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Browsing by Author "DeSimone, Joseph M."

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    Analysis of the Murine Immune Response to Pulmonary Delivery of Precisely Fabricated Nano- and Microscale Particles
    Roberts, Reid A.; Shen, Tammy; Allen, Irving C.; Hasan, Warefta; DeSimone, Joseph M.; Ting, Jenny P.-Y. (PLOS, 2013-04-12)
    Nanomedicine has the potential to transform clinical care in the 21st century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs.
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    Synthesis of well-defined single and multiphase polymers using various living polymerization methods
    DeSimone, Joseph M. (Virginia Tech, 1990-03-15)
    Hexenyl functionalized poly(dimethylsiloxane) and methacryloyloxy functionalized poly(methyl methacrylate) (PMMA) and poly(dimethylsiloxane) (PDMS) macromonomers were synthesized using living polymerization techniques. The PDMS macromonomers were prepared by the anionic ring-opening polymerization of hexamethylcyclotrisiloxane followed by termination with a functionalized chlorosilane derivative. The methacryloyloxy functionalized PMMA macromonomers were prepared using group transfer polymerization with a protected hydroxyl functional initiator. The molar masses of the macromonomers ranged from 1000 g/mol up to 20000 g/mol with narrow molar mass distributions, less than 1.1, and high percent functionalities. The hexenyl functionalized PDMS macromonomers, having a range of molar masses, were statistically terpolymerized with l-butene and sulfur dioxide to yield poly(l-butene sulfone)-g-PDMS copolymers of various chemical compositions up to 20 wt% PDMS. The bulk and surface phase morphologies were investigated using DSC, TEM, XPS, and water contact angle measurements. The graft copolymer was shown to be an excellent resist for electron beam lithography with a 44u4C/cm4 sensitivity and a 33:1 etch ratio relative to a cross linked novolac resin. The 7000 g/mol methacryloyloxy functionalized PMMA macromonomers were copolymerized anionically with MMA to yield PMMA-g-PMMA polymers having absolute molar mass distributions less than 1.1 containing from 5 wt% to 40 wt% of the macromonomer at constant overall molar mass of 250000 g/mol. The graft polymers were utilized as model homopolymers exhibiting long chain branching. The methacryloyloxy functionalized PDMS macromonomers were free radically and anionically copolymerized with MMA to yield PMMA-g-PDMS copolymers. The graft copolymers were fractionated and their chemical composition distributions were determined as a function of copolymerization mechanism. In addition, preliminary studies were started using aluminum-27 NMR to study several different aluminum porphyrins based on (5,10,15,20-tetraphenyl) porphine (TPPH₂) . The aluminum porphyrins were formed by reacting trimethylaluminum with TPPH₂ to yield TPPAIMe. The resulting aluminum porphyrin was modified by adding a stoichiometric amount of various carboxylic acids to form aluminum porphyrin carboxylates that had varying steric and electronic effects on the macrocycle.