CN116473940A - 一种caf靶向的载药脂质纳米粒及其制备方法 - Google Patents
一种caf靶向的载药脂质纳米粒及其制备方法 Download PDFInfo
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Abstract
本发明提供了一种CAF靶向载药脂质纳米粒、制备方法及其在胰腺癌中的应用，属于药物制剂技术领域。本发明针对CAF在PDAC治疗中的渗透屏障作用，设计并制备了用于克服胰腺癌CAF屏障的药物递送***和药物组合。本发明制备可靶向CAF屏障的载药脂质纳米粒，可以诱导CAF屏障产生装载抗肿瘤药物的外泌体，促进药物外排以克服CAF对药物的BSB效应，增加药物到达深层肿瘤部位并提高抗肿瘤效果。
Description
技术领域
本发明涉及一种CAF靶向的载药脂质纳米粒、及其制备方法和在胰腺癌中的应用，属于药物制剂技术领域。
背景技术
胰腺癌是预后最差的恶性肿瘤之一。胰腺导管腺癌(PDAC)是最常见的胰腺癌类型(占80％以上)，即使使用标准的一线化疗药物吉西他滨进行治疗后，PDAC的5年生存率低于10％。由大量肿瘤相关成纤维细胞(CAFs)构成药物递送屏障(CAF屏障)是限制PDAC疗效的最关键因素。
CAFs占晚期PDAC中基质细胞的90％，是CAF屏障中ECM的主要生产者。由于CAFs优先定位在血管附近，对进入肿瘤核心部位的药物和纳米粒子具有很强的结合点屏障(Binding site barrier，BSB)作用。CAFs优先摄取大部分本应该被递送到肿瘤细胞的药物，导致很少的药物到达深层肿瘤部位。CAFs在PDAC中引起的BSB效应阻碍了药物或纳米粒向肿瘤深部的渗透，从而抑制化疗的效果。因此，迫切需要克服CAF屏障、增加药物渗透和提高胰腺肿瘤治疗效率的策略。
目前，要克服CAF屏障以提高疗效，通过基因工程、化学杀伤等方法消除CAF屏障似乎是最直接的方法。通过这种方式，可以直接清除CAF屏障，为药物的有效浸润提供可能。然而，在PDAC模型中过度清除CAFs会诱发强的免疫抑制和加速肿瘤的进展，并降低生存率。此外，诸如缩小颗粒尺寸等策略被应用于帮助药物渗透过CAF屏障，但其疗效仍然受限于CAF的BSB效应。
发明内容
本发明针对CAF在PDAC治疗中的药物递送的屏障作用，设计并制备了用于克服胰腺癌CAF屏障的载药脂质纳米粒和药物组合。本发明载药脂质纳米粒首先靶向CAF并被摄取，载药脂质纳米粒中具有外泌体诱导作用的神经酰胺诱导CAF外泌体大量分泌，进而使抗肿瘤药物以外泌体形式从CAF中释放并被递送至肿瘤细胞，克服CAF屏障并提升化疗药物的治疗效果。该发明与现有纳米制剂比较，通过新组分具有外泌体诱导作用的神经酰胺的加入，一方面神经酰胺作为脂质，不影响脂质纳米粒的制备和载药；另一方面，在体内有效克服CAF屏障，以外泌体外排的方式帮助抗肿瘤药物跨越CAF实现药物肿瘤递送，提升治疗效果，达到了意想不到的效果，为胰腺癌提供了一种新型药物制剂，具有明显的创造性。
一方面，本发明提供一种CAF靶向的载药脂质纳米粒，其组成包括磷脂、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-靶向分子(DSPE-PEG-靶向分子)、具有外泌体诱导作用的神经酰胺和疏水性抗肿瘤药物。
进一步的，磷脂为大豆卵磷脂、蛋黄卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、二磷脂酰甘油、磷脂酰肌醇、磷脂酰乙醇胺、磷脂酰丝氨酸以及鞘磷脂中的一种或多种。
进一步的，靶向分子为胺乙酰茴香酰胺(AEAA)、Telmisartan、FH肽、AE105肽、成纤维细胞活化蛋白(FAP)抗体中的一种或多种。
进一步的，具有外泌体诱导功能的神经酰胺为C18神经酰胺、C16神经酰胺、C6神经酰胺中的一种或多种。
进一步的，疏水性抗肿瘤药物为CP4126、紫杉醇、多柔比星、索拉非尼中的一种或多种。
