CN108078914B - 一种可注射温敏磁性超分子凝胶的制备和应用方法 - Google Patents
一种可注射温敏磁性超分子凝胶的制备和应用方法 Download PDFInfo
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Abstract
本发明公开一种可注射温敏磁性超分子凝胶的制备和应用方法,其制备方法为:步骤1、将α‑环糊精和水溶性抗肿瘤药物加入超纯水中,涡旋混匀,超声加热使其完全溶解,形成溶液一;步骤2、用二硬脂酰磷脂酰乙酰胺‑甲氧基聚乙二醇DSPE‑mPEG2000对高温热分解法制备的油溶性四氧化三铁纳米颗粒进行水相转移,同时负载脂溶性抗肿瘤药物,得到溶液二;步骤3、将溶液一和溶液二混合,搅拌均匀,室温静置,得到磁性超分子凝胶。该凝胶具有剪切变稀可注射、相变温度可调的性质,其分级结构可负载亲疏水双相抗肿瘤药物。凝胶长时间瘤区均匀分级释放药物外加相变适形过程中磁性纳米颗粒介导的热引起的细胞热疗和热促局部高浓度药物释放三方面可清除残余肿瘤。
Description
技术领域
本发明属于生物与医学纳米材料及技术领域,具体涉及一种可注射温敏磁性超分子凝胶的制备方法及其应用。
背景技术
超分子凝胶作为一种重要的新型智能凝胶材料,在药物传递、组织工程、生物传感等方面具有广阔的应用前景。超分子凝胶是有机小分子在特定的溶剂中通过分子间氢键相互作用、π–π堆积作用、静电相互作用、范德华相互作用、偶极–偶极相互作用、配位相互作用等非共价键作用力自组装成的三维网络状结构。超分子凝胶可依据多种方式进行分类,按照所固定的溶剂不同可分为有机凝胶(organogel)、水凝胶(hydrogel)与离子液体凝胶(ionogel)。相比于传统的共价键高分子凝胶,超分子凝胶是通过非共价相互作用将低分子量胶凝剂分子自组装形成具有各种纳米结构的三维网络,使溶剂固定化而失去流动性。超分子水凝胶具有较高的载药量,同时可避免化学交联反应破坏被包封药物的分子结构和细胞活性,适合包载多肽、蛋白质等物质。超分子凝胶可对外界刺激做出一定的响应,如对温度、pH、离子强度、磁场、光照、氧化还原等,基于对剪切力的刺激响应性质,超分子水凝胶可以以注射植入的方式在体内原位形成,降低植入过程对机体造成的损伤,有效避免了二次手术对机体的损伤。
基于主客体相互作用形成的包合物是超分子凝胶的重要研究内容。这类包合物由主体分子和相应的客体分子通过超分子识别自组装形成。环糊精(Cyclodextrin,CD)是一系列由D-吡喃葡萄糖单元通过α-1,4糖苷键首尾相连形成的水溶性大环低聚糖。常见的α-、β-和γ-CD分别由6、7和8个葡萄糖单元构成。环糊精具有疏水性内腔和亲水性外壁,这一独特的两亲性结构使其常作为主体分子与其特定的客体分子通过疏水作用形成主客体包合物。Harada等首先报道了α-CD在水溶液中可与聚乙二醇(PEG)形成“分子项链”式结晶包合物。其包合的主要驱动力来自相邻CD之间的氢键作用、主-客体分子的立体空间适配及其疏水相互作用。多个CD穿过线性聚合物链形成的超分子包合物称为多聚准轮烷,以较大基团封端则得到多聚轮烷。由于其独特的超分子特性,此类包合物组装体在智能分子开关、药物释放载体设计等方面具有重要的理论与应用价值。
