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

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

doi:10.1371/journal.pone.0128910

Abstract

PurposeRadiofrequency 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.MethodsWe 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 150nm 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: 20ug/200ul), 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 6-72hr, and distant tumor growth, tumor proliferation (Ki-67) and microvascular density (MVD, CD34) in subcutaneous R3230 and MATBIII breast adenocarcinoma models at 7 days.ResultsFor 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).ConclusionsAdjuvant 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.

Highlights

There has been much recent interest in using RNA interference (‘post-transcriptional gene silencing’) and small interfering RNAs in cancer therapies
Adjuvant micelle-like nanoparticle (MNP) anti-IL6- small interfering RNAs (siRNA) suppressed increased distant tumor growth and Ki-67 observed in R3230 and MATBIII tumors post hepatic Radiofrequency thermal ablation (RFA) (p
In an attempt to ensure completeness of treatment, we have shown that administration of even a single-dose of drug-loaded nanoparticle chemotherapy concurrently with RF ablation can lead to increases in local periablational drug delivery, with resultant increased tumor destruction, increased animal endpoint survival, and greater amounts of tumor destruction in patients with hepatic tumors [14,15,16]

Summary

Introduction

There has been much recent interest in using RNA interference (‘post-transcriptional gene silencing’) and small interfering RNAs (siRNA) in cancer therapies. This has largely focused on either modulating cellular protein responses to improve efficacy of primary pharmacologic/oncologic therapies [1,2], augmenting anti-tumor immunity through selective knockdown of immune response suppressing proteins, or chemo-sensitization through silencing of growth factor receptor genes [3,4,5,6]. We have further successfully leveraged this improved focal delivery to target specific RFA-induced tissue responses (such as increased DNA intercalation or suppressing HSP production) [16,17]

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Results

Conclusion