BOA)dtDTNPNPC纳米颗粒孵育的鼻咽癌5-8F细胞,其荧光强度大大提高,是空白对照组的~120倍。
为了研究dtDTNPNPC纳米颗粒是诱导鼻咽癌5-8F细胞凋亡还是坏死,2μmol(DiR-BOA)dtDTNPNPC纳米颗粒与鼻咽癌5-8F细胞孵育1h后,再用Annexin V-FITC/PI试剂定量检测细胞的FITC/PI荧光信号。图12为激光共聚焦成像检测DiR-BOA、FITC和PI三种荧光信号的结果。DiR通道呈示出很强的荧光信号;同时,PI通道部分细胞也表现出强PI信号,标志着部分细胞的死亡;而FITC通道的信号荧光较弱,由此初步判断(DiR-BOA)dtDTNPNPC纳米颗粒诱导的是鼻咽癌5-8F细胞坏死。使用流式细胞仪进一步定量检测(DiR-BOA)dtDTNPNPC纳米颗粒作用的细胞在FITC和PI通道的荧光信号强度。图13为含8μmol多肽的(DiR-BOA)-dtDTNPNPC纳米颗粒与鼻咽癌5-8F细胞孵育1h,然后用Annexin V-FITC/PI试剂进行复染,最后通过流式细胞仪检测FITC(FL1)/PI(FL3)通道的细胞荧光强度来判定凋亡或坏死的细胞数量。相对于对照组(DiR-BOA)-dtDTNPNPC纳米颗粒孵育过的肿瘤细胞,FL1与FL3通道都有很强的信号,表明(DiR-BOA)dtDTNPNPC纳米颗粒主要是通过坏死机制来杀死鼻咽癌5-8F细胞的。
实施例4
实施例2中制备的(DiR-BOA)dtDTNPNPC纳米颗粒在体靶向性评价。
将1×106个5-8F细胞接种到裸鼠皮下构建鼻咽癌荷瘤裸鼠模型。当5-8F肿瘤体积达到0.5cm3时,对荷瘤裸鼠进行整体荧光成像,一般设定4个曝光时间点。然后尾静脉注射2.5nmol(DiR-BOA)dtDTNPNPC纳米颗粒。尾静脉注射后的3h、6h、12h、24h、48h、72h和96h进行整体荧 光成像,选择的曝光时间与尾静脉注射之前的相同。整体荧光成像系统使用的是氙灯光源,716/40nm的激发滤光片,接收滤光片为800FS40-25带通滤光片。为了获得更好的信噪比,使用685/40nm激发滤光片以采集来源于组织的自发荧光,并在后续的图像处理中扣除自发荧光对荧光信号的干扰。如图14所示,(DiR-BOA)dtDTNPNPC纳米颗粒在尾静脉注射24h时就能有效地蓄积于5-8F肿瘤,48h时5-8F肿瘤处的荧光信号最强,而在72h后5-8F肿瘤与正常组织之间具有最佳的信噪比。活体动态荧光成像结果充分证实了dtDTNPNPC纳米颗粒的肿瘤靶向标记能力。图15为图14中所示荷瘤鼠在尾静脉注射(DiR-BOA)dtDTNPNPC纳米颗粒96h后各脏器的整体荧光成像结果,进一步显示,(DiR-BOA)dtDTNPNPC纳米颗粒在肿瘤部位的靶向蓄积能力,仅在肝脏和脾脏部位有一定程度的富集。
实施例5
实施例2中制备的dtDTNPNPC纳米颗粒对鼻咽癌肿瘤治疗效果的在体评价。
构建鼻咽癌5-8F和肺癌LLC的裸鼠皮下模型。LLC肿瘤作为dtDTNPNPC纳米颗粒靶向的阴性对照组。消化5-8F和LLC细胞,使用灭菌的PBS漂洗两次后进行细胞计数,裸鼠接种5-8F细胞的数目为1×106个/只,接种后的荷瘤裸鼠随机共分为PBS对照组和dtDTNPNPC纳米颗粒5-8F肿瘤治疗组;LLC肿瘤对照组的裸鼠皮下接种LLC细胞2×106个/只。这三组荷瘤裸鼠每组的数量为5只。在肿瘤细胞皮下接种后第3天,即开始尾静脉注射dtDTNPNPC进行治疗,给药频率为隔天尾静脉注射一次。
PBS组为尾静脉注射等体积的无菌PBS,即注射量为0.25ml/只。
5-8F肿瘤治疗组和LLC肿瘤治疗对照组的尾静脉注射剂量为含10nmol多肽的dtDTNPNPC纳米颗粒。
皮下接种肿瘤细胞的裸鼠,在第3天和第4天时肿瘤的体积都为零, 第五天时肿瘤才开始长出来。肿瘤体积的计算公式为V=0.5×L×H×H。