磁性纳米颗粒,作为一类具有特殊功能的纳米材料。除了纳米颗粒普遍拥有的物理化学性质,如小尺寸效应、表面效应等,它还有着独特的磁学特性(如超顺磁性)以及良好的生物相容性,是目前唯一可用于临床的无机纳米材料,在生物医学上的磁共振成像、肿瘤磁感应热疗、药物载体、细胞与生物分子分离及生物传感与检测等领域有着广泛的应用。基于磁性纳米材料的磁感应热疗是将磁性纳米材料定位于肿瘤部位,并将其放置于一定功率、频率的交变磁场(Alternating Current Magnetic Field,ACMF)中,通过一些特殊的物理效应,如聂耳布朗弛豫效应、磁滞效应等,可将ACMF能量转变为热能,从而提高肿瘤部位的温度,达到损伤或破坏肿瘤细胞的目的。这种新型的具有靶向、微创、低毒副作用和疗效明显等优势的肿瘤疗法引起了人们的极大关注。将磁性纳米颗粒通过包埋嫁接等方式引入到水凝胶中,即赋予了水凝胶磁性和在交变磁场下升温的能力,拓展了凝胶的性质和应用。
目前,对于早期肿瘤,手术切除是主流治疗方式,术后辅助治疗手段主要为全身性化疗和放疗,因化疗靶向到病灶的效率低加上放疗副作用明显,术后肿瘤复发及患者生活质量低下一直是肿瘤难治的重要因素。以乳腺癌为例,我国每年女性乳腺癌新发病数超过二十万,死亡超过六万。时至今日,其发病率在众多肿瘤中依然高居不下,且呈不断增长趋势。随着乳腺癌普查广泛推行,很多患者尤其是年轻患者被检查为早期乳腺癌时往往选择保乳术治疗。加上辅助治疗收效甚微,术后易复发转移是导致生存率低的主要原因之一。
因此,探索新型的肿瘤术后辅助治疗手段,对于清除术后残余病灶和防止恶性肿瘤复发至关重要。新型的辅助治疗手段不仅需要实现在术后病灶区域高浓度持续药物释放,还要求联合模式治疗,避免单一模式治疗中肿瘤产生耐受性,如热化疗协同作用清除残余等。
发明内容
技术问题:本发明的目的是提供一种可注射温敏磁性超分子凝胶的制备和应用方法,对于目前临床上实体瘤术后残留复发的问题,提供一种新型的术后辅助治疗手段,
以微创的方式在术后创面植入负载抗肿瘤药物的超分子凝胶,联合磁性纳米颗粒在
交变磁场下可产热杀伤肿瘤细胞的磁感应热疗,清楚肿瘤术后残余,防止复发,改
善患者术后生存质量,延长生存时间。
本发明的可注射温敏磁性超分子凝胶的制备方法包括:
步骤1、将α-环糊精和水溶性抗肿瘤药物加入超纯水中,涡旋混匀,超声加热使其完全溶解,形成溶液一;
步骤2、用二硬脂酰磷脂酰乙酰胺-甲氧基聚乙二醇DSPE-mPEG2000对高温热分解法制备的油溶性四氧化三铁纳米颗粒进行水相转移,同时负载脂溶性抗肿瘤药物,得到溶液二;
步骤3、将溶液一和溶液二混合,搅拌均匀,室温静置,得到磁性超分子凝胶。
其中,
在步骤1中,所述的α-环糊精的浓度为100~400mg/mL。
在步骤1中,所述的水溶性抗肿瘤药物的浓度为1~5mg/mL。
在步骤1中,所述的α-环糊精与水溶性抗肿瘤药物的质量比例为25:1~400:1。
在步骤2中,所述的DSPE-mPEG2000的用量为100~300mg/mL。
在步骤2中,所述的油溶性四氧化三铁纳米颗粒尺寸在10~50纳米之间,铁元素含量1~6mg/ml,其分散的溶剂为三氯甲烷。
在步骤2中,所述的脂溶性抗肿瘤药物用量为1~4mg/mL。
