温度响应性高分子偶联干扰素-<italic style="font-style: italic">α</italic>有效提高抗肿瘤功效

刘欣宇; 胡瑾; 郭建文; 王贵林; 高卫平

doi:10.11777/j.issn1000-3304.2018.17195

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温度响应性高分子偶联干扰素-α有效提高抗肿瘤功效

研究论文 | 更新时间：2021-01-26

- 温度响应性高分子偶联干扰素-α有效提高抗肿瘤功效
- Temperature-responsive Polymer Conjugation of Interferon-α Enhances Antitumor Efficacy
- 高分子学报 2018年第1期页码：90-98
- 作者机构：
  
  清华大学医学院北京 100084
- 作者简介：
  
  高卫平，E-mail: gaoweiping@tsinghua.edu.cn Wei-ping Gao, E-mail:gaoweiping@tsinghua.edu.cn
- 基金信息：
  
  国家自然科学基金(21534006)
- DOI：10.11777/j.issn1000-3304.2018.17195
  中图分类号：
- 纸质出版日期：2018-1-20，
  
  收稿日期：2017-7-21，
  
  修回日期：2017-8-16，
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刘欣宇, 胡瑾, 郭建文, 王贵林, 高卫平. 温度响应性高分子偶联干扰素-α有效提高抗肿瘤功效[J]. 高分子学报, 2018,(1):90-98.

Liu Xin-yu, Hu Jin, Guo Jian-wen, Wang Gui-lin, Gao Wei-ping. Temperature-responsive Polymer Conjugation of Interferon-α Enhances Antitumor Efficacy[J]. Acta Polymerica Sinica, 2018,(1):90-98.
刘欣宇, 胡瑾, 郭建文, 王贵林, 高卫平. 温度响应性高分子偶联干扰素-α有效提高抗肿瘤功效[J]. 高分子学报, 2018,(1):90-98. DOI： 10.11777/j.issn1000-3304.2018.17195.

Liu Xin-yu, Hu Jin, Guo Jian-wen, Wang Gui-lin, Gao Wei-ping. Temperature-responsive Polymer Conjugation of Interferon-α Enhances Antitumor Efficacy[J]. Acta Polymerica Sinica, 2018,(1):90-98. DOI： 10.11777/j.issn1000-3304.2018.17195.

摘要

利用定点原位生长技术，合成了一种温度响应性的干扰素-聚（2-甲基-2-丙烯酸-2-（2-甲氧基乙氧基）乙酯）偶联物（IFN-PDEGMA）.当温度低于22℃时，IFN-PDEGMA处于溶解状态；当温度高于22℃时，IFN-PDEGMA则会发生聚集.由于小鼠体温高于22℃，因此，将IFN-PDEGMA原位注射到小鼠肿瘤组织处之后，它会在肿瘤组织处聚集驻留.体外实验结果显示，IFN-PDEGMA有效保持了干扰素的结构和活性；动物实验结果显示，相比于原药IFN-

，非温敏性IFN-POEGMA、商业化的长效干扰素PEGASYS以及IFN-PDEGMA可以更好地聚集驻留在肿瘤处，荷黑色素瘤小鼠的生存时间得以显著延长，分子量为10 kDa、30 kDa、60 kDa、100 kDa的IFN-PDEGMA所治疗的小鼠，其生存时间分别为36.5、31、29.5、28天，其中，10 kDa和30 kDa的IFN-PDEGMA的治疗效果均要优于PEGASYS.同时，生物安全性实验显示IFN-PDEGMA对正常组织器官不存在显著的毒副作用.

Abstract

Interferon-

(IFN) has a short circulating half-life

which not only leads to limited clinical efficacy

but also causes severe side effects and poor patient compliance. Previously

we developed ELPfusion and site-specific

in situ

growth (SIG) methods to prolong the half-life of IFN

while the adopted intravenous administration still could not well concentrate IFN inside tumour tissues. In order to enhance the tumour accumulation and antitumour efficacy of IFN

in this study

we report intratumoural administration of temperature responsive interferon-poly(di(ethylene glycol) methyl ether methacrylate) conjugates (IFN-PDEGMA). First

we employed SIG method to synthesize a series of temperature responsive IFN-PDEGMAs with different molecular weights (10 kDa

30 kDa

60 kDa and 100 kDa). The preparation process was monitored by SDS-PAGE

and the molecular weights

hydrodynamic radius and secondary structures of conjugates were characterized by GPC

DLS and CD (circular dichroism)

respectively. The phase transition temperatures were determined to be around 22℃. Thus

IFN-PDEGMA were soluble below 22℃; and they became insoluble above 22℃. Since the body temperature of mice is above 22℃

IFN-PDEGMA injected into the tumour tissue of mice aggregated locally and became a drug depot in the tumour.

In vitro

characterization demonstrated that the structure and anti-proliferative activity of IFN were well remained for IFN-PDEGMA.

In vivo

experiments showed that the survival time of A375 melanoma-bearing mice were well extended by IFN-PDEGMA treatment compared with IFN-

. To be specific

the survival times of mice treated by IFN-PDEGMA of 10 kDa

30 kDa

60 kDa and 100 kDa were 36.5

29.5 and 28 days

respectively. IFN-PDEGMA of 10 kDa and 30 kDa both exhibited better anti-melanoma efficacy than commercial long-acting interferon

PEGASYS. Meanwhile

the biological safety experiments also showed that IFN-PDEGMA treatment did not have obvious side effects on normal tissues. In summary

for the first time

reported intratumoural administration of temperature responsive IFN-PDEGMA and studied the rule about how the molecular weight impacts on their properties

in vitro

and

in vivo

. This study not merely displayed an instance of temperature responsive protein-polymer conjugates and their anti-tumour efficacy

but also provided inspiration to further build a series of smart protein-polymer conjugates and seek for their potential applications in the diagnosis and treatment of major diseases such as cancer

virosis

diabetes and cardiovascular disease.

关键词

干扰素蛋白质-高分子偶联物原子转移自由基聚合药物递送温度响应

Keywords

InterferonProtein-polymer conjugateAtom transfer radical polymerizationDrug deliveryTemperature responsiveness

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蛋白质定点原位可控聚合方法(SICP)的发展与应用

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温度响应性高分子偶联干扰素-α有效提高抗肿瘤功效

Temperature-responsive Polymer Conjugation of Interferon-α Enhances Antitumor Efficacy

DOI：10.11777/j.issn1000-3304.2018.17195

摘要

Abstract

关键词

Keywords

references