Primiano, Thomas;
Chang, Bey-Dih;
Heidel, Jeremy D.
Abstract LB-103: L1CAM-targeted delivery of siRNA using elastin-like polypeptide (ELP) nanoparticles inhibits the growth of human tumors implanted in mice
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Medientyp:
E-Artikel
Titel:
Abstract LB-103: L1CAM-targeted delivery of siRNA using elastin-like polypeptide (ELP) nanoparticles inhibits the growth of human tumors implanted in mice
Beteiligte:
Primiano, Thomas;
Chang, Bey-Dih;
Heidel, Jeremy D.
Erschienen:
American Association for Cancer Research (AACR), 2014
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Small interfering RNA (siRNA) drugs provide ideal means for perturbing intracellular oncogenic targets. However, specific delivery of siRNA to tumors has proven to be difficult. An ELP was engineered with an N-terminal region that binds to L1 cell adhesion molecule (L1CAM), and a C-terminal region that binds siRNA. Upon binding of siRNA, the L1CAM targeted ELP (ELP-L) spontaneously assembled into a spherical nanocomplex with the siRNA protected within, and the CAM-binding region protruding from the surface. These nanoparticles were used to deliver siRNA to SKOV3 tumors formed following surgical implantation of the cells into the left ovary of mice. Two weeks after implantation, mice were dosed with vehicle, ELP-L-complexed control siRNA (siCON), or ELP-L-complexed siEVI1, an siRNA to the oncogenic transcription factor EVI1, that is known to enable cell proliferation and inhibits apoptosis in ovarian tumor cells. To initially assess biodistribution, a single dose of ELP-L-DY800-labeled siEVI1 (10 mg/kg, ip) localized into ovarian tumors as early as 4 h, and remained for 72 h, as measured by co-registration of near infrared fluorescence with tumor bioluminescence in live mice. The ELP-L-DY800-siEVI1 was eliminated via kidney and did not accumulate in heart, lung, spleen or liver showing specific localization to tumors. To evaluate efficacy, the mean flux of bioluminescence from ovarian tumors of ten mice receiving 14 doses of 10 mg/kg siEVI1 in ELP-L over 28 days decreased by 92% with respect to mice dosed with 5% dextrose. Immunoblot and qPCR results showed EVI1 protein and mRNA levels decreased more than 50% in mice dosed with siEVI1 compared to siCON or vehicle. There were no observable adverse effects in the mice throughout the dosing period. These results are consistent with an RNA interference mechanism and suggest that ELP-L effectively delivers siEVI1 to tumors with limited toxicity. Furthermore, EVI1 appears to be a good target for ovarian cancer therapy and silencing by siRNAs is an effective means of triggering the death of ovarian tumor cells.</jats:p>
<jats:p>Citation Format: Thomas Primiano, Bey-Dih Chang, Jeremy D. Heidel. L1CAM-targeted delivery of siRNA using elastin-like polypeptide (ELP) nanoparticles inhibits the growth of human tumors implanted in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-103. doi:10.1158/1538-7445.AM2014-LB-103</jats:p>