在步骤2中,所述的水相转移,其过程采用旋转蒸发法,油相溶剂为三氯甲烷,油水体积比为1:1~1:3,利用疏水相互作用将四氧化三铁纳米颗粒和脂溶性抗肿瘤药物包在DSPE-mPEG2000的脂溶性部分,水溶性PEG链端优异亲水性使得纳米颗粒在水溶液中稳定分散。
在步骤3中,所述的溶液一和溶液二混合,其混合的体积比例为2:1~1:1,搅拌均匀后,室温静置时间范围1s~30min。
本发明的可注射温敏磁性超分子凝胶在作为抗肿瘤药物或制备抗肿瘤药物中的应用。
所述的可注射温敏磁性超分子凝胶,在室温时,为剪切变稀可注射凝胶,当达到相
转变温度时,即可实现固液转变开始流动,并且这个过程是可逆的,反复多次不出现异常。
所述的可注射温敏磁性超分子凝胶通过注射器可微创地植入到肿瘤术后创面,施加交变磁场,凝胶中磁性纳米颗粒产热触发凝胶液化,液态适形填满术后创面的凹陷与边缘处,不留死角,液化过程中产生的热即可对肿瘤细胞产生热疗作用且促进药物释放;关闭交变磁场,凝胶重新恢复至胶状,药物持续释放,对术后残余病灶长时精准化疗。
有益效果:与现有技术相比,本发明具有如下有益效果
本发明中制备的四氧化三铁纳米颗粒形貌良好,尺寸均一,升温性能优良;DSPE-mPEG2000修饰后的氧化铁纳米颗粒外层为亲水的PEG链,内层包覆着脂溶性的抗肿瘤药物,当和溶有水溶性抗癌药的α-环糊精水溶液以一定比例混合时,PEG链会穿过α-环糊精空腔,形成包合物,继而溶液凝胶化,得到以四氧化三铁为交联点,负载亲疏水双药物的磁性超分子凝胶。磁性超分子凝胶具有温敏特性,在室温25度及体温37度时,为凝胶态且因剪切变稀效应可注射;当磁性纳米颗粒在交变磁场下产热,使磁性超分子凝胶温度升至45度时,凝胶中α-环糊精与PEG链形成的包合物结构被破坏,凝胶开始发生相变液化。当恢复到37度时,重新恢复原来凝胶状态。该特性使得磁性超分子凝胶可用于肿瘤术后清除残余防止复发的辅助治疗中,室温的可注射性确保凝胶可以以注射器注射的方式微创的在创面形成,且不会如磁流体般流走,交变磁场作用后,凝胶液化,液态适形术后残余病灶,完美贴合创面,不留缝隙与死角,撤去交变磁场,凝胶温度降至体温左右,即恢复原有凝胶滞留性能,长时精准释药,清除残余恶性肿瘤细胞,防止术后复发,提高生存小鼠质量,延长患者生存期。
附图说明
图1为磁性超分子凝胶机制及应用过程说明图。
图2a至图2b是四氧化三铁纳米颗粒的表征。其中,图2a为高温热分解法合成的有机相四氧化三铁纳米颗粒透射电镜图,图2b为DSPE-mPEG2000修饰后的四氧化三铁纳米颗粒透射电镜图。
图3a至图3b是磁性超分子凝胶的表征。其中,图3a为凝胶合成实物图,图3b为凝胶冷冻干燥后扫描电镜图。
图4a至图4d是磁性超分子凝胶清除肿瘤术后残余过程图。其中图4a为肿瘤手术切除及凝胶填充和液态适形过程图;图4b为药物释放曲线;图4c为15天后凝胶在小鼠病灶部位残留情况;图4d为凝胶在病灶部位不同时间点的滞留情况荧光观察图。图5是小鼠术后情况监测。
具体实施方式
本发明可注射温敏磁性超分子凝胶的制备方法的主要步骤是:将α-环糊精和水溶性抗肿瘤药物盐酸阿霉素加入超纯水中,涡旋混匀,超声加热使其完全溶解,形成溶液一;用二硬脂酰磷脂酰乙酰胺-甲氧基聚乙二醇(DSPE-mPEG2000)对高温热分解法制备的油溶性四氧化三铁纳米颗粒进行水相转移,同时负载脂溶性抗肿瘤药物紫杉醇和可观察凝胶被降解过程的脂溶性荧光分子Cy7,得到溶液二;将溶液一和溶液二以一定比例混合,搅拌均匀,室温静置,得到磁性超分子凝胶。
其中,α-环糊精的浓度为100~400mg/mL,水溶性抗肿瘤药物盐酸阿霉素的浓度为1~5mg/mL。DSPE-mPEG2000的用量为100~300mg/mL。油溶性四氧化三铁纳米颗粒尺寸在10~50纳米之间,铁元素含量1~6mg/ml,其分散的溶剂为三氯甲烷。脂溶性抗肿瘤药物紫杉醇用量为1~4mg/mL,脂溶性荧光分子Cy7的用量为100-800μg/mL。水相转移过程采用旋转蒸发法,油相溶剂为三氯甲烷,油水体积比为1:1~1:3,利用疏水相互作用将四氧化三铁纳米颗粒和脂溶性抗肿瘤药物和荧光分子包在DSPE-mPEG2000的油溶性部分,水溶性PEG链端优异亲水性使得纳米颗粒在水溶液中稳定分散。溶液一和溶液二以一定比例混合,搅拌均匀后,室温静置时间范围1s~30min。
图1中,磁性超分子凝胶在室温时,为凝胶态,在45度时环糊精和PEG链的包合作用被破坏,凝胶开始液化流动,且这个过程是可逆的,将其注射到术后残余病灶创面,并不能完美的匹配层次不齐的创口,施加交变磁场,纳米颗粒产热导致凝胶升温液化填满创面的凹陷处和边缘,撤去交变磁场,凝胶恢复其机械强度,停留在创面上精准长期释药。液化过程中产生的热可促进细胞凋亡,也可加速药物释放。以下结合实施例和附图来进一步解释本发明,但实施例并不对本发明做任何形式的限定。
实施例1
高温热分解法制备四氧化三铁纳米颗粒及其PEG修饰
在500毫升斜口三颈烧瓶中加入20mmol的乙酰丙酮铁以及反应溶剂二苄醚100mL,表面活性剂油酸60mmol,持续通入氮气以去除体系中的氧气并起到搅拌作用,同时冷凝回流。程序控温以3.3℃/min的加热速率加热反应体系到220℃成核温度,保持该温度1h,此阶段为磁性氧化铁纳米颗粒的成核阶段,该过程中溶液由棕红色转变为透亮的黑色。接着,仍以3.3℃/min的加热速率加热反应体系到290℃生长温度,于该温度下维持反应体系30min,结束反应。反应结束后,移去热源,待反应物自然冷却至室温后转移至烧杯中,加入无水乙醇,磁分离进行洗涤三次,充分去除溶液中残留的油酸、二苄醚和未反应完全的前驱物,最后将磁性氧化铁纳米颗粒定容于三氯甲烷中保存。利用DSPE-mPEG2000一段亲水一段疏水的特性对油溶性四氧化三铁纳米颗粒进行水相转移,选用方法为旋转蒸发法,原理为疏水相互作用。图2a为有机相氧化铁纳米颗粒透射电镜图,纳米颗粒平均尺寸为三十五纳米,通过透射电镜高分辨图可以看出,晶格条纹间距均为0.295nm,对应于[220]晶格类型;电子衍射图中,具有比较明显电子衍射光环,结晶度良好。图2b所示为PEG修饰的纳米颗粒负染后透射电镜,可明显看出白色PEG层。
实施例2
磁性超分子凝胶制备
将实施例1中制得的PEG修饰的磁性纳米颗粒溶液1mL加入到2mL的环糊精水溶液中,其中,DSPE-mPEG2000的浓度为100mg/mL,铁元素浓度为2mg/mL,脂溶性抗肿瘤药物紫杉醇浓度为1mg/mL,脂溶性荧光分子Cy7浓度为200μg/mL,水溶性抗肿瘤药物阿霉素浓度为2mg/mL,环糊精浓度为200mg/mL。将所得混合溶液涡旋搅拌均匀,然后室温静置30min,得到磁性超分子凝胶。
实施例3
