Pinto Miguel, Fernandes Carlos, Martins Eva, Silva Renata, Benfeito Sofia, Cagide Fernando, Mendes Ricardo F, Almeida Paz Filipe A, Garrido Jorge, Remião Fernando, Borges Fernanda
CIQUP, Departmento de Química e Bioquímica, Centro de Investigação em Química, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
Pharmaceutics. 2019 Jul 12;11(7):331. doi: 10.3390/pharmaceutics11070331.
The current pharmacological treatments for Parkinson's disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC = 670 ± 130 M) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (CMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and CMEC/D3 cells was also observed, and their permeation across Caco-2 and CMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC value, which provides evidence of their relevance to solving the drug discovery pitfalls.
目前帕金森病的药物治疗仅能为患者提供症状缓解，且基于左旋多巴以及儿茶酚 - O - 甲基转移酶或单胺氧化酶 - B抑制剂（MAO - B）的给药。由于大多数候选药物在临床前和临床试验中失败，主要原因是生物利用度方面的问题，因此据报道，使用聚合物纳米颗粒（NPs）作为药物递送系统是一种有趣的工具，可提高药物的隐身能力或帮助候选药物跨越生物屏障等。因此，通过纳米沉淀法将一种新型强效、选择性且可逆的MAO - B（色酮C27，IC = 670 ± 130 nM）封装在聚己内酯（PCL）纳米颗粒中。所得负载C27的聚乙二醇化PCL纳米颗粒（约213 nm）在神经元（SH - SY5Y）、上皮（Caco - 2）和内皮（CMEC/D3）细胞中表现出高稳定性且无细胞毒性作用。还观察到聚乙二醇化PCL纳米颗粒在SH - SY5Y和CMEC/D3细胞的细胞质中积累，并证明它们分别穿过用作人肠道和血脑屏障体外模型的Caco - 2和CMEC/D3细胞单层。聚乙二醇化PCL纳米颗粒以高于MAO - B IC值的浓度递送C27，这为它们在解决药物研发困境方面的相关性提供了证据。
