Microfluidic Platform for Combinatorial Synthesis and Optimization of Targeted Nanoparticles for Cancer Therapy
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.
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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.Colloids and Surfaces A Physicochemical and Engineering Aspects 04/2015; 471. DOI:10.1016/j.colsurfa.2015.02.029
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ABSTRACT: The development of new and improved particle-based drug delivery is underpinned by an enhanced ability to engineer particles with high fidelity and integrity, as well as increased knowledge of their biological performance. Microfluidics can facilitate these processes through the engineering of spatiotemporally highly controlled environments using designed microstructures in combination with physical phenomena present at the microscale. In this review, we discuss microfluidics in the context of addressing key challenges in particle-based drug delivery. We provide an overview of how microfluidic devices can: (i) be employed to engineer particles, by providing highly controlled interfaces, and (ii) be used to establish dynamic in vitro models that mimic in vivo environments for studying the biological behavior of engineered particles. Finally, we discuss how the flexible and modular nature of microfluidic devices provides opportunities to create increasingly realistic models of the in vivo milieu (including multi-cell, multi-tissue and even multi-organ devices), and how ongoing development toward commercialization of microfluidic tools are opening up new opportunities for the engineering and evaluation of drug delivery particles.Journal of Controlled Release 04/2014; 190. DOI:10.1016/j.jconrel.2014.04.030
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ABSTRACT: Nucleic acids based therapeutics has been widely explored to treat genetic and acquired diseases. However, the clinical translation of nucleic acid based therapies has been challenged by low delivery efficiency, off-target effects, poor cellular uptake and limited serum stability. Lipopoplex nanoparticles, as one of the major nanocarrier systems, have shown great potential in overcoming these challenges. Current techniques for lipoplex nanoparticle preparation rely on self-assembly at macroscale, which suffers from limited control over particle structure and composition due to local fluctuations in the concentration of the constituent materials. We have developed a discontinuous dewetting/imprinting method that guided the assembly of lipoplex nanoparticles containing siRNA in a microwell array, which achieved much better control on particle size and composition. The lipoplex nanoparticles prepared by the discontinuous dewetting/imprinting method showed unilamellar core-shell like structure in contrary to the multi-lamellar onion like structure generally observed in lipoplex nanoparticles prepared by the conventional bulk mixing method.Langmuir 02/2014; 30(10). DOI:10.1021/la404366p