Particulate drug delivery systems have been developed for delivering drugs to a subject, and such particles can be modified to target particular organs, tissues, cells, or intracellular compartments; to increase circulation time before clearance by the liver or kidney; and/or to sequester toxic drugs during transport and to release them only upon delivery to a targeted site. In order to effectively perform all of these tasks, particle characteristics (e.g. composition, size, charge, etc.) must be precisely controlled.
However, current methods for manufacturing particles for drug delivery do not allow for controlled synthesis of particles with engineered properties. Nor do existing methods of manufacturing particles allow for rapid production and screening of particle libraries or economically feasible production of particles.
For effective drug therapy, it is desirable to deliver sustained and controlled amounts of drugs to target tissues and to reduce delivery to non-target tissues in order to minimize side effects. Parameters such as particle composition, size, charge, targeting moieties, drug encapsulation, etc. can affect the biodistribution and pharmacokinetics of the drug to be delivered.
Massachusetts Institute of Technology (Cambridge, MA) and The Brigham and Women's Hospital , Inc. researchers detail microfluidic systems and methods for the production of particles (e.g., nanoparticles) for drug delivery in U.S. Patent Application20100022680. The device is able to control the properties of polymeric particles so they are optimized for the most effective delivery of a drug.
MIT Assistant Professor of Mechanical Engineering Rohit Karnik with Frank X Gu, Pamela Basto, Chris Cannizzaro, Alireza Khademhosseini, Robert S. Langer and Omid C Farokhzad developed a series of microfluidic devices useful for production of particles by nanoprecipitation. The microfluidic devices provides highly homogenous compositions of nanoparticles and is able to synthesizes a 100 different types of nanoparticle in just minutes.
The microfluidic systems produces polymeric drug delivery particles by nanoprecipitation by using controlled mixing of polymeric solutions in a fluid that is not a solvent for the polymer (i.e. a non-solvent such as water). The mixing can be achieved by any techniques or mixing apparatus known in the art of microfluidics, including hydrodynamic flow focusing.
The device meets the need for systems and methods that provide controlled synthesis of particles with engineered properties, such as a particular composition, size, targeting moiety, agent to be delivered, and/or charge. It also provides for rapid screening of particle libraries and economically feasible production of particles for drug delivery.
FIG. 1: Synthesis of nanoparticles by controlled nanoprecipitation using hydrodynamic flow focusing in microfluidic channels. Shown are two water streams that converge and flow into a central stream. One water stream was split into two in the fabricated devices.
FIG. 2: Nanoparticle synthesis by nanoprecipitation using a staggered herringbone mixer (top) and using a zigzag channel mixer (bottom).
FIG. 3: Nanoparticle synthesis using a droplet mixer (top) and using a shear superposition mixer (bottom).
FIG. 4: Method for combinatorial synthesis of nanoparticles. Composition of the polymeric stream may be varied by controlling the flow rates of inlet streams that subsequently mix and form the polymeric stream. The polymeric stream is then used for nanoprecipitation using hydrodynamic focusing to form nanoparticles.
FIG. 5: System for combinatorial synthesis of nanoparticles depicted in FIG. 4. Precursors for nanoparticle synthesis are loaded in separate syringes mounted on computer-controlled syringe pumps. Different formulations are produced sequentially and collected for screening using a collector controlled by the same computer.
FIG. 6: Design for large-scale synthesis of nanoparticles using two-layer microfluidic channels.
FIG. 7: An exemplary microfluidic device for mixing three precursor streams and subsequently mixing the resulting stream with a water stream for nanoprecipitation.