Microfluidic Synthesis of Polymeric Nanoparticles

1. Microfluidic Synthesis of Polymeric Nanoparticles Rohit Karnik Department of Mechanical Engineering Massachusetts Institute of Technology October 25, 2007

2. Acknowledgements • Frank Gu, Pamela Basto, Chris Cannizzaro, Suman Bose, Eliza Vasile • Omid Farokhzad • Robert Langer • MTL staff • NIH

3. Add to water + PEG PLGA Drug Nanoprecipitation Nanoparticle EDC/NHS + Aptamer Nanoparticle Targeted nanoparticle NH2 Targeted polymeric nanoparticles • Versatile carriers • Targeting capability • FDA approved polymers • Controlled release • Tunable properties Farokhzad, et al. PNAS (2006)

4. Challenges • Uptake by organs such as liver and spleen • Optimization required • Size • Surface characteristics • Charge • Targeting moieties • Batch-to-batch variation • Polydispersity

5. + PEG PLGA NH2 PLGA PEG APT Single step nanoparticle synthesis Single step synthesis Precursor composition  nanoparticle properties

6. Water Nanoparticles out Rapid mixing and homogenization • Controlled nanoprecipitation Combinatorial synthesis • Screening and optimization Other advantages  On-chip purification, scale up w wf Polymeric solution Water Formation of nanoparticles by nanoprecipitation Controlled Combinatorial Purification High Throughput Screening precipitation Synthesis Inlet streams Inlet streams Aptamer Aptamer Aptamer Aptamer … … … … PEG PEG PEG PEG Aptamer Aptamer Aptamer Aptamer Aptamer Aptamer Aptamer Aptamer Aptamer COOH COOH COOH COOH COOH COOH COOH NH NH NH NH NH NH NH 2 2 … … … … … … … … … PEG PEG PEG PEG PEG PEG PEG PEG PEG PLGA PLGA PLGA PLGA + + + + + + + + + + + + + + + + Drug Drug Drug PLGA PLGA PLGA PLGA PLGA PLGA PLGA PLGA PLGA Mix Mix Mixed Mixed Mix in selected ratio Mix in selected ratio Mix in selected ratio stream stream Precipitate nanoparticles Precipitate nanoparticles Precipitate nanoparticles by dilution in water by dilution in water by dilution in water Synthesis of 100 types of Synthesis of 100 types of Synthesis of 100 types of nanoparticles per minute nanoparticles per minute nanoparticles per minute Advantages of microfluidic synthesis

7. Water Nanoparticles out w wf PLGA-PEG in acetonitrile Water Formation of nanoparticles by nanoprecipitation Mixing by hydrodynamic flow focusing Mixing timescale Approximate flow profile Width of focused stream Typical timescale ~ 0.5 to 5 ms

8. Effect of mixing time Nucleation Growth by insertion and aggregation Barrier to insertion Johnson and Prud’homme PRL 2003

9. Effect of mixing time Johnson and Prud’homme PRL 2003

10. Nanoparticles Device Syringe pump to control flow rate Nanoprecipitation by flow focusing

11. Nanoprecipitation by flow focusing TEM Image- Eliza Vasile

12. Effect of flow ratio on nanoparticle size tmix~3000 ms tmix~0.04 ms tmix~0.4 ms (1/R)

13. Faster mixing Effect of flow ratio on nanoparticle polydispersity

14. Sensitivity of polymer composition to mixing time

15. Effect of mixing time and polymer composition on drug loading

16. Future Work • Characterize effects of mixing time and precursor composition • Design automated system for controlled combinatorial synthesis and screening

17. Thank you!