1. Macrocyclization of Interferon–Poly(α-amino acid) Conjugates Significantly Improves the Tumor Retention, Penetration, and Antitumor Efficacy
- Author
-
Hao Wang, Sheng-Tao Yang, Kai Sheng, Juan Feng, Ruijue Wang, Yingqin Hou, Yu Zhou, Yali Hu, Hua Lu, and Jingsong Yuan
- Subjects
Steric effects ,Macrocyclic Compounds ,Cell ,Antineoplastic Agents ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Rats, Sprague-Dawley ,Mice ,Colloid and Surface Chemistry ,Interferon ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Cell Proliferation ,chemistry.chemical_classification ,Mice, Inbred BALB C ,In vitro toxicology ,Biological activity ,General Chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Amino acid ,medicine.anatomical_structure ,Polyglutamic Acid ,chemistry ,Pharmacodynamics ,Female ,Interferons ,0210 nano-technology ,medicine.drug ,Conjugate - Abstract
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(EG3Glu)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(EG3Glu)20-IFN, C-IFN-P(EG3Glu)20, and C-IFN-PEG. Our results found circ-P(EG3Glu)20-IFN to show considerably greater stability, binding affini...
- Published
- 2018
- Full Text
- View/download PDF