详细记录  
题名:Materializing the Potential of Small Interfering RNA via a Tumor-Targeting Nanodelivery System.
作者:Pirollo KF, Rait A, Zhou Q, Hwang SH, Dagata JA, Zon G, Hogrefe RI, Palchik G, Chang EH.
来源:Cancer Res[IF=7.616]. 2007 Apr 1;67(7):2938-43.
URL :http://dx.doi.org/10.1158/0008-5472.CAN-06-4535
日期:070415
摘要: Kathleen F. Pirollo1, Antonina Rait1, Qi Zhou1, Sung Hee Hwang1, John A. Dagata2, Gerald Zon3, Richard I. Hogrefe3, Guillermo Palchik1 and Esther H. Chang1

1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; 2 National Institute of Standards and Technology, Gaithersburg, Maryland; and 3 TriLink Biotechnologies, San Diego, California

Requests for reprints: Esther H. Chang, Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, TRB/E420, 3970 Reservoir Road, Northwest, Washington, DC 20057-1469. Phone: 202-687-8418; Fax: 202-687-8434; E-mail: change@georgetown.edu.

Abstract

The field of small interfering RNA (siRNA) as potent sequence-selective inhibitors of transcription is rapidly developing. However, until now, low transfection efficiency, poor tissue penetration, and nonspecific immune stimulation by in vivo administered siRNAs have delayed their therapeutic application. Their potential as anticancer therapeutics hinges on the availability of a vehicle that can be systemically administered, safely and repeatedly, and will deliver the siRNA specifically and efficiently to the tumor, both primary tumors and metastases. We have developed a nanosized immunoliposome-based delivery complex (scL) that, when systemically administered, will preferentially target and deliver molecules useful in gene medicine, including plasmid DNA and antisense oligonucleotides, to tumor cells wherever they occur in the body. This tumor-targeting nanoparticle delivery vehicle can also deliver siRNA to both primary and metastatic disease. We have also enhanced the efficiency of this complex by the inclusion of a pH-sensitive histidine-lysine peptide in the complex (scL-HoKC) and by delivery of a modified hybrid (DNA-RNA) anti-HER-2 siRNA molecule. Scanning probe microscopy confirms that this modified complex maintains its nanoscale size. More importantly, we show that this nanoimmunoliposome anti-HER-2 siRNA complex can sensitize human tumor cells to chemotherapeutics, silence the target gene and affect its downstream pathway components in vivo, and significantly inhibit tumor growth in a pancreatic cancer model. Thus, this complex has the potential to help translate the potent effects of siRNA into a clinically viable anticancer therapeutic. [Cancer Res 2007;67(7):2938C43] 17:

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