title: 4PD Functionalized Dendrimers: A Flexible Tool for In Vivo Gene Silencing of Tumor-Educated Myeloid Cells.
abstract: Myeloid cells play a key role in tumor progression and metastasis by providing nourishment and immune protection, as well as facilitating cancer invasion and seeding to distal sites. Although advances have been made in understanding the biology of these tumor-educated myeloid cells (TEMCs), their intrinsic plasticity challenges our further understanding of their biology. Indeed, in vitro experiments only mimic the in vivo setting, and current gene-knockout technologies do not allow the simultaneous, temporally controlled, and cell-specific silencing of multiple genes or pathways. In this article, we describe the 4PD nanoplatform, which allows the in vivo preferential transfection and in vivo tracking of TEMCs with the desired RNAs. This platform is based on the conjugation of CD124/IL-4Rα-targeting peptide with G5 PAMAM dendrimers as the loading surface and can convey therapeutic or experimental RNAs of interest. When injected i.v. in mice bearing CT26 colon carcinoma or B16 melanoma, the 4PD nanoparticles predominantly accumulate at the tumor site, transfecting intratumoral myeloid cells. The use of 4PD to deliver a combination of STAT3- and C/EBPβ-specific short hairpin RNA or miR-142-3p confirmed the importance of these genes and microRNAs in TEMC biology and indicates that silencing of both genes is necessary to increase the efficacy of immune interventions. Thus, the 4PD nanoparticle can rapidly and cost effectively modulate and assess the in vivo function of microRNAs and mRNAs in TEMCs.
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miami, FL, 33136.
authors.forename: Serena
authors.identifier: 0000-0002-9969-5951
authors.initials: S
authors.lastname: Zilio
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miami, FL, 33136.
authors.forename: Jennifer L
authors.identifier: 0000-0002-6190-8114
authors.initials: JL
authors.lastname: Vella
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miami, FL, 33136.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: De la Fuente
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miami, FL, 33136.
authors.forename: Pirouz M
authors.initials: PM
authors.lastname: Daftarian
authors.affiliation: Department of Otolaryngology, University of Miami, Miami, FL, 33136.
authors.forename: Donald T
authors.identifier: 0000-0002-8551-7142
authors.initials: DT
authors.lastname: Weed
authors.affiliation: Department of Chemistry, University of Miami, Coral Gables, FL, 33146.
authors.forename: Angel
authors.initials: A
authors.lastname: Kaifer
authors.affiliation: Istituto Oncologico Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, IOV-IRCCS, 35128 Padova, Italy; and.
authors.forename: Ilaria
authors.identifier: 0000-0003-2948-3678
authors.initials: I
authors.lastname: Marigo
authors.affiliation: Istituto Oncologico Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, IOV-IRCCS, 35128 Padova, Italy; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Leone
authors.affiliation: Department of Medicine, Verona University Hospital, 37134 Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miami, FL, 33136; pserafini@miami.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Serafini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D050091:Dendrimers / Q000008:administration & dosage / Q000378:metabolism*; D020868:Gene Silencing; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D035683:MicroRNAs; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism; D036103:Nanotechnology / Q000379:methods* / Q000592:standards; D019948:Receptors, Interleukin-4 / Q000276:immunology / Q000378:metabolism
chemical_list: D050091:Dendrimers; D053662:Interleukin-4 Receptor alpha Subunit; D035683:MicroRNAs; C104700:PAMAM Starburst; D019948:Receptors, Interleukin-4