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

Ahmed M, Kumar G, Navarro G, Wang Y, Gourevitch S, Moussa MH, Rozenblum N, Levchenko T, Galun E, Torchilin VP, Goldberg SN - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Hepatic thermal ablation increases liver IL-6 levels at 12hr post-treatment and periablational α-SMA+ activated myofibroblasts infiltration—which are suppressed with single dose adjuvant nanoparticle anti-IL6 siRNA.(A) Liver ELISA quantification of IL-6 levels 12hr after treatment (mean ± standard deviation). C57Bl mice were randomized to receive sham treatment, liver RF ablation, liver RFA / IP MNP anti-IL6 siRNA, MNP anti-IL6 siRNA alone, RFA / MNP scrambled siRNA, or RFA / empty carrier (n = 5–6 per group). Liver RFA increased local 12hr liver IL-6 levels (1,463±108 pg/ml) which was suppressed with adjuvant IP MNP anti-IL6 siRNA (1,139±159 pg/ml, p = 0.04). Additionally, adjuvant MNP anti-IL6 siRNA given 15 minutes after hepatic thermal ablation (D, E) in C57Bl mice suppressed periablational infiltration of α-SMA positive myofibroblasts compared to hepatic thermal ablation alone (B) or RFA combined with scrambled siRNA (C) (F, mean ± standard deviation, p<0.01).
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pone.0128910.g001: Hepatic thermal ablation increases liver IL-6 levels at 12hr post-treatment and periablational α-SMA+ activated myofibroblasts infiltration—which are suppressed with single dose adjuvant nanoparticle anti-IL6 siRNA.(A) Liver ELISA quantification of IL-6 levels 12hr after treatment (mean ± standard deviation). C57Bl mice were randomized to receive sham treatment, liver RF ablation, liver RFA / IP MNP anti-IL6 siRNA, MNP anti-IL6 siRNA alone, RFA / MNP scrambled siRNA, or RFA / empty carrier (n = 5–6 per group). Liver RFA increased local 12hr liver IL-6 levels (1,463±108 pg/ml) which was suppressed with adjuvant IP MNP anti-IL6 siRNA (1,139±159 pg/ml, p = 0.04). Additionally, adjuvant MNP anti-IL6 siRNA given 15 minutes after hepatic thermal ablation (D, E) in C57Bl mice suppressed periablational infiltration of α-SMA positive myofibroblasts compared to hepatic thermal ablation alone (B) or RFA combined with scrambled siRNA (C) (F, mean ± standard deviation, p<0.01).

Mentions: Initial hepatic RF ablation studies were performed in normal C57Bl mice using standardized protocols to allow comparison to prior studies in normal and IL-6 knockout mice [25]. The following 6 treatment arms were compared (n = 5–6 animals/arm): hepatic RF thermal ablation alone (laparotomy and RF application for 5 min, tip temperature titrated to 70±2°C), sham procedure (laparotomy and needle placement without heating), RFA/MNP anti-IL6 siRNA (single dose of 3.5 μg siRNA given IP, 15 min post-ablation), RFA/MNP scrambled siRNA, MNP anti-IL6 siRNA alone, RFA/empty vehicle. Hepatic RF ablation increased local periablational tissue IL-6 levels compared to sham procedure at 12hr after treatment (1,463±108pg/ml vs. 1061±45pg/ml, p = 0.004, Fig 1A). Adjuvant MNP anti-IL6 siRNA given with hepatic RFA reduced local tissue IL-6 levels (1,139±159pg/ml; p = 0.04 vs. RFA alone, p = 0.46 vs. sham). Hepatic RFA/MNP scrambled siRNA increased local tissue IL-6 levels (1,924±141pg/ml; p<0.001 vs. sham, p = 0.01 vs. RFA alone, p = <0.001 vs. RFA/anti-IL6 siRNA). Tissue IL-6 levels after MNP anti-IL6 siRNA with sham treatment was 1,110±42pg/ml, and after RFA/empty carrier was 1783±125pg/ml.


