Site-Selective Zwitterionic Poly(caprolactone-carboxybetaine)-Growth Hormone Receptor Antagonist Conjugate: Synthesis and Biological Evaluation.

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2024-10-29 DOI:10.1021/acs.biomac.4c00828

Jane Yang, Madeline B Gelb, Kyle Tamshen, Neil L Forsythe, Jeong Hoon Ko, Ellie G Puente, Emma Pelegri-O'Day, Stephen M F Jamieson, Jo K Perry, Heather D Maynard

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引用次数: 0

Abstract

Zwitterionic polymers have been found to be biocompatible alternatives to poly(ethylene glycol) (PEG) for conjugation to proteins. This work reports the site-selective conjugation of poly(caprolactone-carboxybetaine) (pCLZ) to human growth hormone receptor antagonist (GHA) B2036-alkyne and investigation of safety, activity, and pharmacokinetics. Azide-end-functionalized pCLZs were synthesized and conjugated to GHA B2036-alkyne via copper-catalyzed click reaction. The resulting inhibitory bioactivity concentration responses in Ba/F3-GHR cells were compared to those of PEGylated GHA B2036. IgG and IgM antibody production was tested in mice, and no measurable antibody or cytokine production was detected for the pCLZ conjugate. Using ¹⁸F-labeled PET/CT imaging, the pCLZ conjugate showed an increase in circulation time compared to that of GHA B2036. Acute toxicity of the polymer was investigated in vivo and found to be nontoxic. Ex vivo degradation of the polymer on the conjugate was investigated. The results suggest that pCLZ-GHA is a potentially safe alternative to PEG-GHA.

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位点选择性聚（己内酰胺-羧基甜菜碱）-生长激素受体拮抗剂共轭物：合成与生物学评价。

人们发现，在与蛋白质共轭方面，聚（乙二醇）(PEG) 之外，还有一种具有生物相容性的聚合体。本研究报告了聚(己内酯-羧基甜菜碱)（pCLZ）与人类生长激素受体拮抗剂（GHA）B2036-炔的位点选择性共轭，以及对其安全性、活性和药代动力学的研究。通过铜催化的点击反应合成了叠氮端功能化的 pCLZ，并与 GHA B2036-alkyne 共轭。在 Ba/F3-GHR 细胞中产生的抑制生物活性浓度反应与 PEG 化 GHA B2036 的抑制生物活性浓度反应进行了比较。在小鼠体内检测了 IgG 和 IgM 抗体的产生，没有检测到 pCLZ 结合物产生可测量的抗体或细胞因子。利用 18F 标记的 PET/CT 成像，pCLZ 结合物的循环时间比 GHA B2036 延长。该聚合物的急性毒性在体内进行了研究，结果表明是无毒的。还研究了共轭聚合物的体内外降解情况。结果表明，pCLZ-GHA 有可能成为 PEG-GHA 的安全替代品。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.