CN112826939A - 一种腹腔灌注纳米药物及其制备方法与应用 - Google Patents

一种腹腔灌注纳米药物及其制备方法与应用 Download PDF

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CN112826939A
CN112826939A CN202110149330.7A CN202110149330A CN112826939A CN 112826939 A CN112826939 A CN 112826939A CN 202110149330 A CN202110149330 A CN 202110149330A CN 112826939 A CN112826939 A CN 112826939A
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赵静
邱妙娟
李宾宾
黄秀玉
张士强
陈俊宗
钱志荣
庞俊
潘逸航
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Seventh Affiliated Hospital Of Sun Yat Sen University Shenzhen
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Abstract

本发明涉及肿瘤治疗和纳米技术领域，尤其涉及一种腹腔灌注纳米药物及其制备方法与应用。本发明的腹腔灌注纳米药物的制备方法，包括以下步骤：(1)将药物纳米化得到纳米颗粒；(2)通过RGD修饰增加纳米颗粒的肿瘤靶向性。本发明通过将抗肿瘤药物纳米化，可解决腹腔灌注的药物靶向性差、腹腔滞留时间短、治疗后容易复发的问题。本发明的纳米颗粒表面带氨基，方便后续修饰及表面正电荷。且本发明通过腹腔灌注纳米药物，以提高局部药物浓度，可减少全身毒副作用。

