Asai Daisuke, Kanamoto Taisei, Takenaga Mitsuko, Nakashima Hideki
Department of Microbiology, St. Marianna University, School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki 216-8511, Japan.
Department of Microbiology, St. Marianna University, School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki 216-8511, Japan.
Acta Biomater. 2017 Dec;64:116-125. doi: 10.1016/j.actbio.2017.10.024. Epub 2017 Oct 14.
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.
In 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.
大多数肽类药物半衰期短，需要频繁注射，这可能会引发皮肤过敏反应；因此，迫切需要多功能的长效释放给药平台。在此，我们聚焦于一种具有周期性半胱氨酸残基的氧化和热响应性重组弹性蛋白样多肽（cELP），它能快速且可逆地形成二硫键交联网络，肽可物理包埋其中。作为概念验证模型，我们使用了恩夫韦肽，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肽。将cELP与恩夫韦肽及少量过氧化氢（以促进交联）混合，然后将可溶混合物皮下注射。氧化交联产生网络结构，使混合物原位形成水凝胶，作为恩夫韦肽储存库。我们制备了一系列含恩夫韦肽的水凝胶，并在体外研究了它们的稳定性、恩夫韦肽释放曲线及抗HIV效力。其中，疏水性cELP水凝胶在大鼠血液中提供有效浓度的恩夫韦肽长达8小时，与单独注射恩夫韦肽后的初始浓度峰值相比有所降低。cELP水凝胶应易于作为平台，为除恩夫韦肽之外的其他抗HIV肽提供有效的储存系统。
在本文中，我们展示了一种使用含多个周期性半胱氨酸残基的氧化和热响应性多肽作为可原位自凝胶化的可注射生物材料的抗HIV肽递送系统，并证明了其作为能够持续释放抗HIV肽的可注射储存库的效用。这项工作的新颖之处在于用于提供包裹肽药物的储存库的平台（无需化学偶联），该平台由合理设计的基因工程多肽组成，能够精确控制肽药物的释放速率。
