Controllable Microfluidic Production of Drug-Loaded PLGA Nanoparticles Using Partially Water-Miscible Mixed Solvent Microdroplets as a Precursor

Jiang Xu,Annie Colin,Anais Machado,Frank Gu,Shusheng Zhang,Sébastien Lecommandoux,Olivier Sandre

doi:10.1038/s41598-017-05184-5

Abstract

We present a versatile continuous microfluidic flow-focusing method for the production of Doxorubicin (DOX) or Tamoxifen (TAM)-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). We use a partially water-miscible solvent mixture (dimethyl sulfoxide DMSO+ dichloromethane DCM) as precursor drug/polymer solution for NPs nucleation. We extrude this partially water-miscible solution into an aqueous medium and synthesized uniform PLGA NPs with higher drug loading ability and longer sustained-release ability than conventional microfluidic or batch preparation methods. The size of NPs could be precisely tuned by changing the flow rate ratios, polymer concentration, and volume ratio of DCM to DMSO (VDCM/VDMSO) in the precursor emulsion. We investigated the mechanism of the formation of NPs and the effect of VDCM/VDMSO on drug release kinetics. Our work suggests that this original, rapid, facile, efficient and low-cost method is a promising technology for high throughput NP fabrication. For the two tested drugs, one hydrophilic (Doxorubicin) the other one hydrophobic (Tamoxifen), encapsulation efficiency (EE) as high as 88% and mass loading content (LC) higher than 25% were achieved. This new process could be extended as an efficient and large scale NP production method to benefit to fields like controlled drug release and nanomedicine.

Highlights

IntroductionThe term nanoprecipitation[5], known as the “solvent-displacement” method, refers to a quite simple processing method for the fabrication of polymeric nanoparticles
Microfluidic technology has been developed for synthesizing series of either organic or inorganic NPs8, 9 in the past decade because of its advantages compared with bulk methods, including homogenous reaction environments from a single batch[10], enhanced reproducibility[11], non-excessive consumption of expensive agents[12], and high, steady and fast throughput motored by mechanical valves and pumps[13]
We used a classical coaxial flow microfluidic device (Fig. 1) constructed by following the protocol developed by the Weitz lab for obtaining self-centring capillaries[19]

Summary

Introduction

The term nanoprecipitation[5], known as the “solvent-displacement” method, refers to a quite simple processing method for the fabrication of polymeric nanoparticles It involves the precipitation of a dissolved material into nanoscale particles after exposure to a nonsolvent of the polymer that is miscible with the solvent. Continuous flow microfluidics has been used in the literature for rapid mixing and nanoprecipitation by mixing a water-miscible organic fluid with an aqueous solution This can provide small NPs (10~100 nm)[18, 19] with a size polydispersity index ranging between 0.1 and 0.418. Hung et al.[19] used solvent evaporation inside a microfluidic device for PLGA-DMSO droplet fusion with a water drop instead of the direct convection of discrete and continuous fluids They succeed in preparing monodisperse submicronic nanoparticles ranging between 70 and 400 nm with a polydispersity index of size less than 0.3.

Methods

Results

Conclusion