Microfluidic Platform for Combinatorial Synthesis and Optimization of Targeted Nanoparticles for Cancer Therapy

Department of Chemical Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
ACS Nano (Impact Factor: 12.88). 11/2013; 7(12). DOI: 10.1021/nn403370e
Source: PubMed


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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    • "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 nanoparticles [2] [3] [4] [5] [6] [7], liposomes [8] [9] [10] [11], and hydrophobically modified polysaccharide nanoparticles [12] [13] [14] [15]. 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. "
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    • "Examples include staggered herringbone micromixers [60,61] and Tesla-type mixers [62]. In a recent example , 3D hydrodynamic focusing and micromixing were combined for the on-chip combinatorial synthesis of targeted drug delivery particles for cancer therapy [63]. Drug delivery particles with different size, zeta potential, ligand density and drug loading were all synthesized on-chip in a rapid and reproducible approach to form a library of 45 variants that was subsequently screened in vitro and in vivo. "
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