CN114848577A - 一种用于治疗皮下肿瘤的双层导电微针贴片及其制备方法和应用 - Google Patents
一种用于治疗皮下肿瘤的双层导电微针贴片及其制备方法和应用 Download PDFInfo
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- CN114848577A CN114848577A CN202210392829.5A CN202210392829A CN114848577A CN 114848577 A CN114848577 A CN 114848577A CN 202210392829 A CN202210392829 A CN 202210392829A CN 114848577 A CN114848577 A CN 114848577A
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Abstract
本发明涉及生物医用材料技术领域,具体涉及一种用于治疗皮下肿瘤的双层导电微针贴片及其制备方法和应用,由不含目标药物的导电微针基底和含有目标药物的双层微针针尖所组成,微针针尖由易溶解聚合物基质制备而成,微针基底及靠近基底部分微针针尖由可降解聚合物基质与导电高分子材料制备而成,具有优异的生物相容性,无潜在的刺激性和免疫原性;基底及靠近基底部分微针针尖采用的导电高分子材料,具有良好的导电性,利于电穿孔增加细胞膜通透性,增加生物制剂或药物吸收率;有效地抑制肿瘤细胞的增殖;通过微针技术,可以将目标药物集中分布在微针针尖,提高局部有效药物浓度且节约用药成本;具有精度高、规模化、经济高效优点。
Description
技术领域
本发明涉及生物医用材料技术领域,具体涉及一种用于治疗皮下肿瘤的双层导电微针贴片及其制备方法和应用。
背景技术
皮下肿瘤是指生长在皮肤下面的肿瘤。皮下肿瘤分为良性肿瘤和恶性肿瘤,良性肿瘤的特点是生长速度比较缓慢,边界比较清楚,有完整的包膜,比较常见的皮下肿瘤是囊性肿瘤,内有液体。皮下的恶性肿瘤生长的特点是生长速度比较快,边界不清楚,有毛刺,一般是实体性的肿瘤,没有完整的包膜,里边有丰富的血流供用。良性皮下肿瘤通过手术切除可以治愈,恶性皮下肿瘤如果能够早发现、早诊断、早治疗,肿瘤没有扩散和转移,通过扩大手术切除,一般可以治愈。皮下肿瘤的种类有很多,比如最常见的有皮脂腺肿瘤,肿瘤的内容物主要是皮脂腺的分泌物,大部分患者的肿瘤比较小,少数患者可以形成巨大的肿物。
口腔癌是世界上最常见的二十种致死性肿瘤之一,2020年大约有17万人死于口腔癌,占全球癌症总死亡人数的2.0%。中国口腔癌发病率在世界上位于第六位,口腔癌在全身恶性肿瘤发病率的比例是1.5%-5.6%,口腔癌俨然已经是一个全球性的公共卫生问题。在口腔癌的病理分类中,口腔鳞状细胞癌占了90%以上。虽然医疗技术在不断进步,但现如今人们仍然是谈“癌”色变,关于大部分癌症,仍然没有找到一种根治的方法,口腔鳞癌也是如此。目前口腔鳞癌的传统治疗手段是以手术为主,放疗、化疗为辅的综合治疗。这些方法存在一些不足:手术本身的风险及切除导致的颜面部美观和功能损伤;放疗范围的扩大对颌面部腺体的损伤;化疗药物靶向性差、生物利用度较低、药物在不希望的周围器官中积聚、在血液中被快速清除导致整体疗效降低。
