Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, 114 Roger Adams Laboratory, 600 S. Mathews Ave., Urbana 61801, USA.
Department of Bioengineering, University of Illinois at Urbana-Champaign, 114 Roger Adams Laboratory, 600 S. Mathews Ave., Urbana 61801, USA.
J Control Release. 2013 Nov 28;172(1):30-37. doi: 10.1016/j.jconrel.2013.07.010. Epub 2013 Jul 23.
Microparticles capable of releasing protein drugs are often incorporated into injectable hydrogels to minimize their displacement at an implantation site, reduce initial drug burst, and further control drug release rates over a broader range. However, there is still a need to develop methods for releasing drug molecules over extended periods of time, in order to sustain the bioactivity of drug molecules at an implantation site. In this study, we hypothesized that a hydrogel formed through the cross-linking of pyrrole units linked to a hydrophilic polymer would release protein drugs in a more sustained manner, because of an enhanced association between cross-linked pyrrole groups and the drug molecules. To examine this hypothesis, we prepared hydrogels of alginate substituted with pyrrole groups, alginate-g-pyrrole, through a horse-radish peroxidase (HRP)-activated cross-linking of the pyrrole groups. The hydrogels were encapsulated with poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with vascular endothelial growth factor (VEGF). The resulting hydrogel system released VEGF in a more sustained manner than Ca(2+) alginate or Ca(2+) alginate-g-pyrrole gel systems. Finally, implantations of the VEGF-releasing HRP-activated alginate-g-pyrrole hydrogel system on chicken chorioallantoic membranes resulted in the formation of blood vessels in higher densities and with larger diameters, compared to other control conditions. Overall, the drug releasing system developed in this study will be broadly useful for regulating release rates of a wide array of protein drugs, and further enhance the quality of protein drug-based therapies.
能够释放蛋白质药物的微粒体通常被纳入可注射水凝胶中，以最小化其在植入部位的移位，减少初始药物释放，并进一步控制更广泛范围内的药物释放率。然而，仍然需要开发延长药物分子释放时间的方法，以维持植入部位药物分子的生物活性。在这项研究中，我们假设通过将与亲水聚合物连接的吡咯单元交联形成的水凝胶会以更持续的方式释放蛋白质药物，因为交联吡咯基团与药物分子之间的结合增强。为了检验这一假设，我们通过辣根过氧化物酶（HRP）激活吡咯基团的交联，制备了取代有吡咯基团的海藻酸钠水凝胶，海藻酸钠-g-吡咯。将该水凝胶包封在载有血管内皮生长因子（VEGF）的聚（乳酸-共-乙醇酸）（PLGA）微球中。与 Ca(2+) 海藻酸钠或 Ca(2+) 海藻酸钠-g-吡咯凝胶系统相比，所得水凝胶系统以更持续的方式释放 VEGF。最后，将释放 VEGF 的 HRP 激活的海藻酸钠-g-吡咯水凝胶系统植入鸡胚绒毛尿囊膜上，与其他对照条件相比，形成了更高密度和更大直径的血管。总的来说，本研究开发的药物释放系统将广泛用于调节各种蛋白质药物的释放率，并进一步提高基于蛋白质药物的治疗质量。
