Macrocyclization of Interferon–Poly(α-amino acid) Conjugates Significantly Improves the Tumor Retention, Penetration, and Antitumor Efficacy

作者：Yingqin Hou, Yu Zhou, Hao Wang, Ruijue Wang, Jingsong Yuan, Yali Hu, Kai Sheng, Juan Feng, Sheng‐Tao Yang, Hua Lu · 发表于：Journal of the American Chemical Society · 年份：2017 · DOI：10.1021/jacs.7b13017 · 被引用次数：73 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Ubiquitin and proteasome pathways、Click Chemistry and Applications

Cyclization and polymer conjugation are two commonly used approaches for enhancing the pharmacological properties of protein drugs. However, cyclization of parental proteins often only affords a modest improvement in biochemical or cell-based in vitro assays. Moreover, very few studies have included a systematic pharmacological evaluation of cyclized protein-based therapeutics in live animals. On the other hand, polymer-conjugated proteins have longer circulation half-lives but usually show poor tumor penetration and suboptimal pharmacodynamics due to increased steric hindrance. We herein report the generation of a head-to-tail interferon–poly(α-amino acid) macrocycle conjugate circ -P(EG 3 Glu) 20 -IFN by combining the aforementioned two approaches. We then compared the antitumor pharmacological activity of this macrocycle conjugate against its linear counterparts, N -P(EG 3 Glu) 20 -IFN, C -IFN-P(EG 3 Glu) 20, and C -IFN-PEG. Our results found circ -P(EG 3 Glu) 20 -IFN to show considerably greater stability, binding affinity, and in vitro antiproliferative activity toward OVCAR3 cells than the three linear conjugates. More importantly, circ -P(EG 3 Glu) 20 -IFN exhibited longer circulation half-life, remarkably higher tumor retention, and deeper tumor penetration in vivo . As a result, administration of the macrocyclic conjugate could effectively inhibit tumor progression and extend survival in mice bearing established xenograft human OVCAR3 or SKOV3 tumors without causing ...