title: Systemic siRNA Nanoparticle-Based Drugs Combined with Radiofrequency Ablation for Cancer Therapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd.-WCC-308B, Boston, Massachusetts, 02215, United States of America.
authors.forename: Muneeb
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd.-WCC-308B, Boston, Massachusetts, 02215, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway, Boston, Massachusetts, 02115, United States of America.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd.-WCC-308B, Boston, Massachusetts, 02215, United States of America.
authors.forename: Yuanguo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Kiryat Hadassah POB 12000, Jerusalem, 91120, Israel.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gourevitch
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd.-WCC-308B, Boston, Massachusetts, 02215, United States of America.
authors.forename: Marwan H
authors.initials: MH
authors.lastname: Moussa
authors.affiliation: The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Kiryat Hadassah POB 12000, Jerusalem, 91120, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Rozenblum
authors.affiliation: Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway, Boston, Massachusetts, 02115, United States of America.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Levchenko
authors.affiliation: The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Kiryat Hadassah POB 12000, Jerusalem, 91120, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway, Boston, Massachusetts, 02115, United States of America.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd.-WCC-308B, Boston, Massachusetts, 02215, United States of America; Division of Image-guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Medical Center, Kiryat Hadassah POB 12000, Jerusalem, 91120, Israel.
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017115:Catheter Ablation; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000601:surgery*; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism*; D011916:Rats, Inbred F344; D040521:Subcutaneous Tissue / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D008823:Micelles; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A