微针透皮给药的出现给人们带来新的思考。由于简单、易于管理、无创、愈合更快,微针可用作皮下注射的替代品,用于在真皮和皮下层局部、安全和无痛地递送疫苗、药物和基因等。针对体表肿瘤,即发生在身体浅表部分的肿瘤,微针可以穿透角质层到达皮下或是皮下体表肿瘤部位,同时还有创口小、痛感轻等优点,因此,使用载有药物/疫苗等的微针将生物制剂输送到皮下可以实现对体表肿瘤的靶向作用,提高药物利用率,降低药物毒副作用。专利CN108379095A公开了一种可溶性微针贴片及其制备方法,所述可溶性微针贴片中添加了可溶性和/或生物可降解性的粘性混合物,起到粘附作皮肤作用,有效的解决了因长时间贴服粘性胶带之后,摘除时的皮肤拉扯,疼痛等不良反应。使得用户的使用过程更加舒服,便捷。专利CN111408047A公开了一种用于创面修复的导电微针贴片及其制备方法,所述的微针贴片包裹“E形”导轨的导电微针单位;两个针尖相对的导电微针单位间隔连接在纱布上,并通过固定在“E形”导轨中的导线分别连接电源正负极,从而制得卡扣状的导电微针贴片,在连接外部电源时,两个微针单位间形成空间电场,可诱导细胞迁移、促进细胞增殖分化,从而加速创面愈合,功能多样、疗效显著,适用范围广。但是,微针作为药物递送系统,只能将药物送至皮下,不能将药物直接送至细胞内,导致了药物药效的降低。
针对上述技术问题,本发明提供了一种双层导电微针贴片,所述的微针贴片低成本、高效率、操作简便,具有良好的生物相容性且无体内毒性,可精准递送生物制剂或药物至皮下肿瘤部位,再利用微针的导电基底,通过电穿孔增加细胞膜通透性,从而利于生物制剂或药物进入细胞,实现治疗目的。
发明内容
为了实现上述目的,本发明的首要目的是提供一种双层导电微针贴片,所述的双层导电微针贴片由不含目标药物的导电微针基底和含有目标药物的双层微针针尖所组成,所述的微针针尖由易溶解聚合物基质制备而成,所述的导电微针基底及靠近基底部分微针针尖由可降解聚合物基质与导电高分子材料制备而成。
本发明的第二目的是提供所述的双层导电微针贴片的制备方法,所述的制备方法包括如下步骤:
(1)微针针尖溶液的制备:取1%-50%w/v易溶解聚合物基质与目标药物溶于去离子水中搅拌均匀;
(2)微针导电基底材料的制备:取1%-50%w/v可降解聚合物基质与0.1%-50%w/v导电高分子材料溶于去离子水中形成混合溶液;
(3)在微针模板上均匀滴加步骤(1)制备的针尖溶液,常温抽真空,干燥,刮去底板多余材料,重复上述操作制备得到药物集中分布的针尖;
(4)将步骤(2)制备的微针导电基底材料溶液均匀涂布于步骤(3)制备得到的微针模板上,常温抽真空,干燥,获得成型微针贴片;
(5)将步骤(4)中成型微针贴片从微针模板上剥离,获得双层导电微针贴片。
优选的,步骤(1)所述的易溶解聚合物基质为透明质酸、海藻酸钠、聚乙烯吡咯烷酮、羧甲基纤维素、聚-L谷氨酸中的一种或几种;步骤(2)所述的可降解聚合物基质为聚乳酸、聚乙酸醇、聚乳酸-乙醇酸共聚物、聚碳酸酯、聚己内酯、聚乙二醇二丙烯酸酯中的一种或几种;所述的导电高分子材料为聚吡咯、碳纳米管、聚乙炔、聚苯胺、聚噻吩中的一种或几种。
优选的,步骤(1)所述的目标药物为核苷酸、DNA、RNA、质粒、多肽、蛋白、糖类、染料、病毒、阿霉素、紫杉醇中的一种或几种。
优选的,步骤(3)和步骤(4)所述的抽真空的压力为-0.8kPa,干燥时间为1-12h。
本发明的第三目的是提供一种透皮给药系统,所述的透皮给药系统通过所述的方法制备得到。
本发明的第四目的是提供所述的双层导电微针贴片用于制备治疗局部疾病药物中的应用。
本发明的第五目的是提供所述的双层导电微针贴片用于制备治疗皮下肿瘤的药物中的应用。
优选的,所述的皮下肿瘤为口腔癌和黑色素瘤。
优选的,所述的口腔癌为口腔鳞癌。
本发明的有益效果是:(1)本发明提供了一种用于治疗皮下肿瘤的双层导电微针贴片,针尖溶液和基底材料采用易溶解且可降解的聚合物基质,具有优异的生物相容性,安全性高,无潜在的刺激性和免疫原性;(2)所述的微针贴片采用真空浇筑法制备,在制备针尖的过程中,干燥后的针尖并没有完全填充模板,后将基底液加入,使得部分基底液进入到针尖根部,完成基底部分和针尖部分的连接;(3)将目标药物添加在针尖中,可无痛、微创、高效地将药物运送到皮下,避免传统注射引起的炎症、感染、出血等副作用,提高局部有效药物浓度且节约用药成本;(4)所述的导电微针贴片基底和针尖根部采用的导电高分子材料,具有良好的导电性和生物相容性,利于电穿孔增加细胞膜通透性,从而增加生物制剂或药物吸收率;能有效地抑制肿瘤细胞的增殖,达到治疗肿瘤的目的;(5)所述的微针贴剂具有精度高、规模化、经济高效等优点,且本发明所述的制备方法,简单明了,制备条件容易满足,易实现批量化生产。
