Dataset Information

Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles.

ABSTRACT: RNA interference holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of small interfering RNA (siRNA). To maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing its receptor: scavenger receptor type B1 (SR-B1). In this study, we exploited this cellular characteristic to achieve efficient siRNA delivery and established a novel formulation of siRNA by incorporating it into reconstituted HDL (rHDL) nanoparticles. Here, we demonstrate that rHDL nanoparticles facilitate highly efficient systemic delivery of siRNA in vivo, mediated by the SR-B1. Moreover, in therapeutic proof-of-concept studies, these nanoparticles were effective in silencing the expression of two proteins that are key to cancer growth and metastasis (signal transducer and activator of transcription 3 and focal adhesion kinase) in orthotopic mouse models of ovarian and colorectal cancer. These data indicate that an rHDL nanoparticle is a novel and highly efficient siRNA carrier, and therefore, this novel technology could serve as the foundation for new cancer therapeutic approaches.

SUBMITTER: Shahzad MM

PROVIDER: S-EPMC3071079 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles.

Shahzad Mian M K MM Mangala Lingegowda S LS Han Hee Dong HD Lu Chunhua C Bottsford-Miller Justin J Nishimura Masato M Mora Edna M EM Lee Jeong-Won JW Stone Rebecca L RL Pecot Chad V CV Thanapprapasr Duangmani D Roh Ju-Won JW Gaur Puja P Nair Maya P MP Park Yun-Yong YY Sabnis Nirupama N Deavers Michael T MT Lee Ju-Seog JS Ellis Lee M LM Lopez-Berestein Gabriel G McConathy Walter J WJ Prokai Laszlo L Lacko Andras G AG Sood Anil K AK

Neoplasia (New York, N.Y.) 20110401 4

RNA interference holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of small interfering RNA (siRNA). To maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing its receptor: scavenger receptor type B1 (SR-B1). In this study, we exploited this cellular characteristic to achieve efficient siRNA delivery ...[more]

PMID: 21472135

Similar Datasets

Project description:Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) plays in the pathophysiology of atherosclerotic plaques, which represents an attractive target for atherosclerosis treatment. In this work, to address the insufficient specificity of conventional reconstituted high-density lipoprotein (rHDL) for iMΦ and its limited cholesterol efflux ability, we designed a hyaluronan (HA)-anchored core-shell rHDL. This nanoparticle achieved efficient iMΦ-targeted drug delivery via a multistage-targeting approach, and excellent cellular cholesterol removal. It contained a biodegradable poly (lactic-co-glycolic acid) (PLGA) core within a lipid bilayer, and apolipoprotein A-I (apoA-I) absorbing on the lipid bilayer was covalently decorated with HA. The covalent HA coating with superior stability and greater shielding was favorable for not only minimizing the liver uptake but also facilitating the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors in atherosclerotic plaques. The ultimate iMΦ homing was achieved via apoA-I after HA coating degraded by hyaluronidase (HAase) (abundant in atherosclerotic plaque). The multistage-targeting mechanism was revealed on the established injured endothelium-macrophage co-culture dynamic system. Upon treatment with HAase in vitro, the nanoparticle HA-(C)-PLGA-rHDL exhibited a greater cholesterol efflux capacity compared with conventional rHDL (2.43-fold). Better targeting efficiency toward iMΦ and attenuated liver accumulation were further proved by results from ex vivo imaging and iMΦ-specific fluorescence localization. Ultimately, HA-(C)-PLGA-rHDL loaded with simvastatin realized the most potent anti-atherogenic efficacies in model animals over other preparations. Thus, the HAase-responsive HDL-mimetic nanoparticle was shown in this study to be a promising nanocarrier for anti-atherogenic therapy, in the light of efficient iMΦ-targeted drug delivery and excellent function of mediating cellular cholesterol efflux.

Dataset Information

Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles.

Publications

Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets