Microfluidics-Assisted Size Tuning and Biological Evaluation of PLGA Particles

Abstract

Polymeric particles made up of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) are promising tools for several biomedical applications including drug delivery. Particular emphasis is placed on the size and surface functionality of these systems as they are regarded as the main protagonists in dictating the particle behavior in vitro and in vivo. Current methods of manufacturing polymeric drug carriers offer a wide range of achievable particle sizes, however, they are unlikely to accurately control the size while maintaining the same production method and particle uniformity, as well as final production yield. Microfluidics technology has emerged as an efficient tool to manufacture particles in a highly controllable manner. Here, we report on tuning the size of PLGA particles at diameters ranging from sub-micron to microns using a single microfluidics device, and demonstrate how particle size influences the release characteristics, cellular uptake and in vivo clearance of these particles. Highly controlled production of PLGA particles with ~100 nm, ~200 nm and >1000 nm diameter is achieved through modification of flow and formulation parameters. Efficiency of particle uptake by dendritic cells and myeloid-derived suppressor cells isolated from mice is strongly correlated with particle size and is most efficient for ~100 nm particles. Particles systemically administered to mice mainly accumulate in liver and ~100 nm particles are cleared slower. Our study shows the direct relation between the particle size varied through microfluidics and the pharmacokinetics behavior of particles, which provides a further step towards the establishment of a customizable production process to generate tailor-made nanomedicines.

Optimized Encapsulation of the FLAP/PGES-1 Inhibitor BRP-187 in PVA-Stabilized PLGA Nanoparticles Using Microfluidics

“…It is known for nanoprecipitation that the initial polymer concentration influences directly the final particle characteristics. With increasing polymer concentration, the particles usually become larger, and more drug molecules can be entrapped within the matrix [ 17 , 26 , 52 ]. Thus, to improve the final drug loading within the PLGA NPs, the formulation was carried out with increased initial polymer concentrations of 15 and 25 mg mL −1 (P13 and P14), whereas all other material parameters were fixed (BRP-187 = 3% ( w / w PLGA), PVA = 0.3% ( w / w ), and flow rate = 2.0:0.5 mL min −1 ).…”

“…However, in microfluidics, the first two steps (nucleation and growth phase) of NP formation may be considered as a function of the distance from the position where the solution is mixed, and this results in a good control over NPs size, size distribution, as well as their morphology [ 22 ]. The NPs properties can be thereby influenced not only by the chip properties, e.g., the aforementioned channel dimensions and structure, but also by the flow velocities and flow rate ratios applied [ 21 , 23 , 25 , 26 ]. Ultimately, an improvement in reproducibility and lower batch to batch, and also inter-batch, variance compared to conventional batch processes can be achieved with microfluidics not only in nano- and microscale but also for scale-up production [ 17 , 27 ].…”

“…To this end, a staggered herringbone mixer chip from microfluidic ChipShop, Jena, Germany, was used that could be easily connected to syringes (with or without the usage of syringe pumps) and is very versatile for application in basically every lab around the world, but it was not established for polymeric NPs formulations up to now [ 31 , 32 , 33 , 34 , 35 ]. A formulation screening of the PLGA(BRP-187) NPs was performed with this mixer chip, whereby important parameters, such as flow velocities, flow rate ratios, solvents, initial concentration of PLGA, BRP-187, as well as of the surfactant poly(vinyl alcohol) (PVA), were varied to determine the best conditions for increased drug loading and stability [ 21 , 23 , 25 , 26 , 36 , 37 ]. Moreover, different purification protocols were established.…”

The roadmap to micro: Generation of micron‐sized polymeric particles using a commercial microfluidic system

“…14,17 Particle hydrodynamic diameter is particularly relevant due to its role in determining drug delivery mechanism, biodistribution, and final fate of the material and drugs in the body. [18][19][20][21][22][23][24][25][26] Some of the parameters that govern final hydrodynamic diameter of hydrophobic polymer-based particle fabrication via microfluidic device are polymer concentration, organic: aqueous flow rates ratios, total flow rate, miscibility of aqueous and organic phases, and surfactant concentration. 14,[27][28][29][30][31][32][33] Of consequence, is also the polydispersity index which is a strong indicator of hydrodynamic diameter homogeneity (or heterogeneity).…”

PLGA Based Drug Carrier and Pharmaceutical Applications: The Most Recent Advances

“…Another relevant study was performed by Operti et al, who used microfluidics technology as a tool to manufacture particles in a highly controllable way [ 30 ]. In their study, they produced PLGA particles at diameters ranging from sub-micron to micron using a single microfluidics device.…”