磁性超分子凝胶制备
将实施例1中制得的PEG修饰的磁性纳米颗粒溶液1mL加入到1.5mL的环糊精水溶液中,其中,DSPE-mPEG2000的浓度为200mg/mL,铁元素浓度为3mg/mL,脂溶性抗肿瘤药物紫杉醇浓度为2mg/mL,脂溶性荧光分子Cy7浓度为300μg/mL,水溶性抗肿瘤药物阿霉素浓度为2mg/mL,环糊精浓度为200mg/mL。将所得混合溶液涡旋搅拌均匀,然后室温静置15min,得到磁性超分子凝胶。
实施例4
磁性超分子凝胶制备
将实施例1中制得的PEG修饰的磁性纳米颗粒溶液1mL加入到1.2mL的环糊精水溶液中,其中,DSPE-mPEG2000的浓度为300mg/mL,铁元素浓度为3mg/mL,脂溶性抗肿瘤药物紫杉醇浓度为2mg/mL,脂溶性荧光分子Cy7浓度为500μg/mL,水溶性抗肿瘤药物阿霉素浓度为2mg/mL,环糊精浓度为200mg/mL。将所得混合溶液涡旋搅拌均匀,然后室温静置10min,得到磁性超分子凝胶。
实施例5
磁性超分子凝胶制备
将实施例1中制得的PEG修饰的磁性纳米颗粒溶液1mL加入到等体积的环糊精水溶液中,其中,DSPE-mPEG2000的浓度为300mg/mL,铁元素浓度为3mg/mL,脂溶性抗肿瘤药物紫杉醇浓度为1mg/mL,脂溶性荧光分子Cy7浓度为800μg/mL,水溶性抗肿瘤药物阿霉素浓度为3mg/mL,环糊精浓度为300mg/mL。将所得混合溶液涡旋搅拌均匀,然后室温静置5min,得到磁性超分子凝胶。
图3a为凝胶合成过程样品展示图,等体积的环糊精和阿霉素溶液与PEG修饰的磁性纳米颗粒溶液简单混合,充分混匀,静置之后即得到可用注射器推动的磁性超分子凝胶。图3b中,磁性超分子凝胶被冷冻干燥,然后用扫描电子显微镜观察其结构,发现其结构为经典的多孔凝胶状。元素分析发现,铁元素均匀分布在凝胶之中。
实施例6
磁性超分子凝胶清除肿瘤术后残余
选取肿瘤体积约为300立方毫米的4T1荷瘤小鼠,用5%水合氯醛将其麻醉,用医用胶带将其固定于手术台上,切开肿瘤表面皮肤组织,切口约2cm长,切除绝大多数肿瘤组织,留3%-5%体积的肿瘤组织,将磁性超分子凝胶用注射器注射于创面,然后将小鼠置于交变磁场线圈之中,确保肿瘤部位在线圈中央,施加条件为410kHz,1.8kA/m的交变磁场5min,磁性超分子凝胶液化填充术后创面的各个角落,撤去交变磁场,温度下降,凝胶重新固化,滞留在术后创面长效精准释放药物。对照组为术后创面植入不具有加热液态适形特性的磁性结冷胶(对照组1),原位注射PEG修饰的磁性氧化铁纳米颗粒溶液(对照组2),静脉注射PEG修饰的磁性氧化铁纳米颗粒溶液(对照组3),术后生理盐水原位注射作为空白对照,除去空白对照,其他对照组包含相同浓度铁元素和药物浓度。治疗结束后,每天监测治疗后小鼠的生命体征,体重,肿瘤复发情况,并记录生存期,观察治疗效果及愈后情况。
图4a为肿瘤手术切除及凝胶填充和液态适形全过程图,切除大部分肿瘤组织,留下部分肿瘤组织保证复发,超分子凝胶注射填充后,交变磁场下加热液化适形,可发现原本孤立的超分子凝胶相互融合病填满了整个创面。液态适形过程中产生的热也对肿瘤细胞有热疗的作用,同时促进药物释放;图4b为体外药物释放曲线,可以看出交变磁场加热后阿霉素和紫杉醇的释放量(阿霉素2,紫杉醇2)都比未提供交变磁场时(阿霉素1,紫杉醇1)要高;图4c为15天后凝胶在小鼠病灶部位残留情况,将伤口重新切开,可发现有黑色的超分子凝胶附着在病灶部位;图4d为凝胶在病灶部位不同时间点的近红外荧光观察滞留情况,十五天内凝胶逐渐减少,被机体吸收,说明凝胶可长期释放药物。
