Nanoparticle drug carriers that combine targeted drug therapy with controlled release are promising candidates for treatment of metastatic cancer. This technology promises to minimize adverse effects of chemotherapeutic drugs that result when the drug affects healthy tissues in addition to cancerous cells. Controlled release can provide optimal drug levels over a longer period of time compared to conventional therapy. However, a key challenge remains to be addressed before targeted controlled release therapy becomes a reality- the characteristics of these nanoparticle carriers have to be optimized in order to minimize their uptake by organs of the mononuclear phagocytic systems (MPS). Several parameters such as density of targeting receptors, surface charge, size, hydrophilicity, etc. must be optimized.
Here we propose to develop a microfluidic platform for reproducible synthesis of libraries of homogeneous nanoparticles and to screen them for optimization of nanoparticle carriers. With a simple yet robust design, we aim for automated synthesis of nanoparticles in a highly controlled nanoprecipitation step using precursor reagents from a single batch, thus minimizing variability and enhancing reproducibility. This platform will enable rapid screening and optimization of nanoparticle carriers with a variety of drug loads and target tissues. We will initially use this technology to optimize nanoparticle carriers for effective therapy of prostate cancer. Opportunities for controlled microfluidic synthesis of homogeneous nanoparticles.
Homogeneity and reproducibility of nanoparticle drug carriers is essential for understanding and optimizing nanoparticle characteristics for optimal drug therapy. The ability of microfluidic systems to rapidly mix reagents and provide homogeneous reaction environments, continuously vary reaction conditions, rapid temperature control, addition of reagents at precise time intervals during the progress of a reaction, are some of the key features make microfluidic systems very useful for the synthesis of nanoparticles6. Rapidly mixing precursor solutions with water results in homogeneous nucleation and condensation steps that yields homogeneous nanoparticle populations compared to uncontrolled mixing. This property is highly desirable for combinatorial synthesis and screening purposes.
The second advantage of microfluidics is its ability to manipulate small volumes of fluid, which enables synthesis of large libraries of nanoparticles without consuming excessive amounts of expensive reagents such as aptamers. Yet, we estimate that the throughput can be sufficiently high for practical screening in 96 or 384 well plates without requiring excessive time for synthesis. Thus, a balance between consuming too much reagents and throughput can be easily achieved. In this project, we will take advantage of the controlled nanoprecipitation environment provided by microfluidic reactors in order to obtain monodisperse nanoparticles.
Figure 1. (a) Schematic of on-chip synthesis of nanoparticles by rapid mixing of precursor solution with water. (b) Micrograph of the device in operation. Scale bar 100 ?m. (c) Nanoparticles synthesized on chip are smaller and more homogeneous compared to those prepared by bulk mixing. TEM image of nanoparticles synthesized on chip (inset). Project Partners and their Roles
Laboratory of Biopolymers and Nanomedicine, University of Waterloo, Waterloo, ON, Canada: Polymer synthesis, nanoparticle formulation, drug encapsulation and controlled release
Laboratory of the Future, Université Bordeaux-I, Bordeaux, Microfluidics, MEMS and fabrication of functional devices
Industry partner : Solvay-Rhodia