附图说明
图1为本发明提供的双层导电微针贴片的显微照片
图2为本发明提供的不同时间、不同处理对肿瘤治疗效果的大体照片
图3为本发明双层导电微针贴片治疗结束后各分组肿瘤剥离后的照片
图4为本发明双层导电微针贴片治疗期间肿瘤体积变化定量折线图
图5为本发明双层导电微针贴片治疗结束后各分组肿瘤组织的染色
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
以下实施例所述的苏木精-伊红染色法(hematoxylin-eosin staining),简称HE染色法,石蜡切片技术里常用的染色法之一。苏木精染液为碱性,主要使细胞核内的染色质与胞质内的核酸着紫蓝色;伊红为酸性染料,主要使细胞质和细胞外基质中的成分着红色。H&E染色法是组织学、胚胎学、病理学教学与科研中最基本、使用最广泛的技术方法。
以下实施例所述的TUNEL染色可检测细胞在凋亡过程中细胞核DNA的断裂情况,其原理是标记(荧光或者生物素)的dUTP在脱氧核糖核苷酸末端转移酶(Tdl Enzyme)的作用下,可以连接到凋亡细胞中断裂的DNA的3’-OH末端,再通过荧光激发或者化学显色的方法,特异准确地检测发生凋亡的细胞,而正常的或正在增殖的细胞几乎没有DNA的断裂,因而没有3'-OH形成,很少能够被染色。本实验适用于组织和细胞样本的凋亡原位检测。
以下实施例所述的免疫组化染色,是应用免疫学中抗原与抗体特异性结合的反应原理,一般采取生物素标记抗体以显示组织内抗原的方法,对抗原进行定位、定性及相对定量的研究。临床根据H&E切片的情况,选择是否加做免疫组化。较为典型不需检查即可明确的情况下,无需加做免疫组化。无法明确诊断的情况,则需加做免疫组化进一步证实肿瘤类型,避免影响患者的治疗。
以下实施例所述的人舌鳞癌细胞(CAL27)购自中国上海iCell生物科学有限公司。
以下实施例所述的质粒购自源井生物有限公司,其主要作用是对PLK1基因进行敲除。实施例1、双层导电微针贴片的制备
(1)制备透明质酸微针针尖溶液(20%w/v):称取1g透明质酸钠(分子量10万~20万)溶于10mL去离子水中,磁力搅拌下搅拌24h,确保充分溶胀;
(2)将步骤(1)中的透明质酸钠溶液与设计对PLK1基因进行敲除的CRISPR/Cas9质粒混合均匀得到载药针尖制作液,质粒浓度为100ng/μL;
(3)20%聚乙烯醇与1%多巴胺改性的聚吡咯溶于去离子水中形成混合溶液。
(4)微针模板上均匀滴加步骤(2)制备的针尖溶液100μL,常温抽真空至-0.8kPa,干燥20min后刮去底板多余材料,重复上述滴加与加压操作,刮除多余材料,干燥12h,形成可溶载质粒的针尖;
(5)将步骤(3)中制备的微针导电基底材料溶液均匀涂布于步骤(4)干燥后的微针模板上,常温抽真空至-0.8kPa,干燥12h,获得成型微针贴片;
(6)将步骤五中成型微针贴片从微针模板上剥离,获得双层导电微针贴片。
制备得到的双层导电微针贴片如图1所示,所载药物集中于微针贴片的针尖部分。此微针贴片的针尖部分为质粒DNA和可快速溶解的透明质酸,基底部分材料为生物相容性和导电性优异的多巴胺改性聚吡咯及在体内外均可降解的聚乙烯醇,且针尖的根部为可导电的基底材料,针尖的根部可插入到皮肤中。
实施例2、双层导电微针贴片的制备
该实施例与实施例1相同,不同之处在于:步骤(1)制备得到的透明质酸溶液的质量分数为15%。
实施例3、双层导电微针贴片的制备
该实施例与实施例1相同,不同之处在于:步骤(3)使用的聚乙烯醇溶液的质量分数为15%。
