John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford Street, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, 77 Massachusetts Avenue, Cambridge 02139, MA, USA.
John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford Street, Cambridge, MA 02138, USA; The Wyss Institute for Biologically Inspired Engineering, 3 Blackfan Circle, Boston, MA 02115, USA.
Acta Biomater. 2018 Jan;65:36-43. doi: 10.1016/j.actbio.2017.11.024. Epub 2017 Nov 8.
Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems.
Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.
持续、局部的蛋白质输送可以提高蛋白质药物在各种疾病环境中的安全性和活性。虽然水凝胶系统被广泛研究作为蛋白质输送的载体，但它们往往由于包裹的货物快速释放而导致治疗时间短暂，并且蛋白质货物可能由于与水凝胶交联化学不相容而发生变性。在这项工作中，我们描述了能够持续、生物活性地释放各种包裹蛋白质的可注射纳米复合水凝胶。通过使用四嗪-降冰片烯偶联物对藻酸盐进行生物正交交联，形成可注射和多孔的冷冻凝胶。为了从这些水凝胶中提供持续释放，将蛋白质货物预先吸附到带电荷的 Laponite 纳米颗粒上，这些纳米颗粒被掺入冷冻凝胶的壁中。Laponite 颗粒的存在大大阻碍了许多蛋白质的释放，否则这些蛋白质会从这些水凝胶中爆发释放。通过在水凝胶中改变 Laponite 含量，可以精确调整蛋白质释放的动力学。这种控制蛋白质释放的多功能策略简化了水凝胶药物输送系统的设计。
这里我们提出了一种可注射的纳米复合水凝胶，用于简单而通用的治疗性蛋白质的控制释放。水凝胶中蛋白质的释放通常需要首先将蛋白质包埋在颗粒中，并将这些颗粒嵌入水凝胶中以允许控制蛋白质释放。这种预包封过程可能很繁琐，可能会破坏蛋白质的活性，并且必须针对每个感兴趣的蛋白质进行优化。本文提出的策略简单地将蛋白质与带电荷的纳米颗粒预混合，这些纳米颗粒与蛋白质结合紧密。然后将这些载有蛋白质的颗粒置于水凝胶中，并将蛋白质缓慢释放到周围环境中。使用这种方法，可以实现各种蛋白质从可注射水凝胶中的可调释放。这种策略极大地简化了用于治疗性蛋白质释放应用的水凝胶系统的设计。
