A critical need still remains for effective delivery of RNA interference (RNAi) therapeutics to target tissues and cells. Self-assembled lipid- and polymer-based systems have been most extensively explored for transfection with small interfering RNA (siRNA) in liver and cancer therapies. Safety and compatibility of materials implemented in delivery systems must be ensured to maximize therapeutic indices. Hydrogel nanoparticles of defined dimensions and compositions, prepared via a particle molding process that is a unique off-shoot of soft lithography known as particle replication in nonwetting templates (PRINT), were explored in these studies as delivery vectors. Initially, siRNA was encapsulated in particles through electrostatic association and physical entrapment. Dose-dependent gene silencing was elicited by PEGylated hydrogels at low siRNA doses without cytotoxicity. To prevent disassociation of cargo from particles after systemic administration or during postfabrication processing for surface functionalization, a polymerizable siRNA pro-drug conjugate with a degradable, disulfide linkage was prepared. Triggered release of siRNA from the pro-drug hydrogels was observed under a reducing environment while cargo retention and integrity were maintained under physiological conditions. Gene silencing efficiency and cytocompatibility were optimized by screening the amine content of the particles. When appropriate control siRNA cargos were loaded into hydrogels, gene knockdown was only encountered for hydrogels containing releasable, target-specific siRNAs, accompanied by minimal cell death. Further investigation into shape, size, and surface decoration of siRNA-conjugated hydrogels should enable efficacious targeted in vivo RNAi therapies.

Historically it is known that presentation of vaccine antigens in particulate form, for a wide range of pathogens, has clear advantages over the presentation of soluble antigen alone [J.C. Aguilar, E.G. Rodriguez, Vaccine adjuvants revisited. Vaccine 25 (2007) 3752-3762, M. Singh, D. O'Hagan, Advances in vaccine adjuvants. Nature Biotechnology 17 (1999) 1075-1081]. Herein we describe a novel particle-based approach, which independently controls size, shape, and composition to control the delivery and presentation of vaccine antigen to the immune system. Highly uniform particles were produced using a particle molding technology called PRINT (Particle Replication in Non-wetting Templates) which is an off-shoot of imprint lithography [J Am Chem Soc 127 (2005) 10096-10100, J Am Chem Soc 126 (2004) 2322-2323, Chem Soc Rev 35 (2006) 1095-1104, J Am Chem Soc 130 (2008) 5008-5009, J Am Chem Soc 130 (2008) 5438-5439, Polymer Reviews 47 (2007) 321-327, Acc Chem Res 41 (2008) 1685-1695, Acc Chem Res 44 (10) (2011) 990-998]. Cylindrical (diameter [d]=80 nm, height [h]=320 nm) poly (lactide-co-glycolide) (PLGA) based PRINT particles were designed to electrostatically bind commercial trivalent injectable influenza vaccine. In a variety of blended PLGA formulations, these particles were safe and showed enhanced responses to influenza hemagglutinin in murine models. FROM THE CLINICAL EDITOR:Shape is one of the determining factors in interactions of nanoparticles with their biologic environment. PRINT technology is able to fabricate nearly uniform nanoparticles and this technology is tested here in murine models to effectively deliver influenza vaccine.

The PRINT® (pattern replication in non-wetting templates) process has been developed as a simple, gentle way to pattern films or generate discrete particles in arrays out of either pure biological materials or biomolecules encapsulated within polymeric materials. Patterned films and particle arrays can be fabricated in a wide array of sizes and shapes using Fluorocur® (a UV-curable perfluoropolyether polymer) from the nanometer to micron scale.

A nanoparticle is fabricated from a reaction of a polymer, a crosslinker, a nucleic acid, and between about 2 wt% and about 75 wt% of a charged monomer within a cavity of a mold resulting in a particle having a substantially predetermined three dimensional shape and a largest cross-sectional dimension of less than about 5 micron. The mold can include perfluoropoly ether and the nucleic acid can include less than about 30 nucleotides and the polymer can be poly( vinyl pyrrolidinone). The particles can be washed after being molded and the mold can include less than about 1 wt% initiator, less than about 0.5 wt% initiator, or less than about 0.1 wt% initiator.

Angewandte Chemie International EditionVolume 46, Issue 6 p. 945-947 Communication Site Isolation and Epoxidation Reactivity of a Templated Ferrous Bis(phenanthroline) Site in Porous Silica† Tracy J. Terry, Tracy J. Terry Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this authorGeraud Dubois Dr., Geraud Dubois Dr. Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this authorAndrew Murphy Dr., Andrew Murphy Dr. Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this authorT. Daniel P. Stack Prof., T. Daniel P. Stack Prof. [email protected] Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this author Tracy J. Terry, Tracy J. Terry Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this authorGeraud Dubois Dr., Geraud Dubois Dr. Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this authorAndrew Murphy Dr., Andrew Murphy Dr. Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this authorT. Daniel P. Stack Prof., T. Daniel P. Stack Prof. [email protected] Department of Chemistry, Stanford University, Stanford, CA 94305, USA, Fax: (+1) 650-725-0259Search for more papers by this author First published: 22 January 2007 https://doi.org/10.1002/anie.200603423Citations: 43 † This work was supported by the NIH (grant GM-50730). We thank Dr. G. Li from the Soils and Environmental Biogeochemistry laboratory at Stanford University for ICP analysis, and Prof. E. I. Solomon for EPR instrument time. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Teaching an old ligand new tricks: Attachment of a CuI–bis(phenanthroline) complex to mesoporous silica and metal exchange create site-isolated FeII–bis(phenanthroline) complexes which efficiently epoxidize terminal olefins with peracetic acid (see scheme). This strategy side-steps the formation of a FeII–tris(phenanthroline) complex, which predominates in solution. Citing Literature Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z603423_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume46, Issue6January 29, 2007Pages 945-947 RelatedInformation

Twenty-two Mn-II complexes were screened for the catalytic epoxidation of terminal olefins using peracetic acid as the oxidant. A limited number of these complexes are efficient catalysts using peracetic acid solutions generated with H2SO4 (PAAc), but most complexes are effective at 1 mol% catalyst loading using peracetic acid generated with strongly acidic resins (PAAR). Under the less acidic conditions of PAAR, [Mn-II(phen)(2)(CF3SO3)(2)] has the highest activity of the catalysts screened, and epoxides terminal olefins using as little as 0.02 mol% catalyst within 5 min. The dimeric species [Mn-2(III.IV)(phen)(4)(O)(2)](ClO4)(3) is also a viable epoxidation catalyst with PAAR, but the dimeric species is reduced by the residual H2O, to monomeric Mu(II) species under the reaction conditions. By comparison, a similar dimeric complex [Mn-2(III,IV)(R,R-MCP)(2)(O)(2)](ClO4)(3), is not reduced by H,O, under the reaction conditions and is not catalytically active, supportive of the notion that the catalytically relevant species is monomeric. (c) 2006 Elsevier B.V. All rights reserved.