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Systemic siRNA Nanoparticle-Based Drugs Combined with Radiofrequency Ablation for Cancer Therapy
Muneeb Ahmed1, Gaurav Kumar1, Gemma Navarro2
1Laboratory 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.
Purpose:
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.
Insights
Micelle-encapsulated siRNA targeting IL-6 suppressed secondary tumor growth after radiofrequency thermal ablation (RFA). This therapy reduced local inflammation and distant tumor proliferation, offering a novel strategy to mitigate RFA side effects.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Radiofrequency thermal ablation (RFA) is used for hepatic and renal tumors.
- RFA can inadvertently promote secondary tumor growth due to residual tumor stimulation.
- Interleukin-6 (IL-6) plays a role in mediating these pro-oncogenic effects.
Purpose of the Study:
- To investigate the efficacy of micelle-encapsulated siRNA targeting IL-6 (anti-IL6 siRNA) in suppressing secondary tumorigenesis post-RFA.
- To evaluate the impact of anti-IL6 siRNA on local and systemic effects of RFA.
Main Methods:
- Standardized hepatic or renal RFA was performed on mice and rats.
- Animals received either anti-IL6 siRNA, scrambled siRNA, or empty nanoparticles (MNPs) post-RFA.
- Evaluated outcomes included local cellular infiltration, hepatocyte proliferation, IL-6/VEGF levels, and distant tumor growth, proliferation, and microvascular density.
Main Results:
- Adjuvant anti-IL6 siRNA significantly reduced RFA-induced IL-6 levels, α-SMA+ stellate cell infiltration, and hepatocyte proliferation in the liver.
- Treatment suppressed distant tumor growth, proliferation (Ki-67), and microvascular density (MVD) in breast cancer models after hepatic RFA.
- Anti-IL6 siRNA also mitigated increased serum IL-6 and distant tumor growth following renal RFA.
Conclusions:
- Nanoparticle-encapsulated siRNA targeting IL-6 effectively modulates local and regional effects of RFA.
- This approach can block potential pro-oncogenic effects of RFA on distant tumors.
- Adjuvant anti-IL6 siRNA represents a promising strategy to improve RFA outcomes.
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