CN110237268B - 一种载有阿霉素的双响应脂质体微泡复合物的制备方法 - Google Patents
一种载有阿霉素的双响应脂质体微泡复合物的制备方法 Download PDFInfo
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Abstract
本发明涉及一种载有阿霉素的双响应脂质体微泡复合物的制备方法，该法由以下步骤组成：(1)将DSPE‑PEG2000‑NHS与cRGD反应得到DSPE‑PEG2000‑cRGD；(2)将DPPC、MSPC、DSPE‑PEG2000‑cRGD和DSPE‑PEG2000‑Biotin水化反应，得到空载携cRGD肽的靶向温敏脂质体纳米粒；(3)用靶向温敏脂质体纳米粒携带阿霉素得到携cRGD肽靶向阿霉素温敏脂质体；(4)将IR780溶液加入到生物素化脂质微泡中；(5)先取所述载IR780脂质微泡加入亲和素孵育，再加入携cRGD肽靶向阿霉素温敏脂质体即得所述的双响应脂质体微泡复合物。本方法所得到的复合物既可减少阿霉素在循环中的损失，又可使阿霉素集中分布于肿瘤中心部位。
Description
技术领域
本发明涉及以所用的非有效成分为特征的医用配制品，具体涉及载有阿霉素的抗肿瘤控释药物。
技术背景
阿霉素是一种蒽环类抗肿瘤抗生素，可阻止肿瘤细胞的生长，抗瘤谱较广，对多种肿瘤均有作用，属周期非特异性药物，对各种生长周期的肿瘤细胞都有杀灭作用。阿霉素对急性淋巴细胞白血病、急性髓细胞性白血病、肾母细胞瘤、神经母细胞瘤，软组织和骨肉瘤、乳腺癌、卵巢癌、膀胱癌，甲状腺癌，胃癌，恶性淋巴瘤和支气管癌都有疗效。目前临床给药多为静脉滴注，但阿霉素不能透过血脑屏障，且静注后该药迅速分布全身，有强烈的毒副作用，主要表现在：心脏毒性，轻者表现为心律失常，重者出现进行性心肌病变而发生充血性心力衰竭；致白细胞和血小板减少，骨髓抑制；毛发脱落；消化道反应，恶心、食欲减退；药物溢出血管外可引起组织溃疡及坏死。这些毒副作用限制了阿霉素在临床化疗的广泛应用，尽管用药剂量很大，能达到病灶部位发挥疗效的比例却很低。为降低其毒性、提高疗效，阿霉素新剂型的研究成为亟待解决的问题。
如何将阿霉素递送至深部肿瘤组织是提高实体肿瘤临床疗效的重要问题。含溶血磷脂温敏脂质体是一种快速释药型阿霉素温敏脂质体制剂，其在预热(41-43℃)的肿瘤血管内可以快速释放大量阿霉素，促使血管内的阿霉素顺浓度梯度弥散进入肿瘤间质，提高肿瘤的药物摄取，可以有效提高阿霉素的抑瘤效果。但是体循环中的一些生物大分子(如血清蛋白)会与温敏脂质体上的溶血磷脂结合，破坏脂质体的稳定性，造成包裹药物的泄露，阻碍药物在肿瘤深部的递送。而以往此类温敏脂质体研究多集中于肿瘤血管内释药的应用，温敏脂质体在间质内释药的应用受到其有效循环时间短的限制一直未有突破。
超声微泡靶向破坏技术(UTMD)是一种具有发展潜力的药物/基因局部靶向递送方法。既往研究表明，微泡表面连接纳米药物形成复合物联合超声辐照可以提高药物递送效率，微泡破裂时产生的瞬态空化作用(微射流、喷射流、瞬间高压)可以使局部的血管内皮间隙增大，血管通透性升高。但以往研究鲜少关注UTMD技术在超声辐照后短时间内纳米药物在肿瘤间质蓄积效应。
发明内容
本发明所要解决的技术问题是提供一种载有阿霉素的双响应脂质体微泡复合物的制备方法，该方法所得到的复合物既可减少阿霉素在循环中的损失，又可使阿霉素集中分布于肿瘤中心部位。
本发明解决上述问题的技术案如下：
一种载有阿霉素的双响应脂质体微泡复合物的制备方法，该法由以下步骤组成：
