Pharmacological Characterization of Chemically Synthesized Monomeric phi29 pRNA Nanoparticles for Systemic Delivery

被引:85
作者
Abdelmawla, Sherine [1 ,2 ]
Guo, Songchuan [1 ,2 ]
Zhang, Limin [1 ]
Pulukuri, Sai M. [1 ]
Patankar, Prithviraj [1 ]
Conley, Patrick [1 ]
Trebley, Joseph [1 ]
Guo, Peixuan [3 ]
Li, Qi-Xiang [1 ]
机构
[1] Kylin Therapeut Inc, W Lafayette, IN 47906 USA
[2] Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA
[3] Univ Cincinnati, Coll Engn & Appl Sci, Sch SEEBME, Nanobiomed Ctr, Cincinnati, OH USA
关键词
DNA-PACKAGING MOTOR; HEPATITIS-B-VIRUS; BACTERIOPHAGE-PHI-29; DNA; RNA NANOTECHNOLOGY; SEQUENCE REQUIREMENT; ANTITUMOR-ACTIVITY; GENE-EXPRESSION; POTENTIAL PARTS; HEXAMERIC RNA; CANCER-CELLS;
D O I
10.1038/mt.2011.35
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Previous studies have shown that the packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor folds into a compact structure, constituting a RNA nanoparticle that can be modularized with functional groups as a nanodelivery system. pRNA nanoparticles can also be self-assembled by the bipartite approach without altering folding property. The present study demonstrated that 2'-F-modified pRNA nanoparticles were readily manufactured through this scalable bipartite strategy, featuring total chemical synthesis and permitting diverse functional modularizations. The RNA nanoparticles were chemically and metabolically stable and demonstrated a favorable pharmacokinetic (PK) profile in mice (half-life (T(1/2)): 5-10 hours, clearance (CI): <0.13 l/kg/hour, volume of distribution (V(d)): 1.2 l/kg). It did not induce an interferon (IFN) response nor did it induce cytokine production in mice. Repeat intravenous administrations in mice up to 30 mg/kg did not result in any toxicity. Fluorescent folate-pRNA nanoparticles efficiently and specifically bound and internalized to folate receptor (FR)-bearing cancer cells in vitro. It also specifically and dose-dependently targeted to FR(+) xenograft tumor in mice with minimal accumulation in normal tissues. This first comprehensive pharmacological study suggests that the pRNA nanoparticle had all the preferred pharmacological features to serve as an efficient nanodelivery platform for broad medical applications. Received 31 October 2010; accepted 7 February 2011; published online 5 April 2011. doi: 10.1038/mt.2011.35
引用
收藏
页码:1312 / 1322
页数:11
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