CIQUP-IMS─Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal.
Associate Laboratory i4HB─Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal.
ACS Appl Mater Interfaces. 2024 Oct 30;16(43):58299-58312. doi: 10.1021/acsami.4c12372. Epub 2024 Oct 21.
Catechol--methyltransferase inhibitors (iCOMT), such as entacapone, have been successfully employed to treat tremor-related symptoms of Parkinson's disease. However, iCOMT has been associated with a short half-life and poor oral bioavailability. Nanobased drug delivery systems have often been used to overcome this type of setbacks. Therefore, entacapone was encapsulated in PEGylated poly(lactic--glycolic acid) (PLGA)-based nanoparticles (NPs) via a nanoprecipitation process, as well as in PEGylated nanostructured lipid carriers (NLCs) using a solvent emulsification/evaporation method. Both nanoformulations presented sub-200 nm populations, with zeta-potential (ZP) values close to -30 mV, and showed stability at different pHs, while maintaining their physicochemical properties mostly intact, presenting only a change in their superficial charge (ZP values), indicating their interaction. Both nanoformulations presented interaction with mucins, which anticipates good permeation and bioavailability for oral and topical administration. No cytotoxic effects were observed for lyophilized PLGA NPs encapsulating entacapone, in which 2-hydroxypropyl-ß-cyclodextrin (HPβCD) was used as a cryoprotectant at 3% concentration (HP-PLGA@Ent), in human hepatocellular carcinoma (HepG2), human neuroblastoma (SH-SY5Y), or human epithelial colorectal adenocarcinoma (Caco-2) cell lines. Conversely, NLCs encapsulating entacapone (W-NLCs@Ent) presented cytotoxic effects on the HepG2 cell line, likely due to intracellular lipid accumulation or storage. Both nanoformulations maintained a COMT inhibition effect in HepG2 cells, using 3-BTD as the COMT probe. An increase of entacapone permeability in both monolayer and coculture models (Caco-2 and Caco-2/HT29-MTX, respectively) was observed for the developed nanoformulations. Overall, this work shows that encapsulated entacapone in different nanocarriers could be a stimulating alternative to solve entacapone setbacks, since they improve its physicochemical properties and permeability while still maintaining the COMT inhibitory activity.
儿茶酚-O-甲基转移酶抑制剂（iCOMT），如恩他卡朋，已成功用于治疗帕金森病震颤相关症状。然而，iCOMT 半衰期短且口服生物利用度差。纳米药物递送系统常被用于克服这种类型的挫折。因此，通过纳米沉淀法将恩他卡朋包封在聚乙二醇化聚乳酸-羟基乙酸共聚物（PLGA）纳米粒（NPs）中，以及通过溶剂乳化/蒸发法将恩他卡朋包封在聚乙二醇化纳米结构化脂质载体（NLCs）中。两种纳米制剂的粒径均小于 200nm，Zeta 电位（ZP）值接近-30mV，在不同 pH 值下均表现出稳定性，同时保持其物理化学性质基本完整，仅改变其表面电荷（ZP 值），表明其相互作用。两种纳米制剂均与粘蛋白相互作用，这预示着口服和局部给药具有良好的渗透性和生物利用度。用 3%浓度的 2-羟丙基-β-环糊精（HPβCD）作为冷冻保护剂包封恩他卡朋的冻干 PLGA NPs（HP-PLGA@Ent）在人肝癌细胞（HepG2）、人神经母细胞瘤（SH-SY5Y）或人结肠直肠腺癌细胞（Caco-2）中无细胞毒性。相反，包封恩他卡朋的 NLCs（W-NLCs@Ent）对 HepG2 细胞系表现出细胞毒性作用，可能是由于细胞内脂质积累或储存。使用 3-BTD 作为 COMT 探针，两种纳米制剂在 HepG2 细胞中均保持 COMT 抑制作用。开发的纳米制剂在单层和共培养模型（Caco-2 和 Caco-2/HT29-MTX）中均观察到恩他卡朋渗透性增加。总的来说，这项工作表明，在不同的纳米载体中包封恩他卡朋可能是解决恩他卡朋问题的一种有前途的替代方法，因为它可以改善其物理化学性质和渗透性，同时保持 COMT 抑制活性。
