Journal Article

Systemic siRNA Nanoparticle-Based Drugs Combined with Radiofrequency Ablation for Cancer Therapy

Levchenko, Tatyana, Goldberg, S. Nahum, Kumar, Gaurav, Galun, Eithan, Torchilin, Vladimir P., Navarro, Gemma, Gourevitch, Svetlana, Rozenblum, Nir, Ahmed, Muneeb, Wang, Yuanguo, Moussa, Marwan H.

2015

Overview

Radiofrequency thermal ablation (RFA) of hepatic and renal tumors can be accompanied by non-desired tumorigenesis in residual, untreated tumor. Here, we studied the use of micelle-encapsulated siRNA to suppress IL-6-mediated local and systemic secondary effects of RFA. We compared standardized hepatic or renal RFA (laparotomy, 1 cm active tip at 70 ± 2 °C for 5 min) and sham procedures without and with administration of 150 nm micelle-like nanoparticle (MNP) anti-IL6 siRNA (DOPE-PEI conjugates, single IP dose 15 min post-RFA, C57Bl mouse:3.5 ug/100ml, Fisher 344 rat: 20 ug/200 ul), RFA/scrambled siRNA, and RFA/empty MNPs. Outcome measures included: local periablational cellular infiltration (α-SMA+ stellate cells), regional hepatocyte proliferation, serum/tissue IL-6 and VEGF levels at 6-72 hr, and distant tumor growth, tumor proliferation (Ki-67) and microvascular density (MVD, CD34) in subcutaneous R3230 and MATBIII breast adenocarcinoma models at 7 days. For liver RFA, adjuvant MNP anti-IL6 siRNA reduced RFA-induced increases in tissue IL-6 levels, α-SMA+ stellate cell infiltration, and regional hepatocyte proliferation to baseline (p < 0.04, all comparisons). Moreover, adjuvant MNP anti-IL6- siRNA suppressed increased distant tumor growth and Ki-67 observed in R3230 and MATBIII tumors post hepatic RFA (p<0.01). Anti-IL6 siRNA also reduced RFA-induced elevation in VEGF and tumor MVD (p < 0.01). Likewise, renal RFA-induced increases in serum IL-6 levels and distant R3230 tumor growth was suppressed with anti-IL6 siRNA (p < 0.01). Adjuvant nanoparticle-encapsulated siRNA against IL-6 can be used to modulate local and regional effects of hepatic RFA to block potential unwanted pro-oncogenic effects of hepatic or renal RFA on distant tumor.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Ablation / Ablation (Surgery) / Adenocarcinoma / Animal models / Animals / Antineoplastic agents / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biotechnology / Cancer / Cancer therapies / Cardiac arrhythmia / Cardiology / Catheter Ablation / CD34 antigen / Cell proliferation / Cell Proliferation - drug effects / Combined Modality Therapy / Comparative analysis / Disease Models, Animal / Drug therapy / Drugs / Encapsulation / Female / Gene therapy / Growth factors / Health aspects / Hepatocytes - drug effects / Hepatocytes - pathology / House mouse / Infiltration / Interleukin 6 / Interleukin-6 - metabolism / Kidney - drug effects / Kidney - pathology / Kidney cancer / Kidneys / Laboratories / Liver / Liver - drug effects / Liver - pathology / Liver - surgery / Liver cancer / Mammary Neoplasms, Experimental - blood supply / Mammary Neoplasms, Experimental - drug therapy / Mammary Neoplasms, Experimental - surgery / Medical schools / Metastases / Mice, Inbred C57BL / Micelles / Microvasculature / Nanoparticles / Nanoparticles - chemistry / Neovascularization, Pathologic - metabolism / Neovascularization, Pathologic - pathology / Pharmaceutical sciences / Polyetherimides / Radio frequency / Radiofrequency ablation / Rats, Inbred F344 / RNA, Small Interfering - metabolism / siRNA / Stellate cells / Studies / Subcutaneous Tissue - pathology / Thoracic surgery / Tumorigenesis / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - metabolism