如图16所示,经过3轮的dtDTNPNPC给药后,5-8F肿瘤治疗组与PBS对照组相比,已表现出明显的肿瘤生长被抑制的现象。经过5轮的dtDTNPNPC给药后,5-8F肿瘤的生长依然处于被抑制状态,而LLC肿瘤的体积已明显增大。5-8F肿瘤治疗组与PBS对照组和LLC肿瘤对照组之间具有显著性的差异。在荷瘤裸鼠的体重变化方面,经过6轮治疗,5-8F肿瘤治疗组与PBS对照组和LLC肿瘤对照组之间无明显的差异(如图17所示),表明dtDTNPNPC纳米颗粒对荷瘤裸鼠本身没有明显的毒副作用。
实施例6
将实施例2中制备dtDTNPNPC所用的胆固醇油酸酯,部分替换为脂溶性药物紫杉醇(PTX-OL)。利用磷脂、dtTPNPC多肽与紫杉醇进行混合,形成(PTX-OL)dtDTNPNPC纳米颗粒,可实现鼻咽癌的协同靶向联合治疗的效果。
实施例7
将实施例2中制备dtDTNPNPC所用的胆固醇油酸酯,部分替换为脂溶性药物姜黄素(Curcumin)。利用磷脂、dtTPNPC多肽与姜黄素进行混合形成(Curcumin)dtDTNPNPC纳米颗粒,对鼻咽癌细胞具有很好的杀伤效果。如图18所示,含2μmol姜黄素的游离姜黄素和(Curcumin)dtDTNPNPC纳米颗粒分别与5-8F-mRFP细胞孵育1h后进行共聚焦荧光成像,与游离姜黄素相比,(Curcumin)dtDTNPNPC更容易被5-8F-mRFP摄取,而且有更好的杀伤作用。
SWQMENCE LISTINE
<110> 华中科技大学
<120>一种具有协同靶向诊疗鼻咽癌功能的多肽和携带此多肽的纳米颗粒及其应用
<160> 1
<210> 1
<211> 35
<212> PRT
<213>人工序列
<400> 1
FAEKFKEAVKDYFAKFWDGSGLTVSPWYLTVSPWY 35
Claims (7)
1.一种具有协同靶向治疗鼻咽癌功能的多肽,其特征在于,所述多肽是由具有靶向治疗鼻咽癌作用的多肽、连接序列肽以及具有α螺旋结构的鼻咽癌靶向治疗多肽以共价键的形式串连而成,所述具有协同靶向治疗鼻咽癌功能的多肽的氨基酸序列为
FAEKFKEAVKDYFAKFWDGSGLTVSPWYLTVSPWY。
2.一种具有协同靶向诊疗鼻咽癌功能的纳米颗粒,其特征在于,所述纳米颗粒由权利要求1所述的具有协同靶向治疗鼻咽癌功能的多肽、磷脂、胆固醇脂和装载物组成。
3.根据权利要求2所述的具有协同靶向诊疗鼻咽癌功能的纳米颗粒,其特征在于,所述装载物为成像对比剂、药物分子或者两者的结合。
4.根据权利要求3所述的具有协同靶向诊疗鼻咽癌功能的纳米颗粒,其特征在于,所述成像对比剂为胆固醇脂修饰的荧光染料分子。
5.根据权利要求4所述的具有协同靶向诊疗鼻咽癌功能的纳米颗粒,其特征在于,所述胆固醇脂修饰的荧光染料分子为DiR-BOA或Fluo-BOA。
6.根据权利要求3所述的具有协同靶向诊疗鼻咽癌功能的纳米颗粒,其特征在于,所述药物分子为紫杉醇、姜黄素。
7.根据权利要求2所述的具有协同靶向诊疗鼻咽癌功能的纳米颗粒,其特征在于,所述磷脂选择DMPC(1,2-dimyristoyl-sn-glycero-3-phosphocholine)。
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Title |
---|
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Haiming Luo等."Tetrameric far-red fluorescent protein as a scaffold to assemble an octavalent peptide nanoprobe for enhanced tumor targeting and intracellular uptake in vivo".《The FASEB Journal》.2011,第25卷第1865-1873页. |
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