Guo Yexuan, Li Xinyang, Macgregor Robert B, Yan Hong, Zhang Rui Xue
Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China.
Xi'an People's Hospital (Xi'an Fourth Hospital), Shaanxi Eye Hospital, Affiliated People's Hospital of Northwest University, 21 Jiefang Road, Xi'an, Shaanxi 710004, China.
Heliyon. 2023 Jul 15;9(7):e18318. doi: 10.1016/j.heliyon.2023.e18318. eCollection 2023 Jul.
Multidrug nanomedicine is an effective therapeutic approach for the treatment of chronic diseases and cancers. However, co-encapsulation and release of drug combination at a fixed ratio by nanoparticles, particularly for long acting ocular formulations, remains challenging. Herein, poly (lactic-co-glycolic acid) nanoparticles ratiometrically co-encapsulating hydrophilic dual drugs, mitomycin C and doxorubicin, was obtained (D/M PLGANPs) by combining microfluidics and the Design of Experiments approaches. The formulation variable of lactide-to-glycolide ratios (L/G 50:50, 75:15 and 85:15) was used to achieve fast, medium and slow drug release rates of D/M PLGANPs. The dissolution of D/M PLGANPs in simulated intraocular fluid exhibited sustained release of dual drugs at the fixed ratio over 7 days, and analysis using the model showed mechanism of drug release to be governed by diffusion. More importantly, in human lens epithelial cells, the drug release rate was negatively correlated with drug potency. The slower drug release from D/M PLGANPs led to lower efficacy of drug combination against pathogenesis of cellular migration and proliferation, the key pathogenic processes of capsular opacification after cataract surgery. Compared to fast (L/G 50:50) and medium (L/G 75:15) drug release rate of D/M PLGANPs, the slow release formulation (L/G 85:15) exhibited the least cellular uptake of the dual drugs and the ratio of drug combination was not maintained intracellularly. The present study implicates the potential of using microfluidics for synthesizing polymeric nanoparticles of ratiometric drug combination and highlights the drug release rate as the critical determinant of efficacy for the long-acting nanomedicine design.
多药纳米药物是治疗慢性疾病和癌症的一种有效治疗方法。然而，通过纳米颗粒以固定比例共包封和释放药物组合，特别是对于长效眼用制剂，仍然具有挑战性。在此，通过结合微流控技术和实验设计方法，获得了聚（乳酸 - 乙醇酸）纳米颗粒，其以比例方式共包封亲水性双药丝裂霉素C和阿霉素（D/M PLGANPs）。使用丙交酯与乙交酯比例（L/G 50:50、75:15和85:15）的配方变量来实现D/M PLGANPs的快速、中等和缓慢药物释放速率。D/M PLGANPs在模拟眼内液中的溶解显示双药以固定比例持续释放超过7天，并且使用该模型的分析表明药物释放机制受扩散控制。更重要的是，在人晶状体上皮细胞中，药物释放速率与药物效力呈负相关。D/M PLGANPs较慢的药物释放导致药物组合对细胞迁移和增殖发病机制（白内障手术后囊膜混浊的关键致病过程）的疗效降低。与D/M PLGANPs的快速（L/G 50:50）和中等（L/G 75:15）药物释放速率相比，缓释制剂（L/G 85:15）显示双药的细胞摄取最少，并且细胞内未维持药物组合的比例。本研究表明了使用微流控技术合成比例药物组合的聚合物纳米颗粒的潜力，并强调药物释放速率是长效纳米药物设计疗效的关键决定因素。
