Shih Han, Lin Chien-Chi
†Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907, United States.
‡Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202, United States.
Biomacromolecules. 2015 Jul 13;16(7):1915-23. doi: 10.1021/acs.biomac.5b00471. Epub 2015 Jun 3.
Polymers or hydrogels containing modified cyclodextrin (CD) are highly useful in drug delivery applications, as CD is a cytocompatible amphiphilic molecule that can complex with a variety of hydrophobic drugs. Here, we designed modular photoclick thiol-ene hydrogels from derivatives of βCD and poly(ethylene glycol) (PEG), including βCD-allylether (βCD-AE), βCD-thiol (βCD-SH), PEG-thiol (PEGSH), and PEG-norbornene (PEGNB). Two types of CD-PEG hybrid hydrogels were prepared using radical-mediated thiol-ene photoclick reactions. Specifically, thiol-allylether hydrogels were formed by reacting multiarm PEGSH and βCD-AE, and thiol-norbornene hydrogels were formed by cross-linking βCD-SH and multiarm PEGNB. We characterized the properties of these two types of thiol-ene hydrogels, including gelation kinetics, gel fractions, hydrolytic stability, and cytocompatibility. Compared with thiol-allylether hydrogels, thiol-norbornene photoclick reaction formed hydrogels with faster gelation kinetics at equivalent macromer contents. Using curcumin, an anti-inflammatory and anticancer hydrophobic molecule, we demonstrated that CD-cross-linked PEG-based hydrogels, when compared with pure PEG-based hydrogels, afforded higher drug loading efficiency and prolonged delivery in vitro. Cytocompatibility of these CD-cross-linked hydrogels were evaluated by in situ encapsulation of radical sensitive pancreatic MIN6 β-cells. All formulations and cross-linking conditions tested were cytocompatible for cell encapsulation. Furthermore, hydrogels cross-linked by βCD-SH showed enhanced cell proliferation and insulin secretion as compared to gels cross-linked by either dithiothreitol (DTT) or βCD-AE, suggesting the profound impact of both macromer compositions and gelation chemistry on cell fate in chemically cross-linked hydrogels.
含有改性环糊精（CD）的聚合物或水凝胶在药物递送应用中非常有用，因为CD是一种具有细胞相容性的两亲分子，能够与多种疏水药物形成复合物。在此，我们从β环糊精（βCD）和聚乙二醇（PEG）的衍生物设计了模块化光点击硫醇-烯水凝胶，包括βCD-烯丙基醚（βCD-AE）、βCD-硫醇（βCD-SH）、PEG-硫醇（PEGSH）和PEG-降冰片烯（PEGNB）。使用自由基介导的硫醇-烯光点击反应制备了两种类型的CD-PEG杂化水凝胶。具体而言，通过使多臂PEGSH与βCD-AE反应形成硫醇-烯丙基醚水凝胶，通过使βCD-SH与多臂PEGNB交联形成硫醇-降冰片烯水凝胶。我们表征了这两种类型硫醇-烯水凝胶的性质，包括凝胶化动力学、凝胶分数、水解稳定性和细胞相容性。与硫醇-烯丙基醚水凝胶相比，在等效大分子单体含量下，硫醇-降冰片烯光点击反应形成的水凝胶具有更快的凝胶化动力学。使用姜黄素（一种抗炎和抗癌的疏水分子），我们证明，与纯PEG基水凝胶相比，基于CD交联的PEG水凝胶在体外具有更高的药物负载效率和更长的递送时间。通过对自由基敏感的胰腺MIN6β细胞进行原位包封来评估这些CD交联水凝胶的细胞相容性。所有测试的配方和交联条件对于细胞包封都是细胞相容的。此外，与通过二硫苏糖醇（DTT）或βCD-AE交联的凝胶相比，通过βCD-SH交联的水凝胶显示出增强的细胞增殖和胰岛素分泌，这表明大分子单体组成和凝胶化化学对化学交联水凝胶中细胞命运都有深远影响。
