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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-induced distant subcutaneous R3230 tumor growth is suppressed with adjuvant nanoparticle anti-IL6 siRNA.(A) Subcutaneous R3230 tumors implanted in Fisher 344 rats with similar growth rates were randomized at Day 0 to one of six different treatment arms (n = 6–7 animals/arm). Hepatic thermal ablation alone or combined with either empty carrier or MNP scrambled siRNA resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment (p<0.01 for all comparisons, mean ± standard deviation for all numbers presented). Adjuvant MNP anti-IL6 siRNA combined with thermal ablation resulted in distant tumor growth rate and end diameter that was the lowest of all treatment arms (p<0.01 for all comparisons). (B) Adjuvant MNP anti-IL6 siRNA combined with hepatic thermal ablation also reduced distant tumor proliferation (Ki-67) to sham levels compared to hepatic thermal ablation alone or combined with empty carrier or MNP scrambled siRNA (p<0.01 for relevant comparisons). (C) Hepatic thermal ablation alone or with MNP scrambled siRNA increased serum IL-6 levels at 6hr compared to the sham procedure (n = 3–4 animals/arm, p<0.02). This effect was suppressed with adjuvant MNP anti-IL6 siRNA (p = 0.03 vs. RF liver alone). (D) Comparison of the effect of siRNA administration timing showed that adjuvant MNP anti-IL6 siRNA administered at Day 0 resulted in the lowest post-treatment tumor growth rate and endpoint diameter (n = 3–4 animals/arm, p<0.05 for all comparisons). Adjuvant MNP anti-IL6 siRNA administered 3d post-ablation reduced the endpoint diameter compared to hepatic ablation alone, but was still significantly greater that either sham or combined-Day 0 treatment (p<0.05 for all comparisons).
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pone.0128910.g003: Hepatic thermal ablation-induced distant subcutaneous R3230 tumor growth is suppressed with adjuvant nanoparticle anti-IL6 siRNA.(A) Subcutaneous R3230 tumors implanted in Fisher 344 rats with similar growth rates were randomized at Day 0 to one of six different treatment arms (n = 6–7 animals/arm). Hepatic thermal ablation alone or combined with either empty carrier or MNP scrambled siRNA resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment (p<0.01 for all comparisons, mean ± standard deviation for all numbers presented). Adjuvant MNP anti-IL6 siRNA combined with thermal ablation resulted in distant tumor growth rate and end diameter that was the lowest of all treatment arms (p<0.01 for all comparisons). (B) Adjuvant MNP anti-IL6 siRNA combined with hepatic thermal ablation also reduced distant tumor proliferation (Ki-67) to sham levels compared to hepatic thermal ablation alone or combined with empty carrier or MNP scrambled siRNA (p<0.01 for relevant comparisons). (C) Hepatic thermal ablation alone or with MNP scrambled siRNA increased serum IL-6 levels at 6hr compared to the sham procedure (n = 3–4 animals/arm, p<0.02). This effect was suppressed with adjuvant MNP anti-IL6 siRNA (p = 0.03 vs. RF liver alone). (D) Comparison of the effect of siRNA administration timing showed that adjuvant MNP anti-IL6 siRNA administered at Day 0 resulted in the lowest post-treatment tumor growth rate and endpoint diameter (n = 3–4 animals/arm, p<0.05 for all comparisons). Adjuvant MNP anti-IL6 siRNA administered 3d post-ablation reduced the endpoint diameter compared to hepatic ablation alone, but was still significantly greater that either sham or combined-Day 0 treatment (p<0.05 for all comparisons).

Mentions: To determine the impact on distant tumor growth to simulate the common condition of distant metastases, we used a subcutaneous breast tumor model (R3230) in which hepatic RF ablation has been associated with distant tumor growth [26]. Here, the following treatment arms were compared (n = 6–7 animals/arm): hepatic RF thermal ablation alone, sham procedure, RFA/MNP anti-IL6 siRNA (20 mcg of siRNA, IP delivery), RFA/MNP scrambled siRNA, MNP anti-IL6 siRNA alone, RFA/empty vehicle. The effect of these six treatment arms on distant subcutaneous tumor growth was assessed. All tumors grew at the same rate over 5d prior to randomization to various treatment arms. Thermal ablation of normal liver increased distant R3230 tumor growth for 7d after treatment compared to sham/control treatment (p<0.001; Fig 3A, Table 1). Adjuvant MNP anti-IL6 siRNA suppressed the thermal ablation-induced effects on distant R3230 tumor growth such that the mean tumor size at 7d with combination therapy was lower than either the sham (non-ablation) and hepatic RFA alone groups (p = 0.02 vs. sham, p<0.001 vs. hepatic RFA alone; Fig 3A, Table 1). Hepatic RF ablation combined with MNP scrambled siRNA resulted in the largest distant tumor diameter at 7d compared to all other treatment arms (19.3±1.7mm, p<0.03 for all comparisons).


