The DeSimone Group has developed a method to mass produce nanoscale (a nanometer is one billionth of a meter) particles of specific size, shape, and function based on the techniques of imprint lithography traditionally used to etch the intricate patterns on microchips. This method, known as “PRINT” (Particle Replication in Non-wetting Templates), has immense potential in the detection and treatment of cancer. PRINT particles can be designed to be ‘smart’ so that they hone in on and precisely fit a cellular target much as a key is designed to fit into a lock, by attaching various biological markers to their surface that help the particles steer toward the desired target and fit their receptor sites. PRINT particles can also be designed to carry specific cargoes. They can be filled with imaging agents to help locate and diagnose the presence of cancer as well as to deliver cancer-fighting drugs directly to the targeted cells. In Project 1, the DeSimone Group is developing a range of ‘smart’ nanoparticles for cancer therapy and imaging. In Project 2, they are evaluating applications for these nanoparticles to cancer therapy and imaging.
The PRINT Process
Particle Replication in Non-wetting Templates (PRINT) utilizes the unique characteristics of perluoropolyether (PFPE) to fabricate monodisperse, shape and size specific particles ranging from the nanometer to micrometer size regime. In step 1-2 (above), a liquid (red) is evenly distributed over the PFPE mold (green) using a roller. In step 3, the liquid is solidified by a variety of methods (photochemically or thermally cured, lyophilized, frozen, etc…) In step 4, the particles are harvested from the mold using a sacrificial adhesive layer. In step 5, the particles are collected in solution after dissolving the sacrificial adhesive.
Clinical Impact
The ultimate goal is to develop targeted delivery of imaging agents to pioneer earlier cancer detection and targeted drug delivery for more efficient and successful cancer treatment.
Research Summary
The recent breakthroughs in the DeSimone laboratories using specifically-designed materials for imprint lithography have enabled an extremely versatile and flexible method for the direct fabrication and harvesting of monodisperse, shape-specific nano-biomaterials. The method, referred to as Particle Replication In Non-wetting Templates, or PRINT, allows for the fabrication of monodisperse particles with simultaneous control over structure (i.e. shape, size, composition) and function (i.e. cargo, surface structure). Current research in nanomedicine is driven by the desire to create a methodology in which to effectively deliver a range of biologically and therapeutically relevant cargos to improve the therapeutic index, reduce side-effects, and more successfully diagnose and treat disease. The power and flexibility of the PRINT technology allows the biomedical or material science application to drive the size, shape and composition of the particle. The shapes and compositions at our disposal are nearly limitless and the technology is compatible with a diverse array of biological cargos, recognition and imaging agents. These next generation, multifunctional, nanoparticle engineered drug therapies have the potential to revolutionize the diagnosis and treatment of a multitude of diseases including cancer.
Unlike other particle fabrication techniques, PRINT is delicate and general enough to be compatible with a variety of important next-generation cancer therapeutic, detection and imaging agents, including various cargos (e.g. DNA, proteins, chemotherapy drugs, biosensor dyes, radio-markers, contrast agents), targeting ligands (e.g. antibodies, cell targeting peptides) and functional matrix materials (e.g. bioabsorbable polymers, stimuli responsive matrices, etc).
PRINT particles can also be decorated with ligands that are specific to certain cell surface receptors in an effort to specifically bind or to trigger receptor mediated endocytotic pathways in specific cell types. The surface of negatively charged PRINT nanoparticles can be decorated with specific ligands such as antibodies, small molecules, peptides and has proven useful for the selective targeting of certain cell types over other cell types. Once targeted with a cell specific ligand, the PRINT particle can deliver a cargo or be used for imaging. In this respect, PRINT particles promise great potential, since it is possible to utilize the ability to specifically target, be shape and size-specific, possess tunable matrixes, as well as the ability to incorporate imaging contrast agents.
The DeSimone Group and the C-CCNE are working on a number of projects aimed at developing targeted imaging agents and drug delivery and evaluating their applications in cancer detection and treatment. These projects include, Effect of particle size, shape, and surface chemistry on cellular internalization; Biodistribution of PRINT particles; Trojan Horse PRINT Particles; Drug Delivery; Nano-molding of Protein Particles
Top-down Nanoparticle Fabrication
