title: Nanotherapy silencing the interleukin-8 gene produces regression of prostate cancer by inhibition of angiogenesis.
abstract: Interleukin-8 (IL-8) is a pro-angiogenic cytokine associated with aggressive prostate cancer (CaP). We detected high levels of IL-8 in sera from patients with CaP compared with healthy controls and patients with benign prostatic hypertrophy. This study examines the role of IL-8 in the pathogenesis of metastatic prostate cancer. We developed a biocompatible, cationic polylactide (CPLA) nanocarrier to complex with and efficiently deliver IL-8 small interfering RNA (siRNA) to CaP cells in vitro and in vivo. CPLA IL-8 siRNA nanocomplexes (nanoplexes) protect siRNA from rapid degradation, are non-toxic, have a prolonged lifetime in circulation, and their net positive charge facilitates penetration of cell membranes and subsequent intracellular trafficking. Administration of CPLA IL-8 siRNA nanoplexes to immunodeficient mice bearing human CaP tumours produced significant antitumour activities with no adverse effects. Systemic (intravenous) or local intra-tumour administration of IL-8 siRNA nanoplexes resulted in significant inhibition of CaP growth. Magnetic resonance imaging and ultrasonography of experimental animals demonstrated reduction of tumour perfusion in vivo following nanoplex treatment. Staining of tumour sections for CD31 confirmed significant damage to tumour neovasculature after nanoplex therapy. These studies demonstrate the efficacy of IL-8 siRNA nanotherapy for advanced, treatment-resistant human CaP.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Aalinkeel
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.
authors.forename: Bindukumar
authors.initials: B
authors.lastname: Nair
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY, USA.
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.
authors.forename: Supriya D
authors.initials: SD
authors.lastname: Mahajan
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Reynolds
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY, USA.
authors.forename: Hanguang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY, USA.
authors.forename: Haotian
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Sykes
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Chadha
authors.affiliation: Department of Pharmacology and Therapeutics, Cancer Cell Center Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Turowski
authors.affiliation: Department of Pharmacology and Therapeutics, Cancer Cell Center Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Katelyn D
authors.initials: KD
authors.lastname: Bothwell
authors.affiliation: Department of Pharmacology and Therapeutics, Cancer Cell Center Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D045744:Cell Line, Tumor; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000628:therapy*; D011091:Polyesters / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001672:Biocompatible Materials; D016209:Interleukin-8; D011091:Polyesters; D034741:RNA, Small Interfering; C033616:poly(lactide)
keywords: angiogenesis; cytokines; interleukin-8; metastasis; nanotherapy