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Microfluidic Synthesis of Polymeric Nanoparticles Rohit Karnik Department of Mechanical Engineering Massachusetts Institute of Technology October 25, 2007 Acknowledgements • Frank Gu, Pamela Basto, Chris Cannizzaro, Suman Bose, Eliza Vasile • Omid Farokhzad • Robert Langer • MTL staff • NIH Targeted polymeric nanoparticles Add to water + • Versatile carriers • Targeting capability PLGA PEG Drug Nanoparticle EDC/NHS + NH2 Nanoparticle Aptamer • FDA approved Nanoprecipitation Targeted nanoparticle polymers • Controlled release • Tunable properties Farokhzad, et al. PNAS (2006) Challenges • Uptake by organs such as liver and spleen • Optimization required – – – – Size Surface characteristics Charge Targeting moieties • Batch-to-batch variation • Polydispersity Single step nanoparticle synthesis PLGA PEG + NH2 PLGA PEG APT Single step synthesis Precursor composition nanoparticle properties Advantages of microfluidic synthesis Water w Polymeric solution Nanoparticles out wf Rapid mixing and homogenization Controlled nanoprecipitation Water Combinatorial synthesis Formation of nanoparticles by nanoprecipitation Screening and optimization Other advantages On-chip purification, scale up Controlled precipitation Combinatorial Synthesis Inlet streams NH 2 Aptamer PEG + PLGA Drug COOH + + + … Mix in selected ratio Precipitate nanoparticles by dilution in water Synthesis of 100 types of nanoparticles per minute Mix Mixed stream Purification High Throughput Screening Mixing by hydrodynamic flow focusing Water wf Nanoparticles out w PLGA-PEG in acetonitrile Water Formation of nanoparticles by nanoprecipitation Approximate flow profile 1 dP 2 u( y) w 4 y2 8 dx Mixing timescale mix w2f w2 1 ~ 4D 9D 1 R 2 Width of focused stream wf 2w 31 R Typical timescale ~ 0.5 to 5 ms Effect of mixing time Nucleation Growth by insertion and aggregation Barrier to insertion Johnson and Prud’homme PRL 2003 Effect of mixing time mix Dap agg Johnson and Prud’homme PRL 2003 Nanoprecipitation by flow focusing Nanoparticles Device Syringe pump to control flow rate Nanoprecipitation by flow focusing TEM Image- Eliza Vasile Effect of flow ratio on nanoparticle size mix~3000 ms mix w2f w2 1 ~ 4D 9D 1 R 2 mix~0.04 ms mix~0.4 ms (1/R) Effect of flow ratio on nanoparticle polydispersity Volume % 25 Flow ratio 0.03 Flow ratio 0.1 Bulk mixing 20 15 Faster mixing 10 5 0 0 20 40 60 Size (nm) 80 100 Sensitivity of polymer composition to mixing time Effect of mixing time and polymer composition on drug loading Drug loading (Mass %) 20 15 10 5 0 Chip w/o PLGA Bulk w/o PLGA Chip w/PLGA Bulk w/PLGA Future Work • Characterize effects of mixing time and precursor composition • Design automated system for controlled combinatorial synthesis and screening Thank you!