Description

一种腹腔灌注纳米药物及其制备方法与应用
技术领域
本发明涉及肿瘤治疗和纳米技术领域，尤其涉及一种腹腔灌注纳米药物及其制备方法与应用。
背景技术
腹膜癌是指在腹膜上发生和/或发展的一类恶性肿瘤。统计数据显示，在中晚期胃癌患者中，有50％会出现腹膜癌的表现特征；在结直肠癌患者中，有17％会出现腹膜癌的表现特征；在卵巢癌患者中，则有80％会合并腹膜癌转移。胃癌患者术后腹膜转移发生率高达50％左右。腹膜转移的病人往往合并大量腹水、肠梗阻等表现，严重影响病人的生活质量。由于腹膜屏障的原因，全身化疗对腹膜转移的病人治疗效果不佳，病人预后极差，自然生存期只有几个月。
腹腔灌注化疗(intraperitoneal perfusion chemotherapy，IPC)是根据卵巢癌具有盆腹腔内转移的生物学特性，向腹腔内灌注抗癌药液，以治疗盆、腹腔肿瘤病灶的一种局部化疗方法。由于其局部药物浓度高、全身不良反应小、可联合多种药物使用等特点，腹腔灌注化疗成为近些年腹膜癌治疗的研究热点。多项临床研究表明，腹腔化疗可改善腹膜癌患者的预后。目前用于腹腔化疗的药物包括：铂类药物、氟尿嘧啶、阿霉素、紫杉醇等单一或者联合用药，取得不同程度的效果，其中以铂类和紫杉醇研究最多。但是，很多小分子药物如顺铂、紫杉醇、氟尿嘧啶和丝裂霉素等都会通过腹膜间皮层被腹膜下毛细血管快速吸收，不会靶向至肿瘤部位。因此，提高药物的肿瘤靶向性及药物滞留时间被认为是腹腔灌注化疗要解决的关键科学问题。
纳米药物是用纳米生物技术将抗肿瘤药物等生物活性分子与载体材料相复合，进而利用纳米效应改变药物的药代动力学、药效及药理等方面的性质而获得显著临床优势的纳米复合体。Vassilevad等通过腹腔注射聚乳酸/紫杉醇纳米颗粒治疗小鼠卵巢癌腹腔播散瘤，通过诱导肿瘤细胞凋亡完全抑制了小鼠肿瘤的生长(Novel biocompatibleintraperitoneal drug delivery system increases tolerability and therapeuticefficacy of paclitaxel in a human ovarian cancer xenograft model)。一项临床实验显示，通过腹腔注射紫杉醇纳米颗粒，与静脉注射紫杉醇相比，不会导致毒性增加。21名患者中有16名腹腔注射纳米紫杉醇有效，其中5名患者生存期长于400天(A phase I studyof intraperitoneal nanoparticulate paclitaxel
Figure BDA0002931734120000021
in patients withperitoneal malignancies)。
发明内容
本发明的目的在于克服现有技术的不足，提供一种腹腔灌注纳米药物及其制备方法与应用。本发明通过将抗肿瘤药物纳米化，解决腹腔灌注的药物靶向性差、腹腔滞留时间短、治疗后容易复发的问题。
为实现上述目的，本发明采取的技术方案为：提供一种腹腔灌注纳米药物的制备方法，其特征在于，所述制备方法包括以下步骤：
(1)将药物纳米化得到纳米颗粒；
(2)通过RGD修饰增加纳米颗粒的肿瘤靶向性。
为了解决化疗药物在腹腔内肿瘤靶向及长时间滞留的问题，本发明提出将化疗药物纳米化，其基本内容包括：将药物装载在有肿瘤靶向功能的纳米载体上，通过腹腔注射打进小鼠体内，实现肿瘤高度靶向。将化疗药通过配位键、化学键、亲疏水作用、物理吸附等制备成纳米颗粒，通过腹腔注射打进小鼠体内，实现肿瘤高度靶向。
作为本发明所述制备方法的优选实施方式，所述药物包括小分子药物和大分子肿瘤药。
作为本发明所述制备方法的优选实施方式，所述小分子药物包括铂类药物、氟尿嘧啶、阿霉素或紫杉醇。
作为本发明所述制备方法的优选实施方式，所述大分子肿瘤药包括多肽、蛋白、抗体、细胞因子或趋化因子。
作为本发明所述制备方法的优选实施方式，步骤(1)具体为：向药物中加入PAMAM，避光搅拌后加入CaCl2溶液，将溶液pH值调至7.0，室温下反应后离心，用去离子水和无水乙醇洗涤，获得装载药物的磷酸钙纳米颗粒。
作为本发明所述制备方法的优选实施方式，步骤(2)具体为：将装载药物的磷酸钙纳米颗粒分散在乙醇中，加入NSH-PEG-RGD，反应获得RGD修饰的装载药物的磷酸钙纳米颗粒。
作为本发明所述制备方法的优选实施方式，所述制备方法中的溶剂体系为水系溶液。
作为本发明所述制备方法的优选实施方式，所述水系溶液包括蒸馏水、生理盐水或葡萄糖注射液。
本发明的阿仑膦酸盐也可替换为其他双膦酸盐，比如依替膦酸钠、氯膦酸钠、伊班膦酸钠、唑来膦酸等。也可以替换为其他具有生物活性的小分子药物，例如没食子酸、山茶酸、槲皮素、香菇多糖、人参皂苷、三七皂苷等中药成分。
本发明用于靶向肿瘤细胞的基团可以是多肽、叶酸、转铁蛋白、核酸适配体等。也可以是纳米药物表面包裹肿瘤细胞膜、NK细胞膜、细菌膜等。
本发明注射的溶液体系可以加热后灌注，加热温度为37～43℃。
本发明还提供所述制备方法制备得到的腹腔灌注纳米药物。
本发明的有益效果：
(1)本发明提出在纳米颗粒表面修饰活性的氨基，继而可以修饰各种靶向肿瘤的基团，例如多肽、叶酸、转铁蛋白、核酸适配体等。
(2)本发明提出通过腹腔灌注纳米药物，以提高局部药物浓度，减少全身毒副作用。
(3)本发明提出部位小分子药物可以纳米化，例如阿仑膦酸钠，没食子酸等。
(4)本发明的纳米颗粒表面带氨基，方便后续修饰及表面正电荷。
附图说明
图1：RGD-DOX-CAPO透射电子显微镜图片。
图2：RGD-CaALN扫描电子显微镜图片。
图3：RGD-DOX-CAPO体内靶向肿瘤器官照片。
图4：RGD-CaALN体内靶向肿瘤器官照片。
图5：RGD-DOX-CAPO治疗小鼠卵巢癌生存曲线。
具体实施方式
为更清楚地表述本发明的技术方案，下面结合具体实施例进一步说明，但不能用于限制本发明，此仅是本发明的部分实施例。
实施例中，所使用的实验方法如无特殊说明，均为常规方法，所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1载阿霉素的磷酸钙纳米颗粒的制备
将4mg阿霉素(后简称为DOX)溶于15mL去离子水中，加入10mg/mL PAMAM 15mL，避光搅拌24小时。之后加入1mmol/L CaCl2溶液15mL，将溶液pH值调至7.0，室温下反应半小时。之后10000转离心10分钟，用去离子水和无水乙醇洗涤，获得装载DOX的磷酸钙纳米颗粒。将0.5g装载DOX的磷酸钙纳米颗粒分散在100mL乙醇中，加入10mL的1mg/mL NSH-PEG-RGD，室温下反应2h。离心，洗涤，获得RGD修饰的装载DOX的磷酸钙纳米颗粒(后续简写为RGD-DOX-CAPO)，避光、冷藏保存在无水乙醇中，定量待用。
实施例2阿仑膦酸钙的制备
将0.05g CaCl2·2H2O分散于40mL去离子水中，搅拌至完全溶解。再将阿仑膦酸钠三水合物分散于40mL去离子水中，搅拌至完全溶解。将氯化钙溶液加入阿仑膦酸钠溶液中，将pH值调为7.0。室温下反应30分钟。之后10000转离心10分钟，用去离子水和无水乙醇洗涤，获得阿仑膦酸钙纳米颗粒。将0.5g阿仑膦酸钙纳米颗粒分散在100mL乙醇中，加入10mL的1mg/mL NSH-PEG-RGD，室温搅拌反应2h。离心，洗涤，获得RGD修饰的阿仑膦酸钙纳米颗粒(后续简写为RGD-CaALN)，冷藏保存在无水乙醇中，定量待用。
实施例3细胞试验
将实施例2中制备得到的RGD-CaALN用PBS分散，最高浓度为100mg/L，2倍梯度稀释，分别给药处理人卵巢癌细胞SKOV3及人肾小管上皮细胞HK2，48小时后由CCK8测定细胞存活率。
实验结果证实，制备得到的RGD-CaALN对人肾小管上皮细胞毒性远远小于肿瘤细胞。
表1 RGD-CaALN的细胞毒性分析
Figure BDA0002931734120000051
实施例4动物模型试验
(1)将3*106SKOV3人卵巢癌细胞(Luciferase稳转细胞系)通过腹腔注射进小鼠体内。14天后在小鼠腹腔内形成腹膜癌肿瘤模型。将0.4mg RGD-CAPO或者0.4mg RGD-CaALN与DIR染料混合后，均匀地分散在400uL PBS中，通过腹腔注射进带瘤小鼠体内，不同时间后通过小动物活体成像仪观察纳米药物在小鼠腹腔内的分布情况。游离的DIR染料作为对照。
结果如图3-4所示，通过腹腔注射后，RGD-CAPO或者RGD-CaALN都可以靶向肿瘤组织，在正常器官几乎没有蓄积。而游离的DIR刚开始分布在全部腹腔，之后被迅速代谢出体内。
(2)将3*106SKOV3人卵巢癌细胞(Luciferase稳转细胞系)通过腹腔注射进小鼠体内。6天后将小鼠随机分为3组：PBS组、DOX组和RGD-DOX-CAPO组。分别每7天给一次相应药物治疗，记录小鼠生存曲线。
结果如图5所示，游离DOX荷瘤小鼠毒性很大，而装载了DOX的磷酸钙通过腹腔注射可以明显延长小鼠生存时间，说明RGD-DOX-CAPO对卵巢癌具有明显的生长抑制作用和延长小鼠生存时间的效果。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (9)

