title: Multifunctional Envelope-Type siRNA Delivery Nanoparticle Platform for Prostate Cancer Therapy.
abstract: With the capability of specific silencing of target gene expression, RNA interference (RNAi) technology is emerging as a promising therapeutic modality for the treatment of cancer and other diseases. One key challenge for the clinical applications of RNAi is the safe and effective delivery of RNAi agents such as small interfering RNA (siRNA) to a particular nonliver diseased tissue (e.g., tumor) and cell type with sufficient cytosolic transport. In this work, we proposed a multifunctional envelope-type nanoparticle (NP) platform for prostate cancer (PCa)-specific in vivo siRNA delivery. A library of oligoarginine-functionalized and sharp pH-responsive polymers was synthesized and used for self-assembly with siRNA into NPs with the features of long blood circulation and pH-triggered oligoarginine-mediated endosomal membrane penetration. By further modification with ACUPA, a small molecular ligand specifically recognizing prostate-specific membrane antigen (PSMA) receptor, this envelope-type nanoplatform with multifunctional properties can efficiently target PSMA-expressing PCa cells and silence target gene expression. Systemic delivery of the siRNA NPs can efficiently silence the expression of prohibitin 1 (PHB1), which is upregulated in PCa and other cancers, and significantly inhibit PCa tumor growth. These results suggest that this multifunctional envelope-type nanoplatform could become an effective tool for PCa-specific therapy.
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Xiaoding
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Phei Er
authors.initials: PE
authors.lastname: Saw
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Tao
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Mikyung
authors.initials: M
authors.lastname: Yu
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Harshal
authors.initials: H
authors.lastname: Zope
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Si
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Victorious
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rasmussen
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Ayyash
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.|King Abdulaziz University , Jeddah 21589, Saudi Arabia.
authors.forename: Omid C
authors.identifier: 0000-0003-2009-270X
authors.initials: OC
authors.lastname: Farokhzad
authors.affiliation: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Jinjun
authors.identifier: 0000-0001-9200-5068
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D005977:Glutarates / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D000091402:Prohibitins; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013499:Surface Properties; D014407:Tumor Cells, Cultured
chemical_list: C000630141:(S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)-pentanedioic acid; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D005977:Glutarates; D008024:Ligands; C000717328:PHB protein, human; D000091402:Prohibitins; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: membrane-penetrating; multifunctional nanoparticle; pH-responsive; prostate cancer; siRNA; targeted delivery