实施例4、双层导电微针贴片的制备
该实施例与实施例1相同,不同之处在于:步骤(3)中将20%聚乙烯醇换为30%聚乙烯吡咯烷酮。
实施例5、双层导电微针贴片的制备
该实施例与实施例1相同,不同之处在于:步骤(3)中将1%多巴胺改性的聚吡咯替换为1%碳纳米管。
实施例6、双层导电微针贴片的制备
该实施例与实施例1相同,不同之处在于:将步骤(1)中的质粒DNA替换为100ng/μL小干扰RNA。
实验例、本发明提供的双层导电微针贴片治疗皮下肿瘤的疗效评估。
使用实施例1制备得到的双层导电微针贴片治疗皮下肿瘤。
1.受试对象:
5周龄的雄性裸鼠,60只,体重15-20g,购于北京维通利华实验动物技术有限公司。裸鼠背部右侧皮下注射0.2mL处于对数期的人舌鳞癌细胞(CAL27)悬液(浓度为1×107个/mL),建立皮下肿瘤模型。待皮下肿瘤直径达到3-5mm或肿瘤体积达到120mm3时(约12天左右)认为裸鼠皮下肿瘤建模成功。
2.实验分组及治疗:
(1)空白对照组(Control组):不进行治疗;
(2)阿霉素治疗组(DOX组):该组每只裸鼠腹腔注射溶于PBS中的阿霉素,浓度为1mg/mL,剂量为5.33mg/kg裸鼠体重,给药频率为一周一次,共3次;
(3)注射器注射质粒(源井生物有限公司)+电刺激组(i.j.+E组):该组每只裸鼠在皮下肿瘤原位使用1mL注射器注射含25μg质粒的溶液后,在肿瘤部位施加脉冲频率10Hz,电压幅值70V的持续脉冲,每次治疗时进行7次脉冲电刺激;
(4)微针注射质粒组(p-MN组):该组每只裸鼠使制备的双层导电载质粒微针刺入肿瘤所在部位皮肤,5min后取下微针贴片;
(5)微针注射质粒+电刺激组(p-MN+E组):同p-MN组中步骤,将双层微针贴片刺入裸鼠肿瘤所在部位5min后,将电刺激直接施加于导电微针贴片的基底上,同样进行7次频率10Hz,电压幅值70V的脉冲电刺激,随后取下微针贴片。
第(3)、(4)、(5)组,每两天治疗一次,共治疗5次。
3.疗效评价:在治疗期间,每3天用游标卡尺测量肿瘤长短径并计算肿瘤体积。当肿瘤长径达2cm或者所有治疗完成72h后,过量麻醉处死裸鼠,并取肿瘤组织置于4%多聚甲醛内固定,进行H&E染色、TUNEL染色、免疫组化染色,观察各组裸鼠肿瘤组织病理变化。
4.实验结果:
图2和3分别显示了各分组裸鼠治疗过程中及治疗后的肿瘤照片。图4定量显示了各治疗分组的肿瘤体积变化曲线。可以看到,空白对照组肿瘤一直呈现增长的趋势,18天后约为初始体积的17.87倍;微针注射质粒但未施加电刺激的p-MN组与对照组无显著性差异,在没有电场或其他载体的情况下质粒几乎无法进入细胞内实现转染和基因敲除;其余组均有一定的治疗效果。其中治疗效果最优异的是p-MN+E组,肿瘤体积减小为初始体积的44.13%,表明微针将CRISPR/Cas9质粒释放至皮下后,电穿孔促使其进入细胞内,从而使得肿瘤细胞中PLK1敲除,抑制了肿瘤细胞有丝分裂。阿霉素作为一线化疗药物,治疗效果次之,肿瘤体积仅增为初始体积的2.45倍。i.j.+E组最终肿瘤体积为初始的8.68倍,由于使用注射器进行质粒的瘤内注射较难实现质粒的均匀分布,但在电刺激的作用下也实现了部分肿瘤细胞的转染。
图5显示了对各分组治疗后肿瘤组织的一些染色。H&E染色结果中,p-MN+E组治疗后较其余组肿瘤细胞死亡和炎性浸润的范围更大,且存在出血点、坏死灶、核固缩等病理损伤。TUNEL染色结果中,p-MN+E组绿色荧光所占比最大,凋亡细胞数最多。免疫组化染色所选蛋白PLK1和Ki67均与细胞增殖呈正相关。可以看到,各分组中Ki67与PLK1阳性细胞率的趋势大致相同。其中,对照组的阳性细胞率均为最高,表明细胞增殖较快;p-MN+E组阳性细胞率最低,表明肿瘤细胞的增殖得到了明显抑制。动物实验表明本发明提供的双层导电微针贴片用于治疗皮下肿瘤,使用后肿瘤体积明显减小,肿瘤细胞增殖得到明显抑制,疗效显著。