1.一种腹腔灌注纳米药物的制备方法，其特征在于，所述制备方法包括以下步骤：
(1)将药物纳米化得到纳米颗粒；
(2)通过RGD修饰增加纳米颗粒的肿瘤靶向性。
2.根据权利要求1所述的制备方法，其特征在于，所述药物包括小分子药物和大分子肿瘤药。
3.根据权利要求2所述的制备方法，其特征在于，所述小分子药物包括铂类药物、氟尿嘧啶、阿霉素或紫杉醇以及其他化疗药物。
4.根据权利要求2所述的制备方法，其特征在于，所述大分子肿瘤药包括多肽、蛋白、抗体、细胞因子或趋化因子等生物大分子。
5.根据权利要求1所述的制备方法，其特征在于，步骤(1)具体为：向药物中加入PAMAM，避光搅拌后加入CaCl2溶液，将溶液pH值调至7.0，室温下反应后离心，用去离子水和无水乙醇洗涤，获得装载药物的磷酸钙纳米颗粒。
6.根据权利要求5所述的制备方法，其特征在于，步骤(2)具体为：将装载药物的磷酸钙纳米颗粒超声辅助分散在乙醇中，加入NSH-PEG-RGD，反应获得RGD修饰的装载药物的磷酸钙纳米颗粒。
7.根据权利要求1所述的制备方法，其特征在于，所述制备方法中的溶剂体系为水系溶液。
8.根据权利要求7所述的制备方法，其特征在于，所述水系溶液包括蒸馏水、生理盐水或葡萄糖注射液以及PBS磷酸盐缓冲液。
9.根据权利要求1-8任一所述制备方法制备得到的腹腔灌注纳米药物。
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