CN107737127B - 一种氯喹和靶向共输送纳米复合物的组合物的应用 - Google Patents
一种氯喹和靶向共输送纳米复合物的组合物的应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，具体涉及一种由治疗有效量的氯喹和靶向共输送纳米复合物组成的药物组合物的应用。本发明的药物组合物作为联合制剂供同时、分开或顺序使用用于治疗肿瘤。经体内实验和体外实验，结果显示，能够获得优于两种药物单独使用的药效。本发明的药物组合物可用于制备治疗肿瘤的药物，有效地提高了药物的生物利用度，提升其临床应用价值。
Description
技术领域
本发明属于生物医药技术领域，涉及一种氯喹促进血管正常化增加靶向共输送纳米复合物输送以获得更佳抗癌疗效的应用。
背景技术
肿瘤血管能为肿瘤组织提供营养，运走代谢产物，实体肿瘤的生长和转移依赖新生血管的生成。目前，临床上使用的抗肿瘤血管生成药物，如血管内皮生长因子（vescularendothelial grother factor，VEGF）特异性阻断剂贝伐单抗和酪氨酸激酶受体抑制剂索拉非尼等，就是通过抑制肿瘤组织血管的新生以及摧毁已经存在的血管，从而使肿瘤组织处于无血管、无营养的状态（虞永峰，庄兰妹 ，陆 舜. 抗肿瘤血管生成：肺癌治疗新希望——2006年ASCO新进展[J]. 肿瘤，2006, (7):592-595）。诸多临床研究显示，这些药物均有一定的抗肿瘤疗效，且可以延长患者的生存时间。
但不幸的是，近年来许多临床前和临床研究发现，抗肿瘤血管生成治疗（如VEGF特异性抗体贝伐单抗）仅有短暂和轻微的治疗效果，长期使用会出现耐药性，甚至在使用抗血管疗法数月后，患者的病情会出现复发的现象（Van Cutsem E, Lambrechts D, PrenenH, Jain RK, Carmeliet P. Lessons from the adjuvant bevacizumab trial on coloncancer: what next Journal of clinical oncology : official journal of theAmerican Society of Clinical Oncology. 2011;29:1-4）。究其原因可能在于肿瘤组织内的血管结构和功能与正常血管有很大的差异。若使用这些抗血管生成药物则会加重肿瘤血管的异常，减少氧的供给，产生缺氧和酸性微环境，使肿瘤细胞更具侵袭性和转移性。这种血管的异常还能够阻断药物与氧气的递送，降低化疗和放疗的抗肿瘤效果，导致癌症患者的病情复发，产生恶性循环（Crawford Y, Ferrara N. VEGF inhibition: insightsfrom preclinical and clinical studies. Cell and tissue research. 2009;335:261-9）。针对临床上出现的这些问题，Jain 提出了肿瘤血管正常化理论。合理地运用抗血管生成药物，使肿瘤血管趋于正常，更有效地输送化疗药物和氧气到肿瘤部位，从而增强化疗和放疗的治疗效果。
氯喹（chloroquine）是一种人工合成含有4-氨基喹啉环结构的化合物，其结构如下：
。