综上所述,本发明提供了一种用于治疗皮下肿瘤的双层导电微针贴片,针尖溶液和基底材料采用易溶解且可降解的聚合物基质,具有优异的生物相容性,安全性高,无潜在的刺激性和免疫原性;所述的微针贴片采用真空浇筑法制备,在制备针尖的过程中,干燥后的针尖并没有完全填充模板,后将基底液加入,使得部分基底液进入到针尖根部,完成基底部分和针尖部分的连接;将目标药物添加在针尖中,可无痛、微创、高效地将药物运送到皮下,避免传统注射引起的炎症、感染、出血等副作用,提高局部有效药物浓度且节约用药成本;所述的导电微针贴片基底和针尖根部采用的导电高分子材料,具有良好的导电性和生物相容性,利于电穿孔增加细胞膜通透性,从而增加生物制剂或药物吸收率;能有效地抑制肿瘤细胞的增殖,达到治疗肿瘤的目的;所述的微针贴剂具有精度高、规模化、经济高效等优点,且本发明所述的制备方法,简单明了,制备条件容易满足,易实现批量化生产。
最后应说明的是:虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施例中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式,以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围内。
Claims (10)
1.一种双层导电微针贴片,其特征在于,所述的双层导电微针贴片由不含目标药物的导电微针基底和含有目标药物的双层微针针尖所组成,所述的微针针尖由易溶解聚合物基质制备而成,所述的导电微针基底及靠近基底部分微针针尖由可降解聚合物基质与导电高分子材料制备而成。
2.如权利要求1所述的双层导电微针贴片的制备方法,其特征在于,所述的制备方法包括如下步骤:
(1)微针针尖溶液的制备:取1%-50%w/v易溶解聚合物基质与目标药物溶于去离子水中搅拌均匀;
(2)微针导电基底材料的制备:取1%-50%w/v可降解聚合物基质与0.1%-50%w/v导电高分子材料溶于去离子水中形成混合溶液;
(3)在微针模板上均匀滴加步骤(1)制备的针尖溶液,常温抽真空,干燥,刮去底板多余材料,重复上述操作制备得到药物集中分布的针尖;
(4)将步骤(2)制备的微针导电基底材料溶液均匀涂布于步骤(3)制备得到的微针模板上,常温抽真空,干燥,获得成型微针贴片;
(5)将步骤(4)中成型微针贴片从微针模板上剥离,获得双层导电微针贴片。
3.如权利要求2所述的双层导电微针贴片的制备方法,其特征在于,步骤(1)所述的易溶解聚合物基质为透明质酸、海藻酸钠、聚乙烯吡咯烷酮、羧甲基纤维素、聚-L谷氨酸中的一种或几种;步骤(2)所述的可降解聚合物基质为聚乳酸、聚乙酸醇、聚乳酸-乙醇酸共聚物、聚碳酸酯、聚己内酯、聚乙二醇二丙烯酸酯中的一种或几种;所述的导电高分子材料为聚吡咯、碳纳米管、聚乙炔、聚苯胺、聚噻吩中的一种或几种。
4.如权利要求2所述的双层导电微针贴片的制备方法,其特征在于,步骤(1)所述的目标药物为核苷酸、DNA、RNA、质粒、多肽、蛋白、糖类、染料、病毒、阿霉素、紫杉醇中的一种或几种。
5.如权利要求2所述的双层导电微针贴片的制备方法,其特征在于,步骤(3)和步骤(4)所述的抽真空的压力为-0.8kPa,干燥时间为1-12h。
6.一种透皮给药系统,其特征在于,所述的透皮给药系统通过权利要求2-5任一项所述的方法制备得到。
7.如权利要求1所述的双层导电微针贴片用于制备治疗局部疾病药物中的应用。
8.如权利要求1所述的双层导电微针贴片用于制备治疗皮下肿瘤的药物中的应用。
9.如权利要求8所述的应用,其特征在于,所述的皮下肿瘤为口腔癌和黑色素瘤。
10.如权利要求9所述的应用,其特征在于,所述的口腔癌为口腔鳞癌。
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