CN117122692B - 一种靶向纳米载体及其制备方法和应用 - Google Patents
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Abstract
本发明涉及一种靶向纳米载体及其制备方法和应用,属于生物医学技术领域。所述靶向纳米载体包括黑磷纳米片及包覆在所述黑磷纳米片表面的改性PAMAM,所述改性PAMAM中含有双硒键,并修饰有FA分子。本发明的靶向纳米载体以黑磷为核心骨架具有光热效果;其次改性的树枝状大分子PAMAM修饰其表面,既能够提高纳米材料的稳定性,又能负载功能基因;此外,FA促进了纳米材料在肿瘤细胞的富集。该纳米材料可应用于治疗肝癌药物,或基因治疗和光热治疗,为肝癌的高效治疗提供新思路。
Description
技术领域
本发明涉及生物医学技术领域,特别是涉及一种靶向纳米载体及其制备方法和应用。
背景技术
肝细胞癌(HCC)是世界范围内最常见的高死亡率癌症之一。近年来,HCC在世界范围内的发病率持续上升,引起越来越多的关注。早期肝癌的有效治疗是手术,手术治疗后5年生存率为89%~93%。然而,只有少数HCC患者(约20%)能够在早期被诊断出来,大多数HCC患者(>70%)都处于晚期,不能手术切除,只能通过其他方法治疗,包括肝移植、经导管动脉化疗栓塞(TACE)和全身化疗。但其他治疗方法存在局限性,使得肝癌的治疗效果不理想。因此,迫切需要探索肝癌的创新治疗方法,弥补临床治疗的不足。
随着对长链非编码rna(long-chain noncoding rna,lncRNAs)研究的深入,lncRNAs被发现在肿瘤发生、发展、转移和凋亡中发挥着重要作用。研究lncRNAs在肝癌发生发展中的作用,也可能为未来肝癌的诊断和治疗提供新的突破。目前,lncRNAs已成为肿瘤生物学领域的重要研究热点,但lncRNAs与肿瘤的关系研究尚处于起步阶段。CRNDE在大多数恶性肿瘤中表达明显上调。CRNDE可通过影响染色质的表观遗传调控、一些重要蛋白的表达、肿瘤特异性信号通路和细胞代谢,参与相关肿瘤的生物学过程,进而促进肿瘤细胞的增殖、迁移和侵袭,抑制细胞凋亡,最终促进肿瘤的发生发展。
目前,lncRNAs分子技术已进入人体实验阶段,是治疗多种基因突变肿瘤最有前途的方法之一。然而,lncRNAs的临床应用仍然面临着很大的挑战,如其在血清中的不稳定性、在细胞外环境中容易被核酸酶降解、带负电荷的lncRNAs与带负电荷的细胞膜的静电排斥等,这些都会严重影响lncRNAs的运输和吸收。由于这些特点,游离lncRNAs难以直接靶向特异性细胞,因此对lncRNAs进行化学修饰或将lncRNAs装载到保护性载体材料中以提高lncRNAs的稳定性成为当前的研究热点之一。叶酸(Folic acid,FA)作为一种被广泛研究的靶向基元,是一种不像许多蛋白质那样引起过敏反应的天然成分。此外,FA受体在肾、肺和乳腺癌组织中过表达,而在正常组织中表达水平较低。因此,FA功能纳米颗粒可以通过FA受体介导的内吞作用特异性增强肿瘤细胞对该复合药物制剂的摄取。同时,FA修饰的复合聚合物纳米颗粒将成为肿瘤靶向药物递送的潜在载体。
近年来,光热疗法(photothermal therapy,PTT)成为一种发展迅速的新型癌症治疗方法。与传统的肿瘤消融方法相比,PTT具有更高的局部效果,可用于手术难度较大的区域。黑磷(BP)是一种新型无机材料,是白磷和红磷的同素异形体,主要应用于锂离子电池、存储器件等领域。近年来,人们发现通过类似石墨烯的机械剥离方法可以获得BP的二维片层结构,并表现出独特的光学性质。BP最早用于生物医学领域的光热治疗。在近红外激光照射(808nm)下,BP可产生高热,可用于实现高效、安全的肿瘤光热治疗。与传统无机纳米材料相比,BP在生理条件下可氧化降解为安全无毒的磷酸盐、亚磷酸酯等小分子。