进一步的，磷脂和DSPE-PEG-靶向分子的质量比为1:1～1:0.05。
进一步的，磷脂、DSPE-PEG-靶向分子、抗肿瘤药物、神经酰胺的质量比为10～20:1～10:1～5:0.1～5。
另一方面，本发明提供一种CAF靶向载药脂质纳米粒的制备方法，包含如下步骤：
(1)将一定比例的磷脂、DSPE-PEG-靶向分子、抗肿瘤药物、神经酰胺，加入有机溶剂中，搅拌形成澄清溶液；
(2)在室温下，以恒定的速度将上述澄清溶液注入等渗溶液中，注入的过程中持续搅拌；
(3)澄清溶液完全注入后继续搅拌2h使有机溶剂挥发完全，得含有活性药物和神经酰胺的具有CAF靶向功能的脂质纳米粒水溶液。
进一步的，磷脂、DSPE-PEG-靶向分子、抗肿瘤药物、神经酰胺的质量比为10～20:1～10:1～5:0.1～5。
进一步的，所述有机溶剂选自乙醇、氯仿、***、甲醇的一种或多种。
进一步的，所述等渗溶液选自磷酸盐缓冲液、5％葡萄糖溶液、0.9％生理盐水的一种或多种。
进一步的，所述注入速度为0.1～2mL/min，搅拌速度为100～3000rpm。
另一方面，本发明提供一种CAF靶向载药脂质纳米粒在制备胰腺癌药物中的应用。
进一步的，本发明提供一种CAF靶向载药脂质纳米粒在制备克服胰腺癌CAF屏障药物中的应用。
进一步的，所述胰腺癌为胰腺导管腺癌。
有益效果：
1、本发明将药物组合装载进脂质纳米粒中并修饰CAF靶向分子，靶向分子的修饰可以将药物有效递送至胰腺癌中的CAF，显著增加了药物在胰腺癌中的蓄积，可以提高其抗肿瘤效果。
2、本发明显著提高了胰腺癌的疗效。被递送至CAF的神经酰胺诱导CAF向深层肿瘤部位大量分泌外泌体；被递送至CAF的疏水性化疗药物在CAF外泌体形成过程中被装载到CAF外泌体中并随着CAF外泌体被分泌到深层肿瘤部位，这个过程显著增加了药物到达深层肿瘤部位的效率。抗肿瘤效果表明，单一化疗药对胰腺癌的抑瘤率为69.57％±2.12％，CAF靶向载药脂质纳米粒给药后，克服了CAF药物递送屏障并增加了药物的深层渗透，将抑瘤率提高至90.65％±3.04％。
3、本发明中添加的药物比例以及磷脂的浓度都是针对胰腺癌设计的优化后的数据，其疗效效果较好。本发明所使用原料简单、安全可靠。载体材料磷脂均为人体内源性物质，安全无毒且生物可降解，具有良好的生物相容性。
4、本发明制备得到的脂质纳米粒粒径适宜(100～200nm)，工艺稳定，简单可行，易于工业化生产。
附图说明
图1为本发明实施例1所制备不同药脂比脂质纳米粒中CP4126的包封率；
图2为本发明实施例2所制备不同浓度DSPE-PEG-AEAA修饰的脂质纳米粒在CAF中的摄取；
图3为本发明实施例3所制备脂质纳米粒CC/L-A的粒径和电镜图；
图4为本发明实验例1所制备脂质纳米粒在CAF中的摄取；
图5为本发明实验例2所制备脂质纳米粒对胰腺癌的抑瘤率；
具体实施方式
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例与对比例详细说明本发明的技术方案。
实施例1
考察不同药脂比对药物包封率的影响。控制空白脂质纳米粒与DSPE-PEG-AEAA的质量比为4:1，空白脂质纳米粒与DSPE-PEG-AEAA的总质量为20mg，C18神经酰胺1mg，分别称取CP4126药物1mg、2mg、4mg加入1ml的乙醇中，在室温下，搅拌形成澄清溶液，以1mL/min速度将溶液注入生理盐水中，注射过程中以1000rpm速度快速搅拌，持续搅拌2h，得含CP4126和C18神经酰胺的脂质纳米粒的水溶液。用HPLC测定CC/L-A中CP4126的含量并计算包封率。根据图1结果可知，当药脂比为1:10时，CP4126具有最优的包封率。获得最优的包封率在一方面减少制备过程中药物的损耗，将绝大部分药物包载到纸质纳米粒中；另一方面可以说明制剂在当前配方下具有最优的稳定性，有利于长期储存。
实施例2
