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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

Thermal ablation of a second primary organ (kidney) leads to increased distant subcutaneous R3230 tumor growth that 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 four different treatment arms (n = 6–7 animals/arm). Thermal ablation of normal kidney alone resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment or MNP anti-IL6 siRNA alone (p<0.01 for all comparisons, mean ± standard deviation for all data). MNP anti-IL6 siRNA combined with thermal ablation reduced distant tumor growth rate and endpoint diameter to baseline sham levels. (B) Adjuvant MNP anti-IL6 siRNA combined with kidney thermal ablation also reduced distant tumor proliferation (Ki-67) and microvascular density (CD34) to baseline levels compared to kidney thermal ablation alone (p<0.01 for relevant comparisons). (C) Adjuvant MNP anti-IL6 siRNA suppressed kidney thermal ablation-induced elevations in serum IL-6 levels at 6hr post-treatment (n = 3–4 animals/arm, p = 0.006).
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pone.0128910.g005: Thermal ablation of a second primary organ (kidney) leads to increased distant subcutaneous R3230 tumor growth that 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 four different treatment arms (n = 6–7 animals/arm). Thermal ablation of normal kidney alone resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment or MNP anti-IL6 siRNA alone (p<0.01 for all comparisons, mean ± standard deviation for all data). MNP anti-IL6 siRNA combined with thermal ablation reduced distant tumor growth rate and endpoint diameter to baseline sham levels. (B) Adjuvant MNP anti-IL6 siRNA combined with kidney thermal ablation also reduced distant tumor proliferation (Ki-67) and microvascular density (CD34) to baseline levels compared to kidney thermal ablation alone (p<0.01 for relevant comparisons). (C) Adjuvant MNP anti-IL6 siRNA suppressed kidney thermal ablation-induced elevations in serum IL-6 levels at 6hr post-treatment (n = 3–4 animals/arm, p = 0.006).

Mentions: For tumor growth studies, kidney RF thermal ablation alone, sham procedure, RFA/MNP anti-IL6 siRNA (20g of siRNA, IP delivery), and MNP anti-IL6 siRNA alone were compared (n = 6–7 animals/arm). Similarly, RF ablation of normal kidney increased distant R3230 tumor growth compared to sham treatment that was also suppressed with single-dose adjuvant MNP anti-IL6 siRNA (given at Day 0) [Fig 5A, Table 1]. Tumor proliferative index and microvascular density for combination nanoparticle anti-IL6 and sham arms were equivalent to each other and lower compared to the group treated with RF ablation of normal kidney alone [Fig 5B, Table 1].


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)

Thermal ablation of a second primary organ (kidney) leads to increased distant subcutaneous R3230 tumor growth that 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 four different treatment arms (n = 6–7 animals/arm). Thermal ablation of normal kidney alone resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment or MNP anti-IL6 siRNA alone (p<0.01 for all comparisons, mean ± standard deviation for all data). MNP anti-IL6 siRNA combined with thermal ablation reduced distant tumor growth rate and endpoint diameter to baseline sham levels. (B) Adjuvant MNP anti-IL6 siRNA combined with kidney thermal ablation also reduced distant tumor proliferation (Ki-67) and microvascular density (CD34) to baseline levels compared to kidney thermal ablation alone (p<0.01 for relevant comparisons). (C) Adjuvant MNP anti-IL6 siRNA suppressed kidney thermal ablation-induced elevations in serum IL-6 levels at 6hr post-treatment (n = 3–4 animals/arm, p = 0.006).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0128910.g005: Thermal ablation of a second primary organ (kidney) leads to increased distant subcutaneous R3230 tumor growth that 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 four different treatment arms (n = 6–7 animals/arm). Thermal ablation of normal kidney alone resulted in significantly greater tumor growth and change in diameter (5d before to 7d after treatment) compared to sham treatment or MNP anti-IL6 siRNA alone (p<0.01 for all comparisons, mean ± standard deviation for all data). MNP anti-IL6 siRNA combined with thermal ablation reduced distant tumor growth rate and endpoint diameter to baseline sham levels. (B) Adjuvant MNP anti-IL6 siRNA combined with kidney thermal ablation also reduced distant tumor proliferation (Ki-67) and microvascular density (CD34) to baseline levels compared to kidney thermal ablation alone (p<0.01 for relevant comparisons). (C) Adjuvant MNP anti-IL6 siRNA suppressed kidney thermal ablation-induced elevations in serum IL-6 levels at 6hr post-treatment (n = 3–4 animals/arm, p = 0.006).
Mentions: For tumor growth studies, kidney RF thermal ablation alone, sham procedure, RFA/MNP anti-IL6 siRNA (20g of siRNA, IP delivery), and MNP anti-IL6 siRNA alone were compared (n = 6–7 animals/arm). Similarly, RF ablation of normal kidney increased distant R3230 tumor growth compared to sham treatment that was also suppressed with single-dose adjuvant MNP anti-IL6 siRNA (given at Day 0) [Fig 5A, Table 1]. Tumor proliferative index and microvascular density for combination nanoparticle anti-IL6 and sham arms were equivalent to each other and lower compared to the group treated with RF ablation of normal kidney alone [Fig 5B, Table 1].

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