发明内容
基于此,有必要针对上述问题,提供一种靶向纳米载体,可实现肝癌的靶向,改善肝癌治疗效果。
本发明的技术方案如下:一种靶向纳米载体,所述纳米载体包括黑磷纳米片及包覆在所述黑磷纳米片表面的改性PAMAM,所述改性PAMAM中含有双硒键,并修饰有FA分子。
该纳米载体以黑磷为核心骨架,通过修饰改性聚合物PMMA,可使载体具有丰富的正电荷,其对增加带负电荷功能基因如基因shCRNDE的负载能;而且双硒键具有GSH响应性,黑磷被具有GSH响应的改性聚合物PAMAM包覆,可防止降解,提高纳米载体的稳定性;同时,将FA修饰为靶向肝癌细胞上FA受体的引导分子,促进了纳米材料在肿瘤细胞的富集,可实现对肝癌肿瘤细胞的高效联合治疗。
在其中一个实施例中,所述靶向纳米载体的粒径为200nm,Zeta电位18mV,在负载基因后,有较好的杀死肝癌细胞的效果。
本发明的另一方面还提供了上述靶向纳米载体的制备方法,包括如下步骤:(1)制备黑磷纳米片BPNPs:将黑磷分散于纯水中,搅拌,用流动氩气对溶液进行脱气,然后,在冰浴条件下对混合溶液进行超声处理,获得的棕色分散体,然后对所述棕色分散体离心,收集上清液并将收集到的上清液进一步离心,得到黑磷纳米片BPNPs。
(2)制备PAMAM-SeSe-FA,包括:
2.1合成NH2-PEG-SeSe-NH2:取硒代胱胺盐酸盐溶于水中,将EDC和NHS加入到硒代胱胺盐酸盐溶液中搅拌反应;然后逐滴加入到NH2-PEG-COOH溶液中,室温搅拌反应、透析、冻干得到NH2-PEG-SeSe-NH2;
2.2取FA溶于DMSO中,将EDC和NHS加入FA溶液中,室温搅拌,再将其逐滴加入到PAMAM溶液中,室温搅拌反应,透析,冻干得到PAMAM-FA;
2.3取PAMAM-FA溶液于水中,将EDC和NHS加入PAMAM-FA溶液中,室温搅拌,再将其逐滴加入到NH2-PEG-SeSe-NH2水溶液中,室温搅拌反应,透析,冻干得到PAMAM-SeSe-FA;
(3)制备BP@PAMAM-SeSe-FA
配置BPNPs水溶液,然后加入PAMAM-SeSe-FA混合,超声、搅拌反应得到BP@PAMAM-SeSe-FA纳米载体,即所述的靶向纳米载体。
该制备方法首先采用液相溶出法制备黑磷纳米片BPNPs;然后以其为核心骨架,通过修饰聚合物PMMA-SeSe-FA得到的纳米载体BP@PAMAM-SeSe-FA,制备方法简单容易操作,利于推广。
在其中一个实施例中,步骤(1)中,黑磷与纯水的质量比为10~30:20~80;超声时间为6~24h;棕色分散体的离心转速为500rpm~1000rpm;收集到的上清液的离心转速为2000rpm~4000rpm。优选地,所述黑磷与纯水的质量比25:50;所述超声时间为12h;所述棕色分散体的离心转速为1000rpm;所述收集到的上清液的离心转速为3750rpm。
在其中一个实施例中,步骤2.1中,原料的质量比为硒代胱胺盐酸盐:去离子水:EDC:NHS:NH2-PEG-COOH=5~15:2~8:5~25:5~20:5~50,EDC和NHS与硒代胱胺盐酸盐的反应时间为1~6h,硒代胱胺盐酸盐溶液与NH2-PEG-COOH的反应时间为6~24h;步骤2.2中,FA与PAMAM的质量比为1~10:30~70;步骤2.3中,PAMAM-FA与NH2-PEG-SeSe-NH2的质量比为10~30:5。