考察DSPE-PEG-AEAA比例对靶向性的影响。用荧光物质香豆素6(C6)代替药物进行摄取实验以筛选DSPE-PEG-AEAA的最佳用量。称取C6 1mg，控制空白脂质纳米粒与DSPE-PEG-AEAA的总质量为20mg，设置大豆卵磷脂与DSPE-PEG-AEAA的质量比为18:2，16:4，12:8。按比例称取以上药物，加入1ml的乙醇中，在室温下，搅拌形成澄清溶液，以1mL/min速度将溶液注入生理盐水中，注射过程中以1000rpm速度快速搅拌，持续搅拌2h，得含香豆素6的CAF靶向脂质纳米粒的水溶液。
将5*104NIH/3T3接种到12孔板中并用10ng/mL TGF-β1活化24h得到CAF细胞。向每孔加入游离不同DSPE-PEG-AEAA比例的C6/L-A(C6终浓度200ng/mL)，37℃孵育0.5h后，将细胞用胰酶消化并重新悬浮于PBS中进行流式荧光定量。根据图2结果可知，大豆卵磷脂与DSPE-PEG-AEAA的比例为16:4时纳米粒具有最好的CAF靶向性，这有助于药物更多的蓄积到肿瘤靶部位，对于提高抗肿瘤效果至关重要。
实施例3
制备AEAA修饰的共载CP4126和C16神经酰胺脂质纳米粒(CC/L-A)。将16mg大豆卵磷脂、4mg DSPE-PEG-AEAA、2mg CP4126、1mg C16神经酰胺，加入1ml的乙醇中，在室温下，搅拌形成澄清溶液，以1mL/min速度将溶液注入生理盐水中，注射过程中以1000rpm速度快速搅拌，持续搅拌2h，得含CP4126和C18神经酰胺的CAF靶向脂质纳米粒的水溶液。
用DLS测定CC/L-A的粒径，透射电镜表征CC/L-A的表面形态。图3是CC/L-A的粒径分布图和透射电镜图。CC/L-A的粒径为140.4±5.6nm，CP4126的包封率为92.3％±1.57，CC/L-A的形态圆整。本实施例所制备脂质纳米粒具有最佳的AEAA修饰比例，获得了最佳的包封率，同时也具有合适的粒径。纳米粒到达肿瘤部位需要通过肿瘤血管间隙(小于200nm)，因此，本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位并长时间蓄积，这对于提高抗肿瘤效果至关重要。
实施例4
制备FH肽修饰的共载CP4126和C16神经酰胺脂质纳米粒(CC/L-FH)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-FH 4mg、CP4126 2mg、C16神经酰胺1mg。
测定CC/L-FH的粒径为142.1±4.0nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例5
制备Telmisartan修饰的共载CP4126和C16神经酰胺脂质纳米粒(CC/L-T)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-Telmisartan 4mg、CP4126 2mg、C16神经酰胺1mg。
测定CC/L-T的粒径为139.2±1.4nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例6
制备AE105肽修饰的共载CP4126和C16神经酰胺脂质纳米粒(CC/L-AE105)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-AE105 4mg、CP4126 2mg、C16神经酰胺1mg。
测定CC/L-AE105的粒径为142.8±0.3nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例7
制备FAP单抗肽修饰的共载CP4126和C16神经酰胺脂质纳米粒(CC/L-FAP)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-FAP 4mg、CP4126 2mg、C16神经酰胺1mg。
测定CC/L-FAP的粒径为145.8±3.5nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例8
