局部递送血管生成促进因子,如小分子,核酸,肽,和蛋白质促进受损组织的修复和再生仍然是血管组织工程的挑战。目前的递送方法如治疗剂的直接施用可能无法维持必要的持续释放曲线,并且通常依赖于超生理剂量来实现期望的治疗效果。通过实施微粒输送系统,局部递送可以与持续受控释放相结合,以减轻目前直接治疗给药所需的高剂量所涉及的风险。为此,聚(乳酸-共-乙醇酸)微粒是通过反溶剂微囊化和负载,释放,和模型血管生成分子的传递,特别是一个小分子,核酸,和蛋白质,使用微血管碎片(MVF)在体外评估。使用的微囊化方法能够快速形成球形颗粒并封装不同大小的模型药物,所有在一个方法。添加纤维蛋白支架,MVF文化所需的,减少了模型药物的初始爆发,在单独的PLGA的释放曲线中观察到。最后,使用MVFs的体外研究表明,更高浓度的微粒导致模型治疗(miRNA)与MVFs的更多共定位,这对于有针对性的交付方法至关重要。还发现,与直接施用相比,使用递送的微粒系统的miRNA的生物分布增强。总的来说,聚(乳酸-乙醇酸共聚物)微粒,一步配制和加载模型治疗化合物,改善了血管模型中的生物分布,从而导致了翻译血运重建的未来。
BACKGROUND: Localized delivery of angiogenesis-promoting factors such as small molecules, nucleic acids, peptides, and proteins to promote the repair and regeneration of damaged tissues remains a challenge in vascular tissue engineering. Current delivery methods such as direct administration of therapeutics can fail to maintain the necessary sustained release profile and often rely on supraphysiologic doses to achieve the desired therapeutic effect. By implementing a microparticle delivery system, localized delivery can be coupled with sustained and controlled release to mitigate the risks involved with the high dosages currently required from direct therapeutic administration.
METHODS: For this purpose, poly(lactic-co-glycolic acid) (PLGA) microparticles were fabricated via anti-solvent microencapsulation and the loading, release, and delivery of model angiogenic molecules, specifically a small molecule, nucleic acid, and protein, were assessed in vitro using microvascular fragments (MVFs).
RESULTS: The microencapsulation approach utilized enabled rapid spherical particle formation and encapsulation of model drugs of different sizes, all in one method. The addition of a fibrin scaffold, required for the culture of the MVFs, reduced the initial burst of model drugs observed in release profiles from PLGA alone. Lastly, in vitro studies using MVFs demonstrated that higher concentrations of microparticles led to greater co-localization of the model therapeutic (miRNA) with MVFs, which is vital for targeted delivery methods. It was also found that the biodistribution of miRNA using the delivered microparticle system was enhanced compared to direct administration.
CONCLUSIONS: Overall, PLGA microparticles, formulated and loaded with model therapeutic compounds in one step, resulted in improved biodistribution in a model of the vasculature leading to a future in translational revascularization.