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-induced distant subcutaneous R3230 tumor growth is suppressed with adjuvant nanoparticle anti-IL6 siRNA.(A) Subcutaneous R3230 tumors implanted in Fisher 344 rats with similar growth rates were randomized at Day 0 to one of six different treatment arms (n = 6–7 animals/arm). Hepatic thermal ablation alone or combined with either empty carrier or MNP scrambled siRNA resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment (p<0.01 for all comparisons, mean ± standard deviation for all numbers presented). Adjuvant MNP anti-IL6 siRNA combined with thermal ablation resulted in distant tumor growth rate and end diameter that was the lowest of all treatment arms (p<0.01 for all comparisons). (B) Adjuvant MNP anti-IL6 siRNA combined with hepatic thermal ablation also reduced distant tumor proliferation (Ki-67) to sham levels compared to hepatic thermal ablation alone or combined with empty carrier or MNP scrambled siRNA (p<0.01 for relevant comparisons). (C) Hepatic thermal ablation alone or with MNP scrambled siRNA increased serum IL-6 levels at 6hr compared to the sham procedure (n = 3–4 animals/arm, p<0.02). This effect was suppressed with adjuvant MNP anti-IL6 siRNA (p = 0.03 vs. RF liver alone). (D) Comparison of the effect of siRNA administration timing showed that adjuvant MNP anti-IL6 siRNA administered at Day 0 resulted in the lowest post-treatment tumor growth rate and endpoint diameter (n = 3–4 animals/arm, p<0.05 for all comparisons). Adjuvant MNP anti-IL6 siRNA administered 3d post-ablation reduced the endpoint diameter compared to hepatic ablation alone, but was still significantly greater that either sham or combined-Day 0 treatment (p<0.05 for all comparisons).
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495977&req=5

pone.0128910.g003: Hepatic thermal ablation-induced distant subcutaneous R3230 tumor growth is suppressed with adjuvant nanoparticle anti-IL6 siRNA.(A) Subcutaneous R3230 tumors implanted in Fisher 344 rats with similar growth rates were randomized at Day 0 to one of six different treatment arms (n = 6–7 animals/arm). Hepatic thermal ablation alone or combined with either empty carrier or MNP scrambled siRNA resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment (p<0.01 for all comparisons, mean ± standard deviation for all numbers presented). Adjuvant MNP anti-IL6 siRNA combined with thermal ablation resulted in distant tumor growth rate and end diameter that was the lowest of all treatment arms (p<0.01 for all comparisons). (B) Adjuvant MNP anti-IL6 siRNA combined with hepatic thermal ablation also reduced distant tumor proliferation (Ki-67) to sham levels compared to hepatic thermal ablation alone or combined with empty carrier or MNP scrambled siRNA (p<0.01 for relevant comparisons). (C) Hepatic thermal ablation alone or with MNP scrambled siRNA increased serum IL-6 levels at 6hr compared to the sham procedure (n = 3–4 animals/arm, p<0.02). This effect was suppressed with adjuvant MNP anti-IL6 siRNA (p = 0.03 vs. RF liver alone). (D) Comparison of the effect of siRNA administration timing showed that adjuvant MNP anti-IL6 siRNA administered at Day 0 resulted in the lowest post-treatment tumor growth rate and endpoint diameter (n = 3–4 animals/arm, p<0.05 for all comparisons). Adjuvant MNP anti-IL6 siRNA administered 3d post-ablation reduced the endpoint diameter compared to hepatic ablation alone, but was still significantly greater that either sham or combined-Day 0 treatment (p<0.05 for all comparisons).
Mentions: To determine the impact on distant tumor growth to simulate the common condition of distant metastases, we used a subcutaneous breast tumor model (R3230) in which hepatic RF ablation has been associated with distant tumor growth [26]. Here, the following treatment arms were compared (n = 6–7 animals/arm): hepatic RF thermal ablation alone, sham procedure, RFA/MNP anti-IL6 siRNA (20 mcg of siRNA, IP delivery), RFA/MNP scrambled siRNA, MNP anti-IL6 siRNA alone, RFA/empty vehicle. The effect of these six treatment arms on distant subcutaneous tumor growth was assessed. All tumors grew at the same rate over 5d prior to randomization to various treatment arms. Thermal ablation of normal liver increased distant R3230 tumor growth for 7d after treatment compared to sham/control treatment (p<0.001; Fig 3A, Table 1). Adjuvant MNP anti-IL6 siRNA suppressed the thermal ablation-induced effects on distant R3230 tumor growth such that the mean tumor size at 7d with combination therapy was lower than either the sham (non-ablation) and hepatic RFA alone groups (p = 0.02 vs. sham, p<0.001 vs. hepatic RFA alone; Fig 3A, Table 1). Hepatic RF ablation combined with MNP scrambled siRNA resulted in the largest distant tumor diameter at 7d compared to all other treatment arms (19.3±1.7mm, p<0.03 for all comparisons).

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