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

TLDR

Nanoparticle development lags behind small molecules because of a lack of systems that enable precise engineering and rapid optimization. The study develops a microfluidic platform for rapid, combinatorial synthesis and optimization of nanoparticles. The platform accepts multiple precursors to generate a reproducible library of formulations varying in size, surface composition, ligand density, and drug load, enabling rapid synthesis, screening for macrophage evasion, and optimization of pharmacokinetic properties. In vitro screening correlated with in vivo pharmacokinetics, and a targeted formulation achieved 3.5‑fold higher tumor accumulation while maintaining low macrophage uptake, demonstrating the platform’s potential to accelerate nanoparticle discovery and clinical translation.

Abstract

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.