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

Mian M.K. Shahzad, Lingegowda S. Mangala, Hee Dong Han, Chunhua Lu, Justin Bottsford-Miller, Masato Nishimura, Edna M. Mora, Jeong Won Lee, Rebecca L. Stone, Chad V. Pecot, Duangmani Thanapprapasr, Ju Won Roh, Puja Gaur, Maya P. Nair, Yun Yong Park, Nirupama Sabnis, Michael T. Deavers, Ju Seog Lee, Lee M. Ellis, Gabriel Lopez-Berestei & 4 others Walter J. McConathy, Laszlo Prokai, Andras G. Lacko, Anil K. Sood

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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.

Original languageEnglish
Pages (from-to)309-319
Number of pages11
JournalNeoplasia
Volume13
Issue number4
DOIs
StatePublished - 1 Jan 2011

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HDL Lipoproteins
Nanoparticles
Small Interfering RNA
Scavenger Receptors
Neoplasms
STAT3 Transcription Factor
Focal Adhesion Protein-Tyrosine Kinases
Growth
RNA Interference
Ovarian Neoplasms
Colorectal Neoplasms
Therapeutics
Neoplasm Metastasis
Technology
Proteins

Cite this

Shahzad, M. M. K., Mangala, L. S., Han, H. D., Lu, C., Bottsford-Miller, J., Nishimura, M., ... Sood, A. K. (2011). Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. Neoplasia, 13(4), 309-319. https://doi.org/10.1593/neo.101372
Shahzad, Mian M.K. ; Mangala, Lingegowda S. ; Han, Hee Dong ; Lu, Chunhua ; Bottsford-Miller, Justin ; Nishimura, Masato ; Mora, Edna M. ; Lee, Jeong Won ; Stone, Rebecca L. ; Pecot, Chad V. ; Thanapprapasr, Duangmani ; Roh, Ju Won ; Gaur, Puja ; Nair, Maya P. ; Park, Yun Yong ; Sabnis, Nirupama ; Deavers, Michael T. ; Lee, Ju Seog ; Ellis, Lee M. ; Lopez-Berestei, Gabriel ; McConathy, Walter J. ; Prokai, Laszlo ; Lacko, Andras G. ; Sood, Anil K. / Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. In: Neoplasia. 2011 ; Vol. 13, No. 4. pp. 309-319.
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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.",
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Shahzad, MMK, Mangala, LS, Han, HD, Lu, C, Bottsford-Miller, J, Nishimura, M, Mora, EM, Lee, JW, Stone, RL, Pecot, CV, Thanapprapasr, D, Roh, JW, Gaur, P, Nair, MP, Park, YY, Sabnis, N, Deavers, MT, Lee, JS, Ellis, LM, Lopez-Berestei, G, McConathy, WJ, Prokai, L, Lacko, AG & Sood, AK 2011, 'Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles', Neoplasia, vol. 13, no. 4, pp. 309-319. https://doi.org/10.1593/neo.101372

Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. / Shahzad, Mian M.K.; Mangala, Lingegowda S.; Han, Hee Dong; Lu, Chunhua; Bottsford-Miller, Justin; Nishimura, Masato; Mora, Edna M.; Lee, Jeong Won; Stone, Rebecca L.; Pecot, Chad V.; Thanapprapasr, Duangmani; Roh, Ju Won; Gaur, Puja; Nair, Maya P.; Park, Yun Yong; Sabnis, Nirupama; Deavers, Michael T.; Lee, Ju Seog; Ellis, Lee M.; Lopez-Berestei, Gabriel; McConathy, Walter J.; Prokai, Laszlo; Lacko, Andras G.; Sood, Anil K.

In: Neoplasia, Vol. 13, No. 4, 01.01.2011, p. 309-319.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Han, Hee Dong

AU - Lu, Chunhua

AU - Bottsford-Miller, Justin

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AU - Deavers, Michael T.

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AU - Ellis, Lee M.

AU - Lopez-Berestei, Gabriel

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Shahzad MMK, Mangala LS, Han HD, Lu C, Bottsford-Miller J, Nishimura M et al. Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. Neoplasia. 2011 Jan 1;13(4):309-319. https://doi.org/10.1593/neo.101372