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Nanotherapy silencing the interleukin‐8 gene produces regression of prostate cancer by inhibition of angiogenesis
Author(s) -
Aalinkeel Ravikumar,
Nair Bindukumar,
Chen ChihKuang,
Mahajan Supriya D.,
Reynolds Jessica L.,
Zhang Hanguang,
Sun Haotian,
Sykes Donald E.,
Chadha Kailash C.,
Turowski Steven G.,
Bothwell Katelyn D.,
Seshadri Mukund,
Cheng Chong,
Schwartz Stanley A.
Publication year - 2016
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12618
Subject(s) - small interfering rna , in vivo , cancer research , angiogenesis , cytokine , rna , gene silencing , prostate cancer , genetic enhancement , biology , cancer , pathology , medicine , immunology , gene , biochemistry , microbiology and biotechnology
Summary 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 (si RNA ) to CaP cells in vitro and in vivo . CPLA IL ‐8 si RNA nanocomplexes (nanoplexes) protect si RNA 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 si RNA 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 si RNA 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 CD 31 confirmed significant damage to tumour neovasculature after nanoplex therapy. These studies demonstrate the efficacy of IL ‐8 si RNA nanotherapy for advanced, treatment‐resistant human CaP.