多功能组织注射水凝胶,能够延长生物活性蛋白疗法的水解释放时间

IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Bioengineering & Translational Medicine Pub Date : 2024-04-15 DOI:10.1002/btm2.10668
Eric S. Nealy, Steven J. Reed, Steven M. Adelmund, Barry A. Badeau, Jared A. Shadish, Emily J. Girard, Kenneth Brasel, Fiona J. Pakiam, Andrew J. Mhyre, Jason P. Price, Surojit Sarkar, Vandana Kalia, Cole A. DeForest, James M. Olson
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引用次数: 0

摘要

水凝胶因其结构适应性强、含水量高和生物相容性好而被广泛应用于医疗保健领域,其应用范围从脊髓再生到局部治疗给药,均已获得美国食品及药物管理局(FDA)批准。然而,临床水凝胶面临着治疗暴露不一致、释放窗口不可调和以及表层下聚合物插入困难等挑战。为了解决这些问题,我们利用聚乙二醇(PEG)为基础的水凝胶,在网络聚合和功能化过程中使用生物正交的 SPAAC 手柄,设计出了可注射的生物相容性水凝胶,作为局部治疗药库。我们的水凝胶溶液能以对温度敏感的方式在原位聚合,在组织中持久存在,并促进生物活性治疗药物在表层下位置的输送。重组抗 CD47 单克隆抗体融入表皮下注射的水凝胶溶液后,对啮齿类动物脑内浸润性高级别胶质瘤异种移植物表现出细胞毒活性,这证明了我们方法的有效性。为了增强凝胶的多功能性,重组蛋白载体可通过可水解的 "叠氮酯 "适配体进行特定位点修饰,从而实现用户自定义的水凝胶释放曲线。在 "冷 "合成黑色素瘤模型中,通过叠氮酯连接体与肿瘤内注射的水凝胶溶液相连的水凝胶产生的小鼠 CXCL10 梯度可显著招募 CD8+ T 细胞并抑制肿瘤生长。这项研究强调了一种高度可定制、基于水凝胶的局部蛋白质治疗给药系统,可满足不同的临床需求。
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Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics

Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable “azidoester” adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T-cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.

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来源期刊
Bioengineering & Translational Medicine
Bioengineering & Translational Medicine Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
8.40
自引率
4.10%
发文量
150
审稿时长
12 weeks
期刊介绍: Bioengineering & Translational Medicine, an official, peer-reviewed online open-access journal of the American Institute of Chemical Engineers (AIChE) and the Society for Biological Engineering (SBE), focuses on how chemical and biological engineering approaches drive innovative technologies and solutions that impact clinical practice and commercial healthcare products.
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