优先地,所述步骤2.1中,原料的质量比为硒代胱胺盐酸盐:去离子水:EDC:NHS:NH2-PEG-COOH=10:6:15:12:30,EDC和NHS与硒代胱胺盐酸盐的反应时间为4h;硒代胱胺盐酸盐溶液与NH2-PEG-COOH的反应时间为24h;所述步骤2.2中,FA与PAMAM的质量比为5:50;所述步骤2.3中,PAMAM-FA与NH2-PEG-SeSe-NH2的质量比为20:5。
在其中一个实施例中,步骤(3)中,BP与PAMAM-SeSe-FA的质量比为0.1~0.5:5~15;超声时间为10~40min;反应时间为2~8h。
优选地,所述步骤(3)中,BP与PAMAM-SeSe-FA的质量比为0.375:10;超声时间为30min;反应时间为6h。
在其中一个实施例中,所述步骤(1)还包括将获得的BPNPs在PBS溶液中重悬,得到BPNPs-PBS溶液,然后保存在4℃下。
在其中一个实施例中,所述步骤(3)中,配置BPNPs水溶液是将所述的BPNPs-PBS溶液离心,去除上清重悬于水中得到。优选地,所述的离心转速为4000rpm~8000rpm;进一步优选地,所述的离心转速为6000rpm。
本发明的再一方面,还提供了上述纳米载体在制备治疗肝癌药物,或基因治疗和光热治疗中的应用。
与现有技术相比,本发明具有以下有益效果:
本发明的纳米载体以黑磷为核心骨架,通过修饰改性聚合物PMMA,可使载体具有丰富的正电荷,增加载体对带负电荷的功能基因如shCRNDE的负载能力;而且双硒键具有GSH响应性,被GSH响应的改性聚合物PAMAM包覆,可防止黑磷降解,提高纳米载体的稳定性;同时,将FA修饰为靶向肝癌细胞上FA受体的引导分子,促进了纳米材料在肿瘤细胞的富集,可实现对肝癌的高效联合治疗。本发明的制备方法首先采用液相溶出法制备黑磷纳米片BPNPs;然后以其为核心骨架,通过修饰聚合物PMMA-SeSe-FA得到的纳米载体BP@PAMAM-SeSe-FA,制备方法简单容易操作,利于推广。本发明的纳米载体可以应用于制备治疗肝癌药物或基因治疗和光热治疗中。
附图说明
图1为本发明实施例的黑磷纳米片BPNPs及纳米载体BP@PAMAM-SeSe-FA的透射电镜图;
图2为Zeta电位测试结果;
图3为细胞毒性测试结果;
图4为不同浓度的BP@PAMAM-SeSe-FA的光热曲线;
图5为细胞存活率测试结果。
具体实施方式
为了便于理解本发明,下面将参照相关附图对本发明进行更全面的描述。附图中给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
定义:
BP:黑磷;
BPNPs:黑磷纳米片;
EDC:1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐;
NHS:N-羟基琥珀酰亚胺;
NH2-PEG-COOH:氨基聚乙二醇羧基
PBS:磷酸盐缓冲液;
DMSO:二甲基亚砜;
FA:叶酸;
PAMAM:聚酰胺-胺型树枝状高分子。
来源:
以下实施例所用试剂,如非特别说明,均为市售可得;以下实施例所用方法,如非特别说明,均为常规方法可实现。
实施例1
(1)黑磷纳米片BPNPs的制备