图5a为超分子凝胶治疗后不同时间点小鼠肿瘤情况观察,小鼠治疗后四周内观察其生存状态并拍照记录,同时进行组织病理学分析,通过观察发现,小鼠瘤区伤口逐渐愈合,毛发长出,四周后伤口愈合完全,留有小伤疤;HE染色发现前两周有肿瘤细胞看以观察到,后两周只有肌肉组织可以看到,普鲁士蓝核固红双染色(PB&NFR)也可看出前两周显现清晰的蓝色的超分子凝胶,随着时间推移,凝胶逐渐减少,肿瘤细胞也被杀死,只剩健康的肌肉组织。图5b小鼠肿瘤体重变化,治疗后第一二天,小树体重呈现下降趋势,之后逐渐恢复并稳定增长。图5c为生存率监测,磁性超分子凝胶治疗后的小鼠肿瘤完全消失,并未再复发,对照组则在一个月内全部复发。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种等同变换,这些等同变换均属于本发明的保护范围。另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合。为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (4)
1.一种可注射温敏磁性超分子凝胶的制备方法,其特征在于,该制备方法包括:
步骤1、将α-环糊精和水溶性抗肿瘤药物加入超纯水中,涡旋混匀,超声加热使其完全溶解,形成溶液一;
步骤2、用二硬脂酰磷脂酰乙酰胺-甲氧基聚乙二醇DSPE-mPEG2000对高温热分解法制备的油溶性四氧化三铁纳米颗粒进行水相转移,同时负载脂溶性抗肿瘤药物,得到溶液二;
步骤3、将溶液一和溶液二混合,搅拌均匀,室温静置,得到磁性超分子凝胶;
其中,
在步骤1中,所述的α-环糊精的浓度为100~400mg/mL;
在步骤1中,所述的α-环糊精与水溶性抗肿瘤药物的质量比例为25:1~400:1;
在步骤2中,所述的水相转移,其过程采用旋转蒸发法,油相溶剂为三氯甲烷,油水体积比为1:1~1:3,利用疏水相互作用将四氧化三铁纳米颗粒和脂溶性抗肿瘤药物包在DSPE-mPEG2000的脂溶性部分,水溶性PEG链端优异亲水性使得纳米颗粒在水溶液中稳定分散;
在步骤2中,所述的DSPE-mPEG2000的用量为100~300mg/mL;
在步骤3中,所述的溶液一和溶液二混合,其混合的体积比例为2:1~1:1,搅拌均匀后,室温静置时间范围1s~30min。
2.根据权利要求1所述可注射温敏磁性超分子凝胶的制备方法,其特征在于:在步骤1中,所述的水溶性抗肿瘤药物的浓度为1~5mg/mL。
3.根据权利要求1所述可注射温敏磁性超分子凝胶的制备方法,其特征在于:在步骤2中,所述的油溶性四氧化三铁纳米颗粒尺寸在10~50纳米之间,铁元素含量1~6mg/ml,其分散的溶剂为三氯甲烷。
4.根据权利要求1所述可注射温敏磁性超分子凝胶的制备方法,其特征在于:在步骤2中,所述的脂溶性抗肿瘤药物用量为1~4mg/mL。
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