Citation: 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 shu

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

School of Medicine, Tsinghua University, Beijing 100084

Corresponding author: Gao Wei-ping, gaoweiping@tsinghua.edu.cn
Received Date: 21 July 2017
Revised Date: 16 August 2017

Interferon-α (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-α. 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, 31, 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, we, 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.
- Interferon,
- Protein-polymer conjugate,
- Atom transfer radical polymerization,
- Drug delivery,
- Temperature responsiveness
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