紫杉醇微球-原位凝胶的制备及其局部注射的抗肿瘤药效

doi:10.19723/j.issn.1671-167X.2019.03.015

北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 477-486. doi: 10.19723/j.issn.1671-167X.2019.03.015

紫杉醇微球-原位凝胶的制备及其局部注射的抗肿瘤药效

詹颖¹,杜祎甜¹,仰浈臻¹,张春丽²,齐宪荣^1△()

收稿日期:2019-03-22 出版日期:2019-06-18 发布日期:2019-06-26
作者简介:齐宪荣,北京大学药学院教授、博士生导师、中国药学会药剂专业委员会委员、北京市药学会药剂专业委员会委员、药物技术创新服务专业委员会副主任委员等。主要研究方向为靶向递送系统、纳米技术与生物技术,多年来在药剂学与纳米药物研究领域开展了系统而富有成效的工作,在载体的构筑、功能化修饰、细胞与载体的相互作用、抗肿瘤药物和基因药物的药动学与药效学等方面做出了突出的贡献。
主持的基金研究工作包括:国家高技术研究发展计划(863计划)、国家自然科学基金、北京市自然科学基金、博士点基金、留学归国启动基金等。作为学术骨干参加国家重大科学研究计划、国家重大新药创制计划等,是“教育部创新团队”、“分子药剂学与新释药系统北京市重点实验室”的学术骨干,主持完成了多个新药的临床前研究工作。
多次在国际、国内专业学术会议上受邀做学术报告,并担任分会场主席。获北京市科技进步奖、教育部自然科学奖、中国中西医结合学会科学技术奖等多项奖励。在Biomaterials、Journal of Controlled Release、NPG Asia Materials、Advanced Healthcare Materials、Cancer Letters、International Journal of Pharmaceutics、Molecular Pharmaceutics等国内外权威学术期刊上发表研究论文140 余篇,引用率超过2 000次,2015年2篇文章被Web of Science评为高被引论文。主编及参编教材与专著14 部,申请和授权中国发明专利8项。担任国家“外专千人”和“高端人才”计划评审专家,国家重点新产品计划评审专家,国家自然科学基金、博士后科学基金、北京市自然科学基金、北京市中小企业创新基金、北京市企业研究开发项目等评审专家。培养的多名研究生获得各种国内外会议优秀论文、北京大学优秀博士论文、国家奖学金、北京市优秀毕业生等奖励和表彰。
基金资助:
国家自然科学基金(81673365)和北大医学交叉研究种子基金(BMU2018MX009)-中央高校基本科研业务费

Preparation and characterization of paclitaxel microspheres in situ gel and its antitumor efficacy by local injection

Ying ZHAN¹,Yi-tian DU¹,Zhen-zhen YANG¹,Chun-li ZHANG²,Xian-rong QI^1△()

Received:2019-03-22 Online:2019-06-18 Published:2019-06-26
Supported by:
Supported by the National Natural Science Foundation of China (81673365) and the Fundamental Research Funds for the Central Universities: Peking University Medicine Seed Fund for Interdisciplinary Research (BMU2018MX009)

摘要/Abstract

摘要： 目的为了减少肿瘤治疗的给药次数,降低化疗药物的毒副作用,更好地控制肿瘤进展以及延缓肿瘤术后复发,制备载紫杉醇微球的温敏原位凝胶(temperature-sensitive in situ gel with paclitaxel microspheres,PTX/M gel),以术前瘤旁或术后瘤腔内局部注射的方式给药。方法首先,通过乳化溶剂挥发法制备紫杉醇微球(paclitaxel microspheres,PTX/M),考察粒径、比表面积、形态、包封率和体外释放特性;其次,通过冷置溶解法制备PTX/M gel,测定相转变温度、弹性模量、溶蚀曲线、溶蚀-释放相关性;最后,分别建立人源U87 MG和鼠源4T1的皮下肿瘤模型,研究PTX/M gel在抑制肿瘤生长、延缓肿瘤复发方面的药效。结果经筛选,PTX/M中位径为(32.24±1.09) μm,比表面积为(206.61±10.23) m ²/kg,包封率为85.29%±1.34%,PTX/M中紫杉醇(paclitaxel,PTX)在第30天的累积释放百分率为33.56%±3.33%;PTX/M gel相转变温度为33 ℃,在25 ℃和37 ℃时的弹性模量分别为4.2×10 ³ Pa和18×10 ³ Pa,体内滞留时间可达48 h。动物实验结果显示,与生理盐水组和泰素-(Taxol)组相比,PTX/M gel组小鼠的肿瘤生长最缓慢(P<0.05),体内安全性良好,同样地,在肿瘤复发实验中,PTX/M gel组小鼠术后的肿瘤复发时间最晚。结论 PTX/M gel作为一种局部缓释制剂,能有效抑制肿瘤生长,延缓肿瘤术后复发,在肿瘤治疗中具有潜在优势。