(1)按DSPE-PEG2000-NHS︰cRGD＝1︰2的摩尔比取DSPE-PEG2000-NHS和cRGD溶于二甲基甲酰胺(DMF)中，加入DSPE-PEG2000-NHS和cRGD质量和0.2％的催化剂三乙胺，室温下搅拌反应4h，真空旋转蒸发去除溶剂及三乙胺后得到DSPE-PEG2000-cRGD；其中，所述的DSPE-PEG2000-NHS为分子量2000的二棕榈酰磷脂酰乙醇胺-聚乙二醇-琥珀酰亚胺酯，所述的cRGD为环状低聚肽；
(2)按DPPC︰MSPC︰DSPE-PEG2000-cRGD︰DSPE-PEG2000-Biotin＝82︰8︰8︰2的摩尔比取DPPC、MSPC、DSPE-PEG2000-cRGD和DSPE-PEG2000-Biotin溶于氯仿中，常温常压旋转混合均匀；然后，室温下抽真空，旋转蒸发挥去溶剂，并在容器底部形成一层白色磷脂薄膜，真空干燥，加入pH4.0的柠檬酸盐缓冲液水化处理，待磷脂水化完全后，用孔径为100nm滤膜的脂质体挤出器挤压，得到空载携cRGD肽的靶向温敏脂质体纳米粒；其中，所述的DPPC为二棕榈酰磷脂酰胆碱，所述的MSPC为溶血磷脂，所述的DSPE-PEG2000-Biotin为生物素化二棕榈酰磷脂酰乙醇胺-聚乙二醇；
(3)将所得到的靶向温敏脂质体纳米粒的pH值调至7.4，然后按阿霉素︰靶向温敏脂质体纳米粒＝1︰20的质量比加入阿霉素(DOX)水溶液，混匀，37℃水浴20min后，用G-50葡聚糖凝胶柱层析，得到携cRGD肽靶向阿霉素温敏脂质体；
(4)取IR-780加入二甲基亚砜(DMSO)配制成浓度为2mg/mL的IR780溶液，然后按IR780溶液︰生物素化脂质微泡＝1︰100的体积比将IR780溶液加入到生物素化脂质微泡中，混匀，4℃条件下低速离心，取上层载IR780脂质微泡；其中，所述的IR780为七甲川花菁染料；
(5)按携cRGD肽靶向阿霉素温敏脂质体︰亲和素(Avidin)︰载IR780脂质微泡＝5︰1︰5的体积比先取所述载IR780脂质微泡加入亲和素，混匀，冰上孵育30min，然后加入所述携cRGD肽靶向阿霉素温敏脂质体，轻柔混匀后4℃条件下孵育30min，洗涤，得到所述的双响应脂质体微泡复合物。
本方法得到的双响应脂质体微泡复合物较现有技术具有以下有益效果：
联合超声/激光辐照提高含溶血磷脂的温敏脂质体在肿瘤血管外间质的递送效率及抗肿瘤效果。携cRGD肽靶向的阿霉素温敏脂质体与载IR780的微泡通过生物素亲和素桥连接成复合物，进入循环的复合物通过cRGD肽靶向肿瘤新生血管，富集于肿瘤区域，在局部超声作用下，复合物破碎为小粒径纳米药物，同时肿瘤血管屏障打开，粒径均一的靶向纳米药物可以通过血管内皮间隙进入肿瘤内部，通过cRGD肽与肿瘤细胞上的受体结合，特异性蓄积于肿瘤血管外间质内。同时，肿瘤区域累积的IR780碘化物在激光辐照下引起局部温度升高，达到温敏脂质体释药温度(约42℃)时，阿霉素从脂质体中快速释放，增强化疗药物的生物利用度及抗肿瘤作用。本方法得到的双响应脂质体微泡复合物还具有超声造影成像及荧光成像功能。
附图说明
图1为本方法得到的双响应脂质体微泡复合物的紫外光谱分析图。
图2为本方法得到的双响应脂质体微泡复合物的效果图，其中，A图为所述复合物激光共聚焦的照片，B图为所述复合物的粒径分布曲线图。
图3为本方法得到的双响应脂质体微泡复合物经超声处理后产物的效果图，其中，A图为该产物的透射电镜图，B图为该产物的粒径分布曲线图。
