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Dual gelation enables delayed antibody release from Diels-Alder hydrogels

机译：双重凝胶化可延迟抗体从Diels-Alder水凝胶中释放

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Introduction: Diels-Alder (DA) cross-linked poly(ethylene glycol) (PEG) hydrogels have the potential to become a promising delivery system for therapeutic proteins. The aim of this study was to combine chemical cross-linking via DA "click chemistry" with physical interactions in a tandem approach to afford hydrogels with improved properties. For this purpose, hydrophobic spacers of different length were inserted between the PEG chains and the functional end-groups required for cross-linking (i.e., maleimide and furan). The hydrophobic interactions between the polymers were studied. The influence of hydrophobic interactions on the gel formation of DA hydrogels was investigated by rheology; the in vitro release of bevacizumab, which served as a model antibody, was determined. Materials and Methods: Eight-armed PEG-amine with a molecular weight of 40 kDa (8armPEG40-NH_2) was functionalized with furyl (8armPEG40k-Fur) and maleimide groups (8armPEG40k-Mal) as previously described. 8armPEG40-NH2 was reacted with Boc-6-aminohexanoic acid (8armPEG40k-C_6-NH-Boc) or Boc-12-aminododecanoic acid (8armPEG40k-C_(12)-NH-Boc). The obtained polymers were then functionalized with furyl (8armPEG40k-C_6-Fur, 8armPEG40k-C_(12)-Fur) and maleimide groups (8armPEG40k-C_6-Mal, 8armPEG40k-C_(12)-Mal). The critical micelle concentration of the polymers was determined by fluorescence spectroscopy using pyrene as a probe molecule (λ_(ex) = 339 nm, λ_(em) = 390 nm). The viscosity (shear rate from 0.10 to 10 s~(-1)) was determined on a TA Instruments Discovery HR-2 rheometer. For hydrogel preparation, both polymer components (e.g., 8armPEG40k-Fur/-Mal) were dissolved in purified water. Gel point was determined at 37 °C as previously described. In vitro release of bevacizumab was studied as previously described. Results and Discussion: Hydrophobic interactions between the polymers were probed using pyrene fluorescence. In contrast to 8armPEG40k-OH, a sharp increase of pyrene fluorescence was observed for 8armPEG40k-C_6-NH-Boc and 8armPEG40k-C_(12)-NH-Boc above a certain concentration. This suggests the formation of micelles. Regarding viscosity, no differences were observed at low polymer concentrations. At higher concentrations, the association of polymers due to hydrophobic interactions led to an increased inner friction of the liquid. As a consequence, 20% aqueous solutions of 8armPEG40k-C_6-NH-Boc and 8armPEG40k-C_(12)-NH-Boc showed a much higher viscosity than a solution of 8armPEG40k-OH. Due to these hydrophobic interactions, gel formation occurred considerably faster for C_6 and C_(12) modified hydrogels (Figure 1 A). Interestingly, no effect was observed when only one of the two components was modified. From this observation it can be concluded that interactions between macromonomers are the underlying mechanism for accelerated gel formation. Release of bevacizumab from 8armPEG40k hydrogels was completed after only 15 days (Figure 1B). In contrast to this, release of bevacizumab was delayed when using C_6 or C_(12) modified hydrogels; the release was completed after 30 and 60 days, respectively. Conclusion: Hydrophobic interactions between the polymers can accelerate gel formation and delay the release of antibodies from DA hydrogels. As a consequence, modification of polymers with hydrophobic spacers represents a powerful tool to improve the characteristics of DA hydrogels and bring them closer to pharmaceutical application.
机译：简介：Diels-Alder（DA）交联的聚乙二醇（PEG）水凝胶有潜力成为有前景的治疗性蛋白质递送系统。这项研究的目的是将通过DA“点击化学”进行的化学交联与物理相互作用相结合，以串联方式提供具有改进性能的水凝胶。为此目的，将不同长度的疏水性间隔基插入到PEG链和交联所需的功能性端基（即，马来酰亚胺和呋喃）之间。研究了聚合物之间的疏水相互作用。通过流变学研究了疏水相互作用对DA水凝胶凝胶形成的影响。确定用作模型抗体的贝伐单抗的体外释放。材料和方法：如前所述，用呋喃基（8armPEG40k-Fur）和马来酰亚胺基团（8armPEG40k-Mal）官能化分子量为40 kDa的八臂PEG-胺（8armPEG40-NH_2）。使8armPEG40-NH2与Boc-6-氨基己酸（8armPEG40k-C_6-NH-Boc）或Boc-12-氨基十二烷酸（8armPEG40k-C_（12）-NH-Boc）反应。然后将获得的聚合物用呋喃基（8armPEG40k-C_6-Fur，8armPEG40k-C_（12）-Fur）和马来酰亚胺基团（8armPEG40k-C_6-Mal，8armPEG40k-C_（12）-Mal）官能化。使用fluorescence作为探针分子，通过荧光光谱法确定聚合物的临界胶束浓度（λ_（ex）= 339 nm，λ_（em）= 390 nm）。在TA Instruments Discovery HR-2流变仪上测定粘度（剪切速率为0.10至10 s〜（-1））。对于水凝胶制备，将两种聚合物组分（例如8armPEG40k-Fur / -Mal）溶解在纯净水中。如前所述，在37℃下测定胶凝点。如先前所述，研究了贝伐单抗的体外释放。结果与讨论：使用pyr荧光探测了聚合物之间的疏水相互作用。与8armPEG40k-OH相比，在一定浓度以上的8armPEG40k-C_6-NH-Boc和8armPEG40k-C_（12）-NH-Boc of光急剧增加。这表明胶束的形成。关于粘度，在低聚合物浓度下未观察到差异。在较高浓度下，由于疏水相互作用而引起的聚合物缔合导致液体的内部摩擦增加。结果，8armPEG40k-C_6-NH-Boc和8armPEG40k-C_（12）-NH-Boc的20％水溶液显示出比8armPEG40k-OH的溶液高得多的粘度。由于这些疏水性相互作用，C_6和C_（12）改性水凝胶的凝胶形成速度明显加快（图1A）。有趣的是，当仅修改两个组件之一时，未观察到任何效果。从该观察结果可以得出结论，大分子单体之间的相互作用是促进凝胶形成的潜在机制。仅15天后，贝伐单抗从8armPEG40k水凝胶中的释放就完成了（图1B）。与此相反，当使用C_6或C_（12）修饰的水凝胶时，贝伐单抗的释放被延迟。分别在30天和60天后完成发布。结论：聚合物之间的疏水相互作用可加速凝胶形成并延迟DA水凝胶中抗体的释放。因此，用疏水性间隔基修饰聚合物代表了一种强大的工具，可改善DA水凝胶的特性并使它们更接近药物应用。

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