Microfluidics-based PLGA nanoparticles of ratiometric multidrug: From encapsulation and release rates to cytotoxicity in human lens epithelial cells

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 Korsmeyer-Peppas 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.

Automated summary

Multidrug nanomedicine is an effective approach for treating chronic diseases and cancers. However, achieving co-encapsulation and release of drug combinations at a fixed ratio by nanoparticles, especially for long acting ocular formulations, is challenging. In this study, poly (lactic-co-glycolic acid) nanoparticles were developed using microfluidics and the Design of Experiments approaches to ratiometrically co-encapsulate mitomycin C and doxorubicin. The drug release rate was found to be a critical determinant of efficacy, with slower release leading to lower effectiveness against pathogenic processes. These findings highlight the potential of microfluidics for synthesizing polymeric nanoparticles and emphasize the importance of drug release rate in long-acting nanomedicine design.