In situ chemically crosslinked injectable hydrogels for the subcutaneous delivery of trastuzumab to treat breast cancer
In situ chemically crosslinked injectable hydrogels for the subcutaneous delivery of trastuzumab to treat breast cancer
复制标题
DOI：
10.1016/j.actbio.2019.01.003
复制
发表时间：
2019-03-01
影响因子：
9.7
通讯作者：
Ho, Hsiu-O
中科院分区：
文献类型：
--
作者：
Lo, Yu-Wen;Sheu, Ming-Thau;Ho, Hsiu-O
最近，用于递送治疗性抗体的新方法引起了很多关注，特别是持续释放制剂。然而，能够携带高抗体载量的持续释放制剂对于实际应用仍然是一个挑战。在这项研究中，开发了一种由马来酰亚胺修饰的γ-聚谷氨酸（γ-PGA-MA）和巯基末端官能化的4-臂聚乙二醇（4-arm PEG-SH）组成的新型可注射水凝胶，用于皮下递送曲妥珠单抗。γ-PGA-MA和4-臂PEG-SH通过巯基-马来酰亚胺反应形成具有剪切变稀特性和可逆流变行为的水凝胶。此外，该水凝胶中可以负载高含量的曲妥珠单抗（>100 mg/mL），并且曲妥珠单抗通过静电吸引在数周内持续释放。此外，从水凝胶释放的曲妥珠单抗在其结构完整性、结合生物活性和对BT-474细胞的抗增殖作用方面具有足够的稳定性。药代动力学研究表明，曲妥珠单抗水凝胶（Her-hydrogel-10，由1.5% γ-PGA-MA、1.5% 4臂PEG-SH和10 mg/mL曲妥珠单抗组成）和曲妥珠单抗/Zn负载的水凝胶（Her/Zn-水凝胶-10，由1.5% γ-PGA-MA、1.5% 4臂PEG-SH、5 mM ZnCl 2、和10 mg/mL曲妥珠单抗）可以比曲妥珠单抗溶液降低最大血浆浓度（C-max）。此外，Her/Zn-水凝胶-10能够以受控方式更好地释放曲妥珠单抗，这归因于静电吸引和曲妥珠单抗/Zn纳米复合物的形成。在BT-474异种移植肿瘤模型中，Her-hydrogel-10具有与曲妥珠单抗溶液相似的肿瘤生长抑制作用。相比之下，Her/Zn-水凝胶-10由于Zn的功能性而表现出上级肿瘤生长抑制能力。这项研究表明，这种水凝胶具有潜在的作为一个载体的局部和全身的蛋白质和antibody.Statement的显著性最近，新的缓释制剂的治疗性抗体引起了人们的广泛关注。然而，由于所需的高剂量，这些制剂应该能够携带高抗体负荷，并且这些制剂对于实际应用仍然是一个挑战。在这项研究中，开发了一种新型的可注射化学交联水凝胶用于曲妥珠单抗的皮下给药。这种新型水凝胶具有负载高含量曲妥珠单抗（>100 mg/mL）、在数周内持续释放曲妥珠单抗以及保持曲妥珠单抗足够稳定性的理想特性。体内研究表明，负载曲妥珠单抗的水凝胶具有控制释放曲妥珠单抗的能力，并保持与曲妥珠单抗相同的抗肿瘤功效。这些结果暗示基于γ-PGA-MA和4臂PEG-SH的水凝胶在充当用于治疗性蛋白质或抗体的局部或全身递送的载体方面具有巨大潜力。(C)2019 Acta Materialia Inc.由Elsevier Ltd.出版。保留所有权利。
Recently, novel approaches for the delivery of therapeutic antibodies have attracted much attention, especially sustained release formulations. However, sustained release formulations capable of carrying a high antibody load remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide-modified gamma-polyglutamic acid (gamma-PGA-MA) and thiol end-functionalized 4-arm poly (ethylene glycol) (4-arm PEG-SH) was developed for the subcutaneous delivery of trastuzumab. gamma-PGA-MA and 4-arm PEG-SH formed a hydrogel through thiol-maleimide reactions, which had shear-thinning properties and reversible rheological behaviors. Moreover, a high content of trastuzumab (>100 mg/mL) could be loaded into this hydrogel, and trastuzumab demonstrated a sustained release over several weeks through electrostatic attraction. In addition, trastuzumab released from the hydrogel had adequate stability in terms of its structural integrity, binding bioactivity, and antiproliferative effect on BT-474 cells. Pharmacokinetic studies demonstrated that trastuzumab-loaded hydrogel (Her-hydrogel-10, composed of 1.5% gamma-PGA-MA, 1.5% 4-arm PEG-SH, and 10 mg/mL trastuzumab) and trastuzumab/Zn-loaded hydro-gel (Her/Zn-hydrogel-10, composed of 1.5% gamma-PGA-MA, 1.5% 4-arm PEG-SH, 5 mM ZnCl2, and 10 mg/mL trastuzumab) could lower the maximum plasma concentration (C-max) than the trastuzumab solution. Furthermore, Her/Zn-hydrogel-10 was better able to release trastuzumab in a controlled manner, which was ascribed to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In a BT-474 xenograft tumor model, Her-hydrogel-10 had a similar tumor growth-inhibitory effect as that of the trastuzumab solution. By contrast, Her/Zn-hydrogel-10 exhibited a superior tumor growth-inhibitory capability due to the functionality of Zn. This study demonstrated that this hydrogel has potential as a carrier for the local and systemic delivery of proteins and antibodies.Statement of SignificanceRecently, novel sustained-release formulations of therapeutic antibodies have attracted much attention. However, these formulations should be able to carry a high antibody load owing to the required high dose, and these formulations remain a challenge for practical use. In this study, a novel injectable chemically cross-linked hydrogel was developed for the subcutaneous delivery of trastuzumab. This novel hydrogel possessed ideal characteristics of loading high content of trastuzumab (>100 mg/mL), sustained release of trastuzumab over several weeks, and maintaining adequate stability of trastuzumab. In vivo studies demonstrated that a trastuzumab-loaded hydrogel possessed the ability of controlled release of trastuzumab and maintained antitumor efficacy same as that of trastuzumab. These results implied that a gamma-PGA-MA and 4-arm PEG-SH-based hydrogel has great potential in serving as a carrier for the local or systemic delivery of therapeutic proteins or antibodies. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.