图4为本方法得到的双响应脂质体微泡复合物体外细胞黏附实验及超声靶向成像效果图，其中，A图为光学显微镜下观察非靶向微泡与本方法得到的双响应脂质体微泡复合物(简称复合物)对乳腺癌MCF-7细胞的靶向黏附的显微照片，B图为对MCF-7细胞黏附的微泡数量统计结果的条形图，图中***表示本方法得到的双响应脂质体微泡复合物(简称复合物)与非靶向微泡比，p<0.001；C图为荷瘤裸鼠体内的超声造影声强度统计结果的条形图，图中***表示本方法得到的双响应脂质体微泡复合物(简称复合物)与非靶向微泡比，p<0.001。
图5为本方法得到的双响应脂质体微泡复合物(简称复合物)、生理盐水、携cRGD肽靶向阿霉素温敏脂质体(简称靶向温敏脂质体)和载IR780微泡在荷瘤裸鼠体内抑瘤实验结果的折线图。
图6为本方法得到的双响应脂质体微泡复合物瘤内递送效率的效果图，其中，A图为携cRGD肽靶向阿霉素温敏脂质体(简称靶向温敏脂质体)联合热疗(下图)和本方法得到的双响应脂质体微泡复合物(简称复合物)联合超声及激光辐射(上图)的肿瘤内阿霉素荧光显微照片，B图则为平均荧光强度统计结果的条形图，图中***表示本方法得到的双响应脂质体微泡复合物(简称复合物)与携cRGD肽靶向阿霉素温敏脂质体(简称靶向温敏脂质体)联合热疗比，p<0.001。
具体实施式
实施例1：
、双响应脂质体微泡复合物的制备
(1)称取1×10-5molDSPE-PEG2000-NHS和2×10-5mol的cRGD溶于1mL二甲基甲酰胺(DMF)中，加入0.065mg的三乙胺，室温下搅拌反应4h，真空旋转蒸发去除溶剂及三乙胺后得到DSPE-PEG2000-cRGD。
(2)取1.025×10-4molDPPC、1×10-5molMSPC、1×10-5molDSPE-PEG2000-cRGD和2.5×10-6molDSPE-PEG2000-Biotin溶于1.5mL氯仿中，常温常压旋转混合均匀；真空旋转蒸发去除溶剂，形成一层白色磷脂薄膜，真空干燥，加入pH4.0的柠檬酸盐缓冲液水化处理，待磷脂水化完全后，用孔径为100nm滤膜的脂质体挤出器挤压，得到空载携cRGD肽靶向温敏脂质体纳米粒。
(3)将所得到的靶向温敏脂质体纳米粒的pH值调至7.4，加入600μL阿霉素水溶液(5mg/L)与1.5mL空载靶向温敏脂质体纳米粒溶液(含60mg空载靶向温敏脂质体纳米粒)混匀，37℃水浴20min后，用G-50葡聚糖凝胶柱层析，得到携cRGD肽靶向阿霉素温敏脂质体；其中所述的阿霉素溶液为阿霉素水溶液。
(4)取2mg IR-780加入1mL二甲基亚砜(DMSO)配制成IR780溶液，然后取20μLIR780溶液加入到2mL生物素化脂质微泡中，混匀，4℃条件下400×g离心3min，取上层载IR780脂质微泡；其中，所述的IR780为七甲川花菁染料；
(5)取1mL浓度为109/ml的载IR780脂质微泡和200μL浓度为0.3mg/ml的亲和素混匀，冰上孵育30min，然后加入所述1mL携cRGD肽靶向阿霉素温敏脂质体，轻柔混匀后4℃条件下孵育30min，洗涤，得到所述的双响应脂质体微泡复合物。
、双响应脂质体微泡复合物的鉴定：
将上述步骤(2)纯化后得到的空载携cRGD肽靶向温敏脂质体、步骤(3)得到的携cRGD肽靶向阿霉素温敏脂质体及游离阿霉素进行紫外光谱分析，游离阿霉素在波长480nm处有特征行紫外吸收峰；磷脂的紫外吸收峰在波长220-330nm处；携cRGD肽靶向阿霉素温敏脂质体的紫外光谱图具有阿霉素及磷脂的吸收峰(见图1)，说明阿霉素成功装载于携cRGD肽靶向阿霉素温敏脂质体中。