关键词: 紫杉醇, 微球, 原位凝胶, 迟效制剂, 治疗结果

Abstract: Objective: The current difficulties in the treatment of tumor include repeated administration and high recurrence rate after tumor resection. In order to reduce the number of doses, avoid side effects of chemotherapeutic drugs, suppress tumor growth and delay tumor recurrence after surgery, a temperature-sensitive in situ gel with paclitaxel microspheres (PTX/M gel) was prepared. PTX/M gel was administered by intratumoral injection once a month.Methods: First of all, paclitaxel microspheres (PTX/M) were prepared by emulsion solvent evaporation method. A laser particle size distribution analyzer was used to investigate the size, distribution, specific surface area of microspheres. Paclitaxel content was determined by high performance liquid chromatography (HPLC). Then encapsulation efficiency of paclita-xel was calculated and in vitro release characteristics were studied. Secondly, PTX/M gel was prepared by cold dissolution method. The phase transition temperature, elastic modulus, dissolution curve, correlation between dissolution and release were measured. Finally, U87 MG and 4T1 subcutaneous tumor mo-dels were established respectively to study the efficacy of PTX/M gel in suppressing tumor growth and delaying tumor recurrence after surgery.Results: The median diameter of the selected PTX/M was (32.24±1.09) μm, the specific surface area was (206.61±10.23) m ²/kg, the encapsulation efficiency was 85.29%±1.34%, and the cumulative release percentage of paclitaxel from PTX/M was 33.56%±3.33% in one month. Phase transition temperature of PTX/M gel was 33 ℃. The elastic modulus of PTX/M gel at 25 ℃ and 37 ℃ were 4.2×10 ³ Pa and 18×10 ³ Pa, respectively. The gel could stay in the body for up to 48 hours. It could be seen from the results of animal experiments that were compared with the saline group and the Taxol group, and the tumor-bearing mice of the PTX/M gel group had the slowest tumor growth (P<0.05). Similarly, in the tumor recurrence experiments, the mice of PTX/M gel group had the latest tumor recurrence after surgery. Conclusion: As a local sustained-release preparation, PTX/M gel can effectively suppress tumor growth and delay postoperative recurrence of tumors. It has potential advantages in tumor treatment.

Key words: Paclitaxel, Microspheres, In situ gel, Delayed-action preparations, Treatment outcome

中图分类号:

R944.1

詹颖,杜祎甜,仰浈臻,张春丽,齐宪荣. 紫杉醇微球-原位凝胶的制备及其局部注射的抗肿瘤药效[J]. 北京大学学报（医学版）, 2019, 51(3): 477-486.

Ying ZHAN,Yi-tian DU,Zhen-zhen YANG,Chun-li ZHANG,Xian-rong QI. Preparation and characterization of paclitaxel microspheres in situ gel and its antitumor efficacy by local injection[J]. Journal of Peking University(Health Sciences), 2019, 51(3): 477-486.

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Items	PTX/M 16	PTX/M 10	PTX/M 06
Size/μm	23.17±0.6	32.24±1.09	99.74±21.61
SSA/(m²/kg)	227.97±5.78	206.61±10.23	113.68±9.94
EE/%	74.55±2.26	85.29±1.34	95.82±1.95
DL/%	15.71±0.40	17.57±0.23	19.32±0.32

紫杉醇微球-原位凝胶的制备及其局部注射的抗肿瘤药效

Preparation and characterization of paclitaxel microspheres in situ gel and its antitumor efficacy by local injection

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Concentration of Poloxamer 188/%	Phase transition temperature/℃
Concentration of Poloxamer 188/%	Blank gel	PTX/M gel
1.8	32	≤25
2.2	35	30
2.6	37	33
3.0	39	36
3.4	40	37
3.6	42	39