作为传统的老药，不仅用于抗疟疾治疗，还用于类风湿关节炎、红斑狼疮等疾病的治疗（Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an olddrug for effective and safe cancer therapies. European journal ofpharmacology. 2009;625:220-33）。研究发现，氯喹具有抗肿瘤活性，可以通过抑制自噬，诱导凋亡以及抑制细胞增殖（Fan C, Wang W, Zhao B, Zhang S, Miao J. Chloroquineinhibits cell growth and induces cell death in A549 lung cancer cells.Bioorganic & medicinal chemistry. 2006;14:3218-22）。最近有报道称，氯喹可通过不依赖于自噬的作用导致肿瘤血管结构和功能正常化，改善肿瘤所处的微环境，增加化疗药物的渗透。氯喹兼具抑制自噬和促进血管正常化的作用，为肿瘤抗血管治疗提供新方向（Maes H, Kuchnio A, Peric A, Moens S, Nys K, De Bock K, et al. Tumor vesselnormalization by chloroquine independent of autophagy. Cancer cell. 2014;26:190-206）。
靶向共输送纳米复合物，相对于一般的化疗药物有显著的靶向治疗作用，通过共输送多种药物，起到联合治疗目的。目前有很多联合氯喹和抗癌药物增加疗效的方法如一种氯喹和长春新碱的组合（CN104906099A）、包含羟基氯喹的用于抗癌治疗的局部投药用注射剂组合物（CN102481253A）等都被开发出来。但还没有通过联合氯喹促血管正常化增加靶向共输送纳米载药复合物输送的应用。
为了克服现有技术的不足，本发明通过利用氯喹的促进血管正常化的作用，提高靶向共输送纳米复合物输送。提升其临床应用价值。检索国内外相关文献和专利结果表明：尚未见报道关于通过联合氯喹促血管正常化增加靶向共输送纳米复合物输送的应用。
发明内容
本发明的目的是为了克服现有技术的不足，提供一种通过联合氯喹促血管正常化作用，改善肿瘤血管微环境，增加靶向共输送纳米复合物的输送。从而有效地提高了药物的生物利用度，提升其临床应用价值。
为了实现上述目的，本发明采用以下技术方案：一种氯喹和靶向共输送纳米复合物的组合物的应用，其作为联合制剂供同时、分开或顺序使用。
本发明所提及的靶向共输送纳米复合物是通过对常见载体聚酰胺-胺型树状高分子（PAMAM）进行修饰产生特异性靶向作用，包括但不限于适配体修饰，叶酸修饰等。
本发明所提及的靶向共输送纳米复合物是通过利用修饰后的PAMAM包载抗肿瘤药物或者压缩基因药物，或者同时包载抗肿瘤药物并压缩基因药物。
所述的肿瘤疾病是选自结肠癌、结肠直肠癌、胃癌、乳腺癌、肺癌、卵巢癌、肝癌、支气管癌、鼻咽癌、喉癌、胰脏癌、膀胱癌、胰腺癌、宫颈癌、脑癌、前列腺癌、骨癌、皮肤癌、甲状腺癌、甲状旁腺癌、肾癌、食道癌、胆道癌、睾丸癌、直肠癌、头颈癌、宫颈癌、输尿管癌、骨肉瘤、神经细胞瘤、黑色素瘤、纤维肉瘤、横纹肌肉瘤、星形细胞瘤、神经母细胞瘤和神经胶质瘤组中的一种或多种。
本发明中，氯喹可以以盐的形式存在，包括但不限于盐酸盐、硫酸盐等。
本发明的有益效果是：
本发明选用氯喹促血管正常化作用，改善肿瘤血管微环境，增加靶向共输送纳米复合物的输送，从而有效地提高了药物的生物利用度，提升临床肿瘤治疗的效果。
附图说明
图1 实施例1中的18 μg/mL的氯喹，25 μg/mL的Apt-G6/ERL，25 μg/mL的Apt-G6/SUV， 25 μg/mL的Apt-G6/ES和组合物（18 μg/mL氯喹和25 μg/mL靶向共输送纳米复合物）对PC9和H1975细胞的体外毒性实验；
图2 实施例3中的生理盐水，Apt-G6/ES（5 mg/kg），组合物（5 mg/kg的Apt-G6/ES和4 mg/kg的氯喹）对体外H1975移植瘤的小鼠体重的影响；
