In situ depot formation of anti-HIV fusion-inhibitor peptide in recombinant protein polymer hydrogel
In situ depot formation of anti-HIV fusion-inhibitor peptide in recombinant protein polymer hydrogel
复制标题
DOI：
10.1016/j.actbio.2017.10.024
复制
发表时间：
2017-12-01
影响因子：
9.7
通讯作者：
Nakashima, Hideki
中科院分区：
文献类型：
--
作者：
Asai, Daisuke;Kanamoto, Taisei;Nakashima, Hideki
大多数多肽药物的半衰期很短，需要频繁注射，可能会引起皮肤过敏反应，因此迫切需要多功能的缓释给药平台。在这里，我们重点研究了一种具有周期性半胱氨酸残基(CELP)的氧化和热响应性重组弹性蛋白样多肽(CELP)，它可以快速和可逆地形成二硫键交联网络，其中的多肽可以物理地结合在其中。作为概念验证的模型，我们使用了恩福韦肽，一种被批准用于治疗人类免疫缺陷病毒(HIV)感染的抗逆转录病毒融合抑制物肽。将CELP与恩福韦肽和少量过氧化氢混合(以促进交联)，并将可溶的混合物注射到皮下。氧化交联会产生网络结构，使混合物在原位形成水凝胶，作为环孢素库。我们制备了一系列含有恩福韦的水凝胶，并考察了它们的稳定性、恩夫韦肽的释放度和体外抗HIV的效力。其中，疏水的cELP水凝胶为大鼠提供了长达8h的有效血药浓度，与单独注射恩夫韦肽相比，初始浓度峰值受到抑制。在这篇文章中，我们提出了一种利用含有多个周期性半胱氨酸残基的氧化和温度响应性多肽作为可注射生物材料的抗HIV多肽递送系统，并证明了其作为能够持续释放抗HIV多肽的可注射库的实用性。这项工作的新颖性来自于提供多肽药物封装库的平台(无化学偶联)，该平台由设计合理的基因工程多肽组成，使多肽药物的释放速度得到精确控制。(C)2017 Acta Materialia Inc.由Elsevier Ltd.出版。保留所有权利。
Most peptide drugs have short half-lives, necessitating frequent injections that may induce skin sensitivity reactions; therefore, versatile prolonged-release delivery platforms are urgently needed. Here, we focused on an oxidatively and thermally responsive recombinant elastin-like polypeptide with periodic cysteine residues (cELP), which can rapidly and reversibly form a disulfide cross-linked network in which peptide can be physically incorporated. As a model for proof of concept, we used enfuvirtide, an antiretroviral fusion-inhibitor peptide approved for treatment of human immunodeficiency virus (HIV) infection. cELP was mixed with enfuvirtide and a small amount of hydrogen peroxide (to promote cross-linking), and the soluble mixture was injected subcutaneously. The oxidative cross-linking generates a network structure, causing the mixture to form a hydrogel in situ that serves as an enfuvirtide depot. We fabricated a series of enfuvirtide-containing hydrogels and examined their stability, enfuvirtide-releasing profile and anti-HIV potency in vitro. Among them, hydrophobic cELP hydrogel provided effective concentrations of enfuvirtide in blood of rats for up to 8 h, and the initial concentration peak was suppressed compared with that after injection of enfuvirtide alone. cELP hydrogels should be readily adaptable as platforms to provide effective depot systems for delivery of other anti-HIV peptides besides enfuvirtide.Statement of SignificanceIn this paper, we present an anti-HIV peptide delivery system using oxidatively and thermally responsive polypeptides that contain multiple periodic cysteine residues as an injectable biomaterial capable of in situ self-gelation, and we demonstrate its utility as an injectable depot capable of sustained release of anti-HIV peptides. The novelty of this work stems from the platform employed to provide the depot encapsulating the peptide drugs (without chemical conjugation), which consists of rationally designed, genetically engineered polypeptides that enable the release rate of the peptide drugs to be precisely controlled. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.