将BP 25mg溶于50ml纯水中,剧烈搅拌。用流动氩气对溶液进行脱气,以消除溶解氧分子,减少汽提过程中的氧化。然后,在冰浴中以250W的功率对混合溶液进行超声处理(开启45s,关闭15s,总时间为12h)。获得的棕色分散体在1000rpm下离心10min,去除大块BP,收集含有BPNPs的上清液。然后将收集到的含有BPNPs的上清液在4℃下以3750rpm离心30min去水。将获得的纯BPNPs在PBS中重悬,得到BPNPs-BPS溶液以供进一步使用,并在4℃下保存。
(2)PAMAM-SeSe-FA的制备
2.1合成NH2-PEG-SeSe-NH2:取10mg硒代胱胺盐酸盐溶于6mL水中,将15mg EDC和12mg NHS加入到硒代胱胺盐酸盐溶液中搅拌反应4h。并将硒代胱胺盐酸盐溶液逐滴加入到15mL的NH2-PEG-COOH溶液中,室温搅拌反应过夜。透析24小时,冻干得到NH2-PEG-SeSe-NH2。
2.2合成PAMAM-FA
取5mg的FA溶于DMSO中,将10.2mg EDC和8.5mg NHS加入FA溶液中,室温搅拌4小时,再将其逐滴加入到10mL,50mg的PAMAM溶液中,室温搅拌反应过夜,透析24小时,冻干得到PAMAM-FA。
2.3合成PAMAM-SeSe-FA
取20mg 2.2中合成的PAMAM-FA溶液于水中,将18mg EDC和16.5NHS加入PAMAM-FA溶液中,室温搅拌4小时,再将其逐滴加入到NH2-PEG-SeSe-NH2水溶液中,室温搅拌反应过夜。透析24小时,冻干得到PAMAM-SeSe-FA。
(3)纳米载体BP@PAMAM-SeSe-FA制备
取0.5mL 750μg/mL的BPNPs-BPS溶液,在转速为6000rpm下离心30min,去除上清重悬于2mL的水中。加入10mg PAMAM-SeSe-FA,超声30min,搅拌反应6h。反应结束后离心(6000rpm,30min),重悬在2mL的水中,备用。
表征与测试:
形貌表征
图1为步骤(1)得到的黑磷纳米片BPNPs及最终合成的纳米载体BP@PAMAM-SeSe-FA的透射电镜图,从图中可以看出各组的黑磷纳米片为片状结构,其粒径集中大小约200nm,聚合物的修饰不影响黑磷的片层结构。
Zeta电位测试
图2为合成的BPNPs、PAMAM-SeSe-FA、BP@PAMAM-SeSe-FA、及负载基因后的BP@PAMAM-SeSe-FA/shCRNDE样品的Zeta电位测试结果,其中负载基因的样品是通过将BP@PAMAM-SeSe-FA水溶液与基因均匀混合,然后在室温条件下复合0.5h得到BP@PAMAM-SeSe-FA/shCRNDE复合物;结果表明,BPNPs电位为-15.3mV,PAMAM-SeSe-FA修饰后,BP@PAMAM-SeSe-FA的电位为+18mV;BP@PAMAM-SeSe-FA相对于PAMAM-SeSe-FA,正电荷略有降低,这是因为黑磷带负电,PAMAM-SeSe-FA带正电,静电相互作用得到BP@PAMAM-SeSe-FA,因此BP@PAMAM-SeSe-FA正电荷略有降低,但正电荷仍保持在约+18mV,负载基因后BP@PAMAM-SeSe-FA/shCRNDE的电位为+13.4mV,说明纳米体系能够很好的负载基因。
细胞毒性
利用CCK-8检测细胞活性的方法来评价纳米载体BP@PAMAM-SeSe-FA对BEL-7402细胞的细胞毒性。具体操作步骤如下:首先将BEL-7402细胞以5000个/孔的密度接种于96孔板中,然后将其置于二氧化碳培养箱中培养贴壁过夜。随后,吸出原有的培养基,换上新鲜的含有不同浓度的BP@PAMAM-SeSe-FA的完全培养基,所选的BP@PAMAM-SeSe-FA的浓度范围为5-300μg/mL,每个浓度有5个平行。