Paka Ghislain Djiokeng, Ramassamy Charles
Institut National de la Recherche Scientifique-Institut Armand Frappier , Laval, Québec H7V 1B7, Canada.
Institut sur la Nutrition et les Aliments Fonctionnels, Laval University , Laval, Québec G1V 0A6, Canada.
Mol Pharm. 2017 Jan 3;14(1):93-106. doi: 10.1021/acs.molpharmaceut.6b00738. Epub 2016 Nov 7.
One major challenge in the field of nanotherapeutics is to increase the selective delivery of cargo to targeted cells. Using polylactic-co-glycolic acid (PLGA), we recently highlighted the importance of polymer composition in the biological fate of the nanodrug delivery systems. However, the route of internalization of polymeric nanoparticles (NPs) is another key component to consider in the elaboration of modern and targeted devices. For that purpose, herein, we effectively synthesized and characterized glutathione-functionalized PLGA-nanoparticles (GSH-NPs) loaded with curcumin (GSH-NPs-Cur), using thiol-maleimide click reaction and determined their physicochemical properties. We found that GSH functionalization did not affect the drug loading efficiency (DLE), the size, the polydispersity index (PDI), the zeta potential, the release profile, and the stability of the formulation. While being nontoxic, the presence of GSH on the surface of the formulations exhibits a better neuroprotective property against acrolein. The neuronal internalization of GSH-NPs-Cur was higher than free curcumin. In order to track the intracellular localization of the formulations, we used a covalently attached rhodamine (PLGA-Rhod), into our GSH-functionalized matrix. We found that GSH-functionalized matrix could easily be taken up by neuronal cells. Furthermore, we found that GSH conjugation modifies the route of internalization enabling them to escape the uptake through macropinocytosis and therefore avoiding the lysosomal degradation. Taken together, GSH functionalization increases the uptake of formulations and modifies the route of internalization toward a safer pathway. This study shows that the choice of ideal ligand to develop NPs-targeting devices is a crucial step when designing innovative strategy for neuronal cells delivery.
纳米治疗领域的一个主要挑战是提高药物向靶细胞的选择性递送。我们最近使用聚乳酸-乙醇酸共聚物（PLGA）强调了聚合物组成在纳米药物递送系统生物学命运中的重要性。然而，聚合物纳米颗粒（NPs）的内化途径是设计现代靶向装置时需要考虑的另一个关键因素。为此，在本文中，我们通过硫醇-马来酰亚胺点击反应有效地合成并表征了负载姜黄素的谷胱甘肽功能化PLGA纳米颗粒（GSH-NPs-Cur），并测定了它们的理化性质。我们发现谷胱甘肽功能化不会影响药物负载效率（DLE）、粒径、多分散指数（PDI）、zeta电位、释放曲线和制剂的稳定性。制剂表面存在的谷胱甘肽无毒，对丙烯醛具有更好的神经保护特性。GSH-NPs-Cur的神经元内化高于游离姜黄素。为了追踪制剂的细胞内定位，我们在谷胱甘肽功能化基质中使用了共价连接的罗丹明（PLGA-Rhod）。我们发现谷胱甘肽功能化基质很容易被神经元细胞摄取。此外，我们发现谷胱甘肽共轭改变了内化途径，使它们能够通过巨胞饮作用逃避摄取，从而避免溶酶体降解。综上所述，谷胱甘肽功能化增加了制剂的摄取，并将内化途径改变为更安全的途径。这项研究表明，在设计针对神经元细胞递送的创新策略时，选择理想的配体来开发NPs靶向装置是关键的一步。