将本发明复合物用去离子水按比例稀释，使用动态光散射仪测量粒径大小；使用激光共聚焦显微镜TRITC通道观察阿霉素荧光的分布位置，确定复合物的形态。激光共聚焦显微镜观察可见复合物粒径大小较均匀，散在分布，无明显聚集现象，TRITC通道激光激发下，阿霉素发射的荧光信号(软件标记为绿色信号)集中出现在微泡外壳层(见图2)，表明带携cRGD肽靶向温敏脂质体成功连接于微泡上。本发明复合物经超声辐照处理1分钟后，破碎成形态较均一，平均粒径约60nm的纳米颗粒(见图3)。紫外分光光度法测定载阿霉素温敏脂质体及复合物载药量；温敏脂质体载药量约4.6％，复合物的载药量约20.3μg DOX/108MBs；10.5μg IR780/108MBs。
实施例2：(体内外肿瘤靶向能力检测)
一、样品及对照品
样品为实施例1的双响应脂质体微泡复合物；对照品为非靶向微泡，其制备方法如下，取20μL二甲基亚砜加入到2mL生物素化脂质微泡中，混匀，4℃条件下400×g离心3min，取上层非靶向微泡。
二、体外肿瘤细胞黏附实验
通过比较非靶向微泡与本发明复合物对人乳腺癌MCF-7细胞黏附微泡数量的差异，验证双响应脂质体微泡复合物的肿瘤靶向性。光学显微镜下观察结果发现非靶向微泡组细胞表面没有明显微泡附着现象，而复合物组在细胞的表面可见大量复合物黏附(见图4中A图)。对MCF-7细胞黏附的微泡数量进行统计(见图4中B图)，发现复合物组每细胞平均附着微泡数与非靶向微泡组比较具有显著差异(p<0.001)。说明复合物上的cRGD肽配体可以和肿瘤细胞表面的整合素受体结合，且这种结合是特异性且牢固的，复合物具有肿瘤靶向性。
三、荷瘤裸鼠体内超声靶向成像功能检测
通过比较普通非靶向微泡与本复合物的超声造影效果及肿瘤靶向能力，结果显示，爆破前后复合物组肿瘤区域的声强度显著高于非靶向微泡组(见图4中C图)，差异具有统计学意义(p<0.001)，提示本发明复合物靶向结合于肿瘤组织的微泡量多于非靶向微泡，显示出较强的肿瘤靶向性。
实施例3(体内抑瘤效果检测)
一、样品及对照品
样品为实施例1的双响应脂质体微泡复合物，对照品1为生理盐水；对照品2为实施例1中步骤(1)-(3)得到的携cRGD肽靶向阿霉素温敏脂质体，简称为靶向温敏脂质体；对照品3为实施例1中步骤(4)得到的载IR780微泡。
二、荷瘤动物模型建立
人乳腺癌MCF-7肿瘤组织块无菌条件下解剖分离成2mm×2mm×2mm大小的瘤块，再把瘤组织块移植于裸鼠右侧下背部。
三、实验分组及处理方法
1、实验分组：
(I)生理盐水组；(II)靶向温敏脂质体联合热疗组；(III)载IR780微泡联合超声辐照组；(IV)复合物联合超声及激光辐照组
2、超声辐照方法
药物经尾静脉注射后，在荷瘤裸鼠肿瘤部位涂布适量耦合剂，消除超声治疗仪探头与裸鼠皮肤之间的空气，立即将探头固定于裸鼠肿瘤上，持续超声辐照1分钟。
3、激光辐照方法
药物经尾静脉注射后，使用1％戊巴比妥钠对荷瘤裸鼠进行麻醉，立即将激光探头固定于裸鼠肿瘤部位上方3cm处，持续激光辐照5分钟。
4、温和热疗方法
热疗组在尾静脉注射靶向温敏脂质体后，荷瘤裸鼠给予麻醉处理，将肿瘤部位暴露于43℃温水中进行热疗处理1h，非肿瘤部位使用隔热材料进行保护，热疗过程中注意监测裸鼠体温及心跳呼吸变化。
四、抑瘤实验
各实验组给药量均含等量阿霉素或IR780(按裸鼠体重1.23mg/kg(阿霉素)，0.3mg/kg(IR780))或每只裸鼠200μL生理盐水，每5天予以一次相应处理，共治疗三次。治疗过程中，每3天测量一次肿瘤体积。统计及分析各处理组对裸鼠皮下移植瘤的抑制效果。