然后在培养箱中培养24h,培养后用PBS将细胞洗涤一次后并向各孔中加入100μL的新鲜培养基(含有10% CCK-8)。置于培养箱中孵育一段时间,最后使用酶标仪检测并记录在450nm波长处的吸光度,通过以下公式计算细胞存活率:细胞存活率(%)=(实验组吸光度-空白组吸光度)/(阴性对照组吸光度-空白组吸光度)×100%。如图3所示,当BP@PAMAM-SeSe-FA纳米粒子浓度为10μg/mL时BEL-7402细胞的细胞存活率为102.5%,可见低浓度的黑磷纳米粒子并未影响细胞增殖。此外,随着黑磷纳米粒子浓度的逐渐增加,BEL-7402细胞的存活率稍有下降但依然保持着很高的存活率,当BP@PAMAM-SeSe-FA纳米粒子浓度为100μg/mL时,细胞的存活率依次为97.4%。当BP@PAMAM-SeSe-FA纳米粒子浓度高达300μg/mL时,细胞的细胞存活率依然大于90%,可见即使黑磷纳米粒子很高,但细胞毒性仍然很低,说明了本发明实施例的纳米载体具有较低的细胞毒性。
光热性能
将得到的纳米载体BP@PAMAM-SeSe-FA分散在水中,配置成不同浓度(40、80、160和320μg/mL)的溶液。在室温下,取1mL上述不同浓度的溶液分别加入比色皿中,***热电偶温度计,用功率为1.5W/cm2的808nm近红外光照射液面5min,每隔10s记录一次温度。以时间为横坐标,温度为纵坐标作图,对比不同浓度的材料体外光热效果。同时以去离子水作为对照组,并用红外热成像仪记录。如图4为不同浓度条件下材料的时间-温度曲线。从图中可以发现,浓度越高,升温越明显。在材料浓度为50μg/mL时,温度在5min内上升至48.3℃。证明本发明实施例的纳米载体具有良好的光热性能。
体外抑制细胞增殖
为了探究本发明实施例的纳米基因载体在基因和光热条件下的细胞毒性,选用肝癌细胞BEL-7402,设立了5组实验对照,对每组细胞分别添加以下纳米粒子共培养:shCRNDE,BP@PAMAM-SeSe-FA,BP@PAMAM-SeSe-FA+NIR,BP@PAMAM-SeSe-FA/shCRNDE+NIR,BP@PAMAM-SeSe-FA/shCRNDE,其中负载基因样品的制备参照上文,然后以PBS组作为对照,其中NIR代表用808nm NIR近红外激光照射处理,激光功率密度为1.5W/cm2,光照时间为5min,每孔的基因量为0.5μg。各组细胞在同等条件下共培养24h后,用CCK-8法细胞增殖检测试剂盒检测细胞活性。结果如图5所示,其中1.PBS,2.shCRNDE,3.BP@PAMAM-SeSe-FA,4.BP@PAMAM-SeSe-FA+NIR,5.BP@PAMAM-SeSe-FA/shCRNDE,6.BP@PAMAM-SeSe-FA/shCRNDE+NIR。
结果标明,单独的材料BP@PAMAM-SeSe-FA的细胞存活率与PBS组的相比无明显差异,证明材料的细胞安全性,BP@PAMAM-SeSe-FA+NIR组的细胞存活率为65.3%,BP@PAMAM-SeSe-FA/shCRNDE组的细胞存活率为50.9%,而BP@PAMAM-SeSe-FA/shCRNDE+NIR细胞存活率为20.9%,证明本发明实施例的纳米载体在应用是,基因与光热联合才能更多的杀死肝癌细胞。