图3实施例3中的生理盐水，Apt-G6/ES（5 mg/kg），组合物（5 mg/kg的Apt-G6/ES和4 mg/kg的氯喹）对体外H1975移植瘤的小鼠肿瘤大小的影响。
具体实施方式
下面，将通过实施例，对本发明进行进一步说明，但发明并不局限于这些实施例，在本发明权利要求所阐明的范围内，可进行各种改变或等同替换。
实施例1
靶向共输送纳米复合物制备：称取100 μL浓度为10 μM Anti-EGFR适配体（Apt）的水溶液，加入10 μg N-羟基琥珀酰亚胺（NHS）和2 μg 1-（3-二甲氨基丙基）-3-乙基碳二亚胺盐酸盐（EDC）的水溶液，室温低速搅拌3 h。加入6 mg第六代PAMAM（10 mg/mL）的水溶液，室温低速搅拌过夜，装入透析袋中透析2 天，冻干，得到Apt-PAMAM聚合物（Apt-G6）。称取100 mg Apt-G6、20 mg 厄洛替尼溶于40 mL 无水甲醇中，装入圆底烧瓶中，密封搅拌反应6h。旋蒸除甲醇，粘稠物用纯水溶解，离心除去沉淀物，将上清液冻干，得到靶向Apt-G6/ERL纳米药物。分别称取100 μL Apt-G6/ERL纳米药物（700μg/mL）和Apt-G6纳米药物（700μg/mL）逐滴加入到高速涡旋的100 μL Survivin shRNA（400 μg/mL）水溶液中，室温孵育25min。得到Apt-G6/ERL/Survivin shRNA（Apt-G6/ES）纳米复合物和Apt-G6/Survivin shRNA（Apt-G6/SUV）纳米复合物。
以人非小细胞肺癌细胞系PC9 细胞和人非小细胞肺癌细胞系H1975 细胞为测试细胞系（细胞购自中国科学院上海生命科学研究所细胞资源中心）。
细胞培养方法：取出液氮中冻存的PC9 细胞，在37℃的温水中解冻，将细胞悬液移入1.5 mL 离心管中，置于离心机中，1500 rpm 离心5 min，弃去上清液，加入1 mL RPMI1640 完全培养液，轻轻吹打均匀，将细胞悬液加入培养皿中，补加3 mL RPMI 1640 完全培养液，将培养皿置于5% CO2、37℃培养箱中培养。取出液氮中冻存的H1975细胞，在37℃的温水中解冻，将细胞悬液移入1.5 mL 离心管中，置于离心机中，1500 rpm 离心5 min，弃去上清液，加入1 mL DMEM 完全培养液，轻轻吹打均匀，将细胞悬液加入培养皿中，补加3 mLDMEM 完全培养液，将培养皿置于5% CO2、37℃培养箱中培养。
细胞毒性实验：将PC9 或H1975 细胞以8×103个细胞/ 孔的密度接种到96 孔培养板中，培养24 h 后，更换培养液为新鲜血清培养液，加入18 μg/mL的氯喹，25 μg/mL的Apt-G6/ERL，25 μg/mL的Apt-G6/SUV和25 μg/mL的Apt-G6/ES，不加纳米药物的孔设为空白对照，孵育1 h 后，吸弃孔中溶液，加入正常完全培养基，继续培养48 h。对于联合用药组，先加25 μg/mL的Apt-G6/ES，孵育1 h 后，吸弃孔中溶液，加入18 μg/mL的氯喹，孵育1 h后，吸弃孔中溶液，加入正常完全培养基，继续培养48 h。吸弃孔中溶液，加入新鲜培养液90μL，同时每孔加入10 μL MTT 溶液（5 mg/mL），继续在37℃、5% CO2（相对湿度90%）培养箱中培养4 h 后，终止培养，小心吸弃上清液，每孔加入150 μL DMSO，避光振荡10 min 使结晶物充分溶解。以酶标仪检测570 nm 处的吸收度（A），按照以下公式计算：细胞存活率%=（试验组平均A值/空白对照组平均A 值）×100%。
纳米药物的细胞毒性结果如图1所示。在PC9和H1975细胞中，氯喹能增加靶向共输送纳米复合物对细胞毒性，比单独使用氯喹或者靶向共输送纳米复合物对细胞的抑制作用更明显，表明所述的氯喹和靶向共输送纳米复合物作为联合制剂能显著增加抗肿瘤效果。