制备AEAA修饰的共载紫杉醇(PTX)和C16神经酰胺脂质纳米粒(CP/L-A)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-A 4mg、PTX 2mg、C16神经酰胺1mg。
测定CP/L-A的粒径为141.8±2.9nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例9
制备AEAA修饰的共载多柔比星(DOX)和C16神经酰胺脂质纳米粒(CD/L-A)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-A 4mg、DOX 2mg、C16神经酰胺1mg。
测定CD/L-A的粒径为142.4±4.6nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例10
制备AEAA修饰的共载索拉非尼(SF)和C16神经酰胺脂质纳米粒(CS/L-A)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-A 4mg、SF 2mg、C16神经酰胺1mg。
测定CS/L-A的粒径为140.6±7.2nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例11
制备AEAA修饰的共载CP4126和C18神经酰胺脂质纳米粒(CC/L-A)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-AEAA 4mg、CP41262mg、C18神经酰胺1mg。
测定CS/L-A的粒径为143.8±3.7nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例12
制备AEAA修饰的共载CP4126和C6神经酰胺脂质纳米粒(CC/L-A)，制备方法同实施例3。其中，大豆卵磷脂16mg、DSPE-PEG-AEAA 4mg、CP41262mg、C6神经酰胺1mg。
测定CS/L-A的粒径为138.2±2.4nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实施例13
分别以蛋黄卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、二磷脂酰甘油、磷脂酰肌醇、磷脂酰乙醇胺、磷脂酰丝氨酸以及鞘磷脂为脂质材料制备AEAA修饰的共载CP4126和C6神经酰胺脂质纳米粒(CC/L-A)，制备方法同实施例3。其中，蛋黄卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、二磷脂酰甘油、磷脂酰肌醇、磷脂酰乙醇胺、磷脂酰丝氨酸以及鞘磷脂16mg、DSPE-PEG-AEAA4mg、CP4126 2mg、C6神经酰胺1mg。
测定CC/L-A的粒径分别为139.4±5.7nm、140.3±2.8nm、141.2±6.9nm、139.9±4.2nm、140.5±1.3nm、140.6±2.9nm、141.5±3.2nm和137.5±3.4nm。本实施例所制备脂质纳米粒可以有效通过肿瘤血管间隙到达肿瘤部位。
实验例1
制备AEAA修饰的载香豆素6(C6)的脂质纳米粒(C6/L-A)和无AEAA修饰的载C6的脂质纳米粒(C6/L-A)，制备方法同实施例3。将5*104NIH/3T3接种到12孔板中并用10ng/mLTGF-β1活化24h得到CAF细胞。向每孔加入游离C6、C6/L、C6/L-A(C6终浓度200ng/mL)37℃孵育0.5h；AEAA+C6/L-A组的细胞在添加C6/L-A前用AEAA对细胞预处理1h以阻断AEAA介导的靶向效应。对于流式细胞分析，将孵育完毕的细胞用胰酶消化细胞并重新悬浮于PBS中进行流式细胞仪分析(BD Accuri C6，BD，USA)。图4是不同靶向能力脂质纳米粒的细胞摄取结果。靶向修饰组C6/L-A组显示出了比非靶组C6/L更高的C6荧光强度(约为1.46倍)，且两组都强于游离C6组，以上结果说明AEAA具有明显的CAF靶向性，可以帮助药物更好的到达CAF屏障，增加药物肿瘤部位蓄积，提高疗效。