综上可以看出,本发明的靶向纳米载体,以黑磷为核心骨架,由于其优异的光学性质,使得纳米载体具有光热效果;通过包覆修饰改性聚合物PMMA可以使载体具有丰富的正电荷,增加其负载带负电荷的功能基因的能力如shCRNDE基因;而且双硒键具有GSH响应性,这样具有GSH响应的改性聚合物PAMAM包覆,可防止黑磷降解,提高载体稳定性;同时,将FA修饰为靶向肝癌细胞上FA受体的引导分子,促进了纳米材料在肿瘤细胞的富集。该纳米载体应用时,可将基因、光热疗法的结合,实现对肝癌的高效联合治疗,为肝癌的高效治疗提供了新思路。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (7)
1.一种靶向纳米载体的制备方法,所述靶向纳米载体包括黑磷纳米片及包覆在所述黑磷纳米片表面的改性PAMAM,所述改性PAMAM中含有双硒键,并修饰有FA叶酸分子;所述纳米载体的粒径为200nm,Zeta电位18 mV;其特征在于,所述制备方法包括如下步骤:
(1)制备黑磷纳米片BPNPs:将黑磷分散于纯水中,搅拌,用流动氩气进行脱气,然后在冰浴条件下对溶液进行超声处理,获得的棕色分散体,然后对所述棕色分散体离心,收集上清液并将收集到的上清液进一步离心,得到黑磷纳米片BPNPs;
(2)制备PAMAM-SeSe-FA,包括:
2.1 合成NH2-PEG-SeSe-NH2:取硒代胱胺盐酸盐溶于水中,将EDC和NHS加入到硒代胱胺盐酸盐溶液中搅拌反应;然后逐滴加入到NH2-PEG-COOH溶液中,室温搅拌反应、透析、冻干得到NH2-PEG-SeSe-NH2;
2.2 取FA溶于DMSO中,将EDC和NHS加入FA溶液中,室温搅拌,再将其逐滴加入到PAMAM溶液中,室温搅拌反应,透析,冻干得到PAMAM-FA;
2.3取PAMAM-FA溶液于水中,将EDC和NHS加入PAMAM-FA溶液中,室温搅拌,再将其逐滴加入到NH2-PEG-SeSe-NH2水溶液中,室温搅拌反应,透析,冻干得到PAMAM-SeSe-FA;
(3)制备BP@ PAMAM-SeSe-FA:
配置BPNPs水溶液,然后加入PAMAM-SeSe-FA混合,超声、搅拌反应得到BP@ PAMAM-SeSe-FA纳米载体,即所述的靶向纳米载体。
2.根据权利要求1所述的制备方法,其特征在于,所述步骤(1),黑磷与纯水的质量体积比为10~30mg:20~80ml;所述超声时间为6 h~24 h;所述的棕色分散体的离心转速为500rpm~1000 rpm;所述收集到的上清液的离心转速为2000 rpm~4000 rpm。
3.根据权利要求1所述的制备方法,其特征在于,
所述步骤2.1中,原料配比为硒代胱胺盐酸盐:去离子水:EDC:NHS:NH2-PEG-COOH=5~15mg:2~8ml:5~25mg:5~20mg:5~50ml;EDC和NHS与硒代胱胺盐酸盐的反应时间为1~6h;硒代胱胺盐酸盐溶液与NH2-PEG-COOH的反应时间为6~24 h;
所述步骤2.2中,FA与PAMAM的质量比为1~10:30~70。
4.根据权利要求1所述的制备方法,其特征在于,所述步骤(3)中,BPNPs与PAMAM-SeSe-FA的质量比为0.1~0.5:5~15;所述的超声时间为10~40 min;所述的反应时间为2~8 h。
5.根据权利要求1所述的制备方法,其特征在于,所述步骤(1)还包括将获得的BPNPs在PBS溶液中重悬,得到BPNPs-PBS溶液,然后保存在4°C下。
6.根据权利要求5所述的制备方法,其特征在于,所述步骤(3)中,配置BPNPs水溶液是将所述的BPNPs-PBS溶液离心,去除上清液然后重悬于水中得到。
7.根据权利要求6所述的制备方法,其特征在于,所述的离心转速为4000 rpm~8000rpm。
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