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

Ahmed M, Kumar G, Navarro G, Wang Y, Gourevitch S, Moussa MH, Rozenblum N, Levchenko T, Galun E, Torchilin VP, Goldberg SN - PLoS ONE (2015)

Hepatic thermal ablation increases liver IL-6 levels at 12hr post-treatment and periablational α-SMA+ activated myofibroblasts infiltration—which are suppressed with single dose adjuvant nanoparticle anti-IL6 siRNA.(A) Liver ELISA quantification of IL-6 levels 12hr after treatment (mean ± standard deviation). C57Bl mice were randomized to receive sham treatment, liver RF ablation, liver RFA / IP MNP anti-IL6 siRNA, MNP anti-IL6 siRNA alone, RFA / MNP scrambled siRNA, or RFA / empty carrier (n = 5–6 per group). Liver RFA increased local 12hr liver IL-6 levels (1,463±108 pg/ml) which was suppressed with adjuvant IP MNP anti-IL6 siRNA (1,139±159 pg/ml, p = 0.04). Additionally, adjuvant MNP anti-IL6 siRNA given 15 minutes after hepatic thermal ablation (D, E) in C57Bl mice suppressed periablational infiltration of α-SMA positive myofibroblasts compared to hepatic thermal ablation alone (B) or RFA combined with scrambled siRNA (C) (F, mean ± standard deviation, p<0.01).
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pone.0128910.g001: Hepatic thermal ablation increases liver IL-6 levels at 12hr post-treatment and periablational α-SMA+ activated myofibroblasts infiltration—which are suppressed with single dose adjuvant nanoparticle anti-IL6 siRNA.(A) Liver ELISA quantification of IL-6 levels 12hr after treatment (mean ± standard deviation). C57Bl mice were randomized to receive sham treatment, liver RF ablation, liver RFA / IP MNP anti-IL6 siRNA, MNP anti-IL6 siRNA alone, RFA / MNP scrambled siRNA, or RFA / empty carrier (n = 5–6 per group). Liver RFA increased local 12hr liver IL-6 levels (1,463±108 pg/ml) which was suppressed with adjuvant IP MNP anti-IL6 siRNA (1,139±159 pg/ml, p = 0.04). Additionally, adjuvant MNP anti-IL6 siRNA given 15 minutes after hepatic thermal ablation (D, E) in C57Bl mice suppressed periablational infiltration of α-SMA positive myofibroblasts compared to hepatic thermal ablation alone (B) or RFA combined with scrambled siRNA (C) (F, mean ± standard deviation, p<0.01).
Mentions: Initial hepatic RF ablation studies were performed in normal C57Bl mice using standardized protocols to allow comparison to prior studies in normal and IL-6 knockout mice [25]. The following 6 treatment arms were compared (n = 5–6 animals/arm): hepatic RF thermal ablation alone (laparotomy and RF application for 5 min, tip temperature titrated to 70±2°C), sham procedure (laparotomy and needle placement without heating), RFA/MNP anti-IL6 siRNA (single dose of 3.5 μg siRNA given IP, 15 min post-ablation), RFA/MNP scrambled siRNA, MNP anti-IL6 siRNA alone, RFA/empty vehicle. Hepatic RF ablation increased local periablational tissue IL-6 levels compared to sham procedure at 12hr after treatment (1,463±108pg/ml vs. 1061±45pg/ml, p = 0.004, Fig 1A). Adjuvant MNP anti-IL6 siRNA given with hepatic RFA reduced local tissue IL-6 levels (1,139±159pg/ml; p = 0.04 vs. RFA alone, p = 0.46 vs. sham). Hepatic RFA/MNP scrambled siRNA increased local tissue IL-6 levels (1,924±141pg/ml; p<0.001 vs. sham, p = 0.01 vs. RFA alone, p = <0.001 vs. RFA/anti-IL6 siRNA). Tissue IL-6 levels after MNP anti-IL6 siRNA with sham treatment was 1,110±42pg/ml, and after RFA/empty carrier was 1783±125pg/ml.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus