Tumor site-specific silencing of NF-kappaB p65 by targeted hollow gold nanosphere-mediated photothermal transfection.

Abstract

NF-kappaB transcription factor is a critical regulator of the expression of genes involved in tumor formation and progression. Successful RNA interference (RNAi) therapeutics targeting NF-kappaB is challenged by small interfering RNA (siRNA) delivery systems, which can render targeted in vivo delivery, efficient endolysosomal escape, and dynamic control over activation of RNAi. Here, we report near-IR (NIR) light-inducible NF-kappaB downregulation through folate receptor-targeted hollow gold nanospheres carrying siRNA recognizing NF-kappaB p65 subunit. Using micro-positron emission tomography/computed tomography imaging, the targeted nanoconstructs exhibited significantly higher tumor uptake in nude mice bearing HeLa cervical cancer xenografts than nontargeted nanoparticles following i.v. administration. Mediated by hollow gold nanospheres, controllable cytoplasmic delivery of siRNA was obtained on NIR light irradiation through photothermal effect. Efficient downregulation of NF-kappaB p65 was achieved only in tumors irradiated with NIR light but not in nonirradiated tumors grown in the same mice. Liver, spleen, kidney, and lung were not affected by the treatments, in spite of significant uptake of the siRNA nanoparticles in these organs. We term this mode of action "photothermal transfection." Combined treatments with p65 siRNA photothermal transfection and irinotecan caused substantially enhanced tumor apoptosis and significant tumor growth delay compared with other treatment regimens. Therefore, photothermal transfection of NF-kappaB p65 siRNA could effectively sensitize the tumor to chemotherapeutic agents. Because NIR light can penetrate the skin and be delivered with high spatiotemporal control, therapeutic RNAi may benefit from this novel transfection strategy while avoiding unwanted side effect.

• Authors: Wei Lu, Guodong Zhang, Rui Zhang, Leo G Flores 2nd, Qian Huang, Juri G Gelovani, Chun Li
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 8 Pg. 3177-88 (Apr 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20388791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c)2010 AACR.

Chemical References

• RNA, Small Interfering
• Transcription Factor RelA
• Gold

Topics

• Animals
• Cytoplasm (metabolism)
• Gene Silencing
• Gold (chemistry)
• HeLa Cells
• Humans
• Light
• Lysosomes (metabolism)
• Metal Nanoparticles (chemistry)
• Mice
• Mice, Nude
• Nanospheres (chemistry)
• Neoplasm Transplantation
• RNA, Small Interfering (metabolism)
• Transcription Factor RelA (chemistry, genetics)