实施例2
H1975裸鼠皮下肿瘤模型的建立：取状态良好且处于对数生长期的H1975细胞，用不含EDTA的胰蛋白酶消化后悬浮于PBS缓冲溶液中，于裸鼠右上肢腋下接种约1×107个细胞，置于清洁无菌环境下继续饲养。
肿瘤血管渗漏实验：当荷瘤鼠的肿瘤长到约100 mm3时，将裸鼠随机地分成三组，分别给药生理盐水，实施例1的Apt-G6/ES（5 mg/kg），组合物（5 mg/kg实施例1的Apt-G6/ES和4 mg/kg的氯喹）。通过尾静脉注射给药，三天一次，给药3次。尾静脉注射TRITC-Dextran（50 mg/kg）标记渗漏的血管，FITC-Lectin（10 mg/kg）标记所有的血管。观察血管结构，发现氯喹和靶向共输送纳米复合物联合可以有效地改善血管渗漏，血管结构更规则。
肿瘤血管成熟度实验：将给药后的肿瘤组织取出，进行石蜡切片，将切片用CD31抗体和α-SMA抗体孵育，发现氯喹和靶向共输送纳米复合物联合给药后，肿瘤微血管数量减少，血管周细胞覆盖率增加，血管趋于成熟化。
实施例3
裸鼠皮下移植瘤生长抑制作用实验：当实施例2中荷瘤鼠的肿瘤体积达到200 mm3左右时，将裸鼠随机地分成三组，分别给药生理盐水，实施例1的Apt-G6/ES（5 mg/kg），组合物（5 mg/kg实施例1的Apt-G6/ES和4 mg/kg的氯喹）。通过尾静脉注射给药，三天一次，给药7次。在此期间，每隔3天用游标卡尺测量肿瘤体积并用电子天平称量裸鼠体重。肿瘤体积根据以下公式计算：肿瘤体积=（最短的垂直直径2×最长的垂直直径）/2。结果如图2所示，在给药期间裸鼠体重变化不大，说明药物对裸鼠不会产生明显的毒性作用，图3所示，氯喹和靶向共输送纳米复合物联合给药后，可以明显抑制肿瘤的生长。
以上所述仅为本发明的较佳实施例，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。
Claims (3)
1.一种氯喹和靶向共输送纳米复合物作为联合制剂在制备抗肿瘤药物中的应用，其特征在于：联合制剂供同时、分开或顺序使用；所述靶向共输送纳米复合物制备：称取100 μL浓度为10 μM Anti-EGFR适配体Apt的水溶液，加入10 μg N-羟基琥珀酰亚胺和2 μg 1-（3-二甲氨基丙基）-3-乙基碳二亚胺盐酸盐的水溶液，室温低速搅拌3 h；加入6 mg第六代PAMAM 10 mg/mL的水溶液，室温低速搅拌过夜，装入透析袋中透析2 天，冻干，得到Apt-PAMAM聚合物Apt-G6；称取100 mg Apt-G6、20 mg 厄洛替尼溶于40 mL 无水甲醇中，装入圆底烧瓶中，密封搅拌反应6 h；旋蒸除甲醇，粘稠物用纯水溶解，离心除去沉淀物，将上清液冻干，得到靶向Apt-G6/ERL纳米药物；称取100 μL 700μg/mLApt-G6/ERL纳米药物逐滴加入到高速涡旋的100 μL 的400 μg/mL Survivin shRNA水溶液中，室温孵育25 min；得到Apt-G6/ERL/Survivin shRNA（Apt-G6/ES）纳米复合物。
2.根据权利要求1所述的应用，其特征在于：氯喹以盐的形式存在，包括但不限于盐酸盐或硫酸盐。
3.根据权利要求1所述的应用，其特征在于：肿瘤是选自结肠癌、结肠直肠癌、胃癌、乳腺癌、肺癌、卵巢癌、肝癌、支气管癌、鼻咽癌、喉癌、胰脏癌、膀胱癌、宫颈癌、脑癌、前列腺癌、骨癌、皮肤癌、甲状腺癌、甲状旁腺癌、肾癌、食道癌、胆道癌、睾丸癌、直肠癌、头颈癌、输尿管癌、骨肉瘤、神经细胞瘤、黑色素瘤、纤维肉瘤、横纹肌肉瘤、星形细胞瘤、神经母细胞瘤和神经胶质瘤组中的一种或多种。
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