Taking a nanoparticle (NP) from discovery to clinical translation has been slow compared to small molecules, in part by the lack of systems that enable their precise engineering and rapid optimization. In this work we have developed a microfluidic platform for the rapid, combinatorial synthesis and optimization of NPs. The system takes in a number of NP precursors from which a library of NPs with varying size, surface charge, target ligand density, and drug load is produced in a reproducible manner. We rapidly synthesized 45 different formulations of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs of different size and surface composition and screened and ranked the NPs for their ability to evade macrophage uptake in vitro. Comparison of the results to pharmacokinetic studies in vivo in mice revealed a correlation between in vitro screen and in vivo behavior. Next, we selected NP synthesis parameters that resulted in longer blood half-life and used the microfluidic platform to synthesize targeted NPs with varying targeting ligand density (using a model targeting ligand against cancer cells). We screened NPs in vitro against prostate cancer cells as well as macrophages, identifying one formulation that exhibited high uptake by cancer cells yet similar macrophage uptake compared to nontargeted NPs. In vivo, the selected targeted NPs showed a 3.5-fold increase in tumor accumulation in mice compared to nontargeted NPs. The developed microfluidic platform in this work represents a tool that could potentially accelerate the discovery and clinical translation of NPs.
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"Developing a high-throughput platform for rapid, combinatorial synthesis and optimization of NP also receives considerable attention. A microfluidic flow focusing device with multiple inlets was described that could mix different NP precursors prior to NP synthesis for screening . In the emulsion-based approach, the disperse phase flow rate used to generate poly(lacticco-glycolic acid) NP was 32 lg/ml versus 50 mg/ml in the hydrodynamic microvortexing approach [50, 54]. "
[Show abstract][Hide abstract]ABSTRACT: Translation of any inventions into products requires manufacturing. Development of drug/gene/cell delivery systems will eventually face manufacturing challenges, which require the establishment of standardized processes to produce biologically-relevant products of high quality without incurring prohibitive cost. Microfluidicu technologies present many advantages to improve the quality of drug/gene/cell delivery systems. They also offer the benefits of automation. What remains unclear is whether they can meet the scale-up requirement. In this perspective, we discuss the advantages of microfluidic-assisted synthesis of nanoscale drug/gene delivery systems, formation of microscale drug/cell-encapsulated particles, generation of genetically engineered cells and fabrication of macroscale drug/cell-loaded micro-/nano-fibers. We also highlight the scale-up challenges one would face in adopting microfluidic technologies for the manufacturing of these therapeutic delivery systems.
"Despite these remarkable advantages, the microfluidic nanoparticle generators have been mainly applied to the hydrophobicitymediated self-assembly of amphiphilic molecules (e.g., lipids or block copolymer) for the production of soft nanoparticles. In detail, when the water-miscible organic solvent containing the amphiphilic precursors is mixed with an amount of water in the microfluidic device, the insoluble hydrophobic parts of the precursors aggregate, inducing their self-assembly to yield nanoparticles, such as block copolymer nanoparticles234567, liposomes891011, and hydrophobically modified polysaccharide nanoparticles12131415. This hydrophobicity-mediated production of nanoparticles essentially requires the use of an organic solvent or acidic reagent, which is toxic and can denature biomolecules, such as proteins and enzymes during encapsulation. "
[Show abstract][Hide abstract]ABSTRACT: Alginate-based nanoparticles were generated by mixing two types of stock solutions through a microfluidic device. In our microfluidic mixing device, aqueous Ca-alginate pre-gels and cationic poly-l-lysine (PLL) solutions were mixed, and the polyelectrolyte complexation that subsequently occurred between the pre-gel and PLL resulted in precipitates, yielding alginate nanoparticles. Due to the faster microfluidic mixing achieved compared with that obtained with the conventional bulk mixing method, the alginate nanoparticles exhibited enhanced aggregation stability. The control of the size of the nanoparticles through the tuning of the flow rates in the microfluidic device was also achieved.
Full-text · Article · Apr 2015 · Colloids and Surfaces A Physicochemical and Engineering Aspects
"Microfluidics is a technology of systems that can process and manipulate nanoliter volumes in microscale fluidic channels , which has brought revolutionary impact on a wide range of ap- plications [7,8] . Among these applications, microfluidic technologies for diffusion, emulsification, or mixing processes have been recently developed for continuous preparation of a variety of nanocarriers, including liposomes , polymeric nanoparticles [5,10,11], and lipidepolymer hybrid nanoparticles . As a result of their ability to regulate nano-and microscale interactions among precursors, microfluidic formulation processes offer effective control over the physicochemical characteristics of the produced nanocarriers, leading to a narrow size distribution and high batchto-batch reproducibility [8,13]. "