结果发现复合物联合超声及激光辐照组的抑瘤效果最佳，联合治疗后肿瘤体积缩小，肿瘤生长受到抑制，协同抗肿瘤效应明显优于靶向温敏脂质体联合热疗组及载IR780微泡联合超声辐照组。结果如图5所示。
实施例4(瘤内药物递送效果检测)
一、样品及对照品
样品为实施例1的双响应脂质体微泡复合物，对照品为实施例1步骤(1)-(3)中得到的携cRGD肽靶向阿霉素温敏脂质体，简称为靶向温敏脂质体。
二、荷瘤动物模型建立
荷瘤动物模型建立方法同实施例3。
三、实验分组及处理方法
1、实验分组：
(I)靶向温敏脂质体联合热疗组；(II)复合物联合超声及激光辐照组
2、实验方法
荷瘤裸鼠经尾静脉注射含相同阿霉素剂量的靶向温敏脂质体或复合物(阿霉素/裸鼠体重：3mg/Kg)后，分别进行温和热疗和超声及激光处理(方法同实施例3)，药物注射1小时后处死裸鼠并完整分离肿瘤组织，肿瘤组织切片进行DAPI和CD31染色，使用全自动数字切片扫描机检测肿瘤组织内的阿霉素荧光水平。
结果发现复合物联合超声及激光辐照组肿瘤组织内阿霉素平均荧光强度高于靶向温敏脂质体联合热疗组，且复合物组阿霉素多分布于肿瘤中心部位，差异具有统计学意义(p<0.001)。结果如图6所示。
Claims (1)
1.一种载有阿霉素的双响应脂质体微泡复合物的制备方法，该法由以下步骤组成：
(1)按DSPE-PEG2000-NHS︰cRGD＝1︰2的摩尔比取DSPE-PEG2000-NHS和cRGD溶于二甲基甲酰胺中，加入DSPE-PEG2000-NHS和cRGD和质量 0.2％的催化剂三乙胺，室温下搅拌反应4h，真空旋转蒸发去除溶剂及三乙胺后得到DSPE-PEG2000-cRGD；其中，所述的DSPE-PEG2000-NHS为分子量2000的二棕榈酰磷脂酰乙醇胺-聚乙二醇-琥珀酰亚胺酯，所述的cRGD为环状低聚肽；
(2)按DPPC︰MSPC︰DSPE-PEG2000-cRGD︰DSPE-PEG2000-Biotin＝82︰8︰8︰2的摩尔比取DPPC、MSPC、DSPE-PEG2000-cRGD和DSPE-PEG2000-Biotin溶于氯仿中，常温常压旋转混合均匀；然后，室温下抽真空，旋转蒸发挥去溶剂，并在容器底部形成一层白色磷脂薄膜，真空干燥，加入pH4.0的柠檬酸盐缓冲液水化处理，待磷脂水化完全后，用孔径为100nm滤膜的脂质体挤出器挤压，得到空载携cRGD肽的靶向温敏脂质体纳米粒；其中，所述的DPPC为二棕榈酰磷脂酰胆碱，所述的MSPC为溶血磷脂，所述的DSPE-PEG2000-Biotin为生物素化二棕榈酰磷脂酰乙醇胺-聚乙二醇；
(3)将所得到的靶向温敏脂质体纳米粒的pH值调至7.4，然后按阿霉素︰靶向温敏脂质体纳米粒＝1︰20的质量比加入阿霉素水溶液，混匀，37℃水浴20min后，用G-50葡聚糖凝胶柱层析，得到携cRGD肽靶向阿霉素温敏脂质体；
(4)取IR-780加入二甲基亚砜配制成浓度为2mg/mL的IR780溶液，然后按IR780溶液︰生物素化脂质微泡＝1︰100的体积比将IR780溶液加入到生物素化脂质微泡中，混匀，4℃条件下低速离心，取上层载IR780脂质微泡；其中，所述的IR780为七甲川花菁染料；
(5)按携cRGD肽靶向阿霉素温敏脂质体︰亲和素︰载IR780脂质微泡＝5︰1︰5的体积比先取所述载IR780脂质微泡加入亲和素，混匀，冰上孵育30min，然后加入所述携cRGD肽靶向阿霉素温敏脂质体，轻柔混匀后4℃条件下孵育30min，洗涤，得到所述的双响应脂质体微泡复合物。
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