实验例2
制备AEAA修饰的单载CP4126的脂质纳米粒(CP4126/L-A)、无AEAA修饰的共载CP4126和C16神经酰胺的脂质纳米粒(CC/L)和AEAA修饰的共载CP4126和C16神经酰胺的脂质纳米粒(CC/L-A)，制备方法同实施例3。将皮下携带胰腺肿瘤的小鼠(106个细胞Panc02和5*105个细胞NIH/3T3)随机分为4组(5只小鼠/组)，NS(生理盐水组)、CP4126/L-A、CC/L和CC/L-A。当肿瘤长到约80立方毫米时，每3天对小鼠进行一次静脉注射，共4次。每两天记录肿瘤大小。16天后，计算得到各组相对于NS组的抑瘤率分别为CP4126/L-A：69.57％±2.12％，CC/L:81.62％±5.81％，CC/L-A：90.65％±3.04％。相比于CP4126/L-A组，CC/L-A组的抑瘤率显著提高，这说明C16神经酰胺的应用能够增加CP4126跨过CAF屏障到达深层肿瘤部位，提高抗肿瘤效果；相比于CC/L组，CC/L-A组的抑瘤率也显著提高，这说明AEAA的修饰能够增加药物在CAF屏障的蓄积，有利于提高抗肿瘤效果。CC/L-A组具有最高的抑瘤率，说明只有三种组分的联合应用才能将抗肿瘤效果最大化。
Claims (10)
1.一种CAF靶向的载药脂质纳米粒，其特征是，其组成包括磷脂、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-靶向分子、神经酰胺和疏水性抗肿瘤药物。
2.如权利要求1所述的CAF靶向的载药脂质纳米粒，其特征是，所述磷脂为大豆卵磷脂、蛋黄卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、二磷脂酰甘油、磷脂酰肌醇、磷脂酰乙醇胺、磷脂酰丝氨酸以及鞘磷脂中的一种或多种。
3.如权利要求1所述的CAF靶向的载药脂质纳米粒，其特征是，靶向分子为胺乙酰茴香酰胺、Telmisartan、FH肽、AE105肽、成纤维细胞活化蛋白抗体中的一种或多种。
4.如权利要求1所述的CAF靶向的载药脂质纳米粒，其特征是，所述神经酰胺为C18神经酰胺、C16神经酰胺、C6神经酰胺中的一种或多种。
5.如权利要求1所述的CAF靶向的载药脂质纳米粒，其特征是，所述疏水性抗肿瘤药物为CP4126、紫杉醇、多柔比星、索拉非尼中的一种或多种。
6.如权利要求1所述的CAF靶向的载药脂质纳米粒，其特征是，所述磷脂和所述二硬脂酰基磷脂酰乙醇胺-聚乙二醇-靶向分子的质量比为1:1～1:0.05。
7.如权利要求1所述的CAF靶向的载药脂质纳米粒，其特征是，磷脂、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-靶向分子、抗肿瘤药物、神经酰胺的质量比为10～20:1～10:1～5:0.1～5。
8.如权利要求1所述的CAF靶向的载药脂质纳米粒的制备方法，其特征是，包含如下步骤：
(1)将一定比例的磷脂、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-靶向分子、抗肿瘤药物、神经酰胺，加入有机溶剂中，搅拌形成澄清溶液；
(2)在室温下，以恒定的速度将上述澄清溶液注入等渗溶液中，注入的过程中持续搅拌；
(3)澄清溶液完全注入后继续搅拌2h使有机溶剂挥发完全，得含有活性药物和神经酰胺的具有CAF靶向功能的脂质纳米粒水溶液。
9.如权利要求1所述的CAF靶向的载药脂质纳米粒在制备胰腺癌药物中的应用。
10.如权利要求1所述的CAF靶向的载药脂质纳米粒在制备克服胰腺癌CAF屏障药物中的应用。
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