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Improved siRNA delivery efficiency via solvent-induced condensation of micellar nanoparticles.

ABSTRACT: Efficient delivery of short interfering RNA (siRNA) remains one of the primary challenges of RNA interference therapy. Polyethylene glycol (PEG)ylated polycationic carriers have been widely used for the condensation of DNA and RNA molecules into complex-core micelles. The PEG corona of such nanoparticles can significantly improve their colloidal stability in serum, but PEGylation of the carriers also reduces their condensation capacity, hindering the generation of micellar particles with sufficient complex stability. This presents a particularly significant challenge for packaging siRNA into complex micelles, as it has a much smaller size and more rigid chain structure than DNA plasmids. Here, we report a new method to enhance the condensation of siRNA with PEGylated linear polyethylenimine using organic solvent and to prepare smaller siRNA nanoparticles with a more extended PEG corona and consequently higher stability. As a proof of principle, we have demonstrated the improved gene knockdown efficiency resulting from the reduced siRNA micelle size in mice livers following intravenous administration.

SUBMITTER: Wu J

PROVIDER: S-EPMC5790992 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Improved siRNA delivery efficiency via solvent-induced condensation of micellar nanoparticles.

Wu Juan J Qu Wei W Williford John-Michael JM Ren Yong Y Jiang Xuesong X Jiang Xuan X Pan Deng D Mao Hai-Quan HQ Luijten Erik E

Nanotechnology 20170307 20

Efficient delivery of short interfering RNA (siRNA) remains one of the primary challenges of RNA interference therapy. Polyethylene glycol (PEG)ylated polycationic carriers have been widely used for the condensation of DNA and RNA molecules into complex-core micelles. The PEG corona of such nanoparticles can significantly improve their colloidal stability in serum, but PEGylation of the carriers also reduces their condensation capacity, hindering the generation of micellar particles with suffici ...[more]

PMID: 28266928

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Project description:Effective systemic treatment for hepatocellular carcinoma (HCC) remains urgently needed. Sorafenib is the first FDA-approved systemic treatment for HCC. However, individual HCC patents’ response to sorafenib varies greatly. How to enhance the anti-HCC effect of sorafenib is still a significant challenge. T cell immunoglobulin mucin-3 (Tim-3) is a newly identified immune checkpoint molecule and a promising target for HCC treatment. Herein, we developed a novel pH-triggered drug-eluting nanoparticle (CC@SR&SF@PP) for simultaneously delivery of Tim-3 siRNA and sorafenib to HCC in situ. By a single emulsification method, a representative HCC targeted-therapeutic drug sorafenib (SF) was encapsulated into the pH-triggered positive-charged mPEG5K-PAE10K (PP) nanoparticles, followed by condensing of negative-charged Tim-3 siRNA. Then, carboxymethyl chitosan (CMCS), an amphoteric polysaccharide with negative charge in the physiological pH and positive charge in the acidic environment of the tumor, was eventually adsorbed onto the surface of nanoparticles. This co-delivery nanoparticle rapidly and specifically accumulated in the tumor site of the liver and enhanced the targeted, specific and multiple release of siRNA and sorafenib. Enhanced Tim-3 siRNA transfected into tumor cells can not only directly inhibit the growth of tumor cells by knock down the expression Tim-3, but also induce the immune response and enhance the recruitment of cytotoxic T cells to kill tumor cells. The following pH-triggered sorafenib release from SF@PP NPs greatly inhibited the tumor proliferation and angiogenesis, resulting in remarkable tumor growth inhibition in a mouse hepatoma 22 (H22) orthotopic tumor model. Thus, co-delivery of Tim-3 siRNA and sorafenib via this novel pH triggered drug-eluting nanoparticle enhances their anti-tumor efficacy. We expect that such combination treatment strategy will have great potential in future clinical applications. Graphical abstract Image 1

Dataset Information

Improved siRNA delivery efficiency via solvent-induced condensation of micellar nanoparticles.

Publications

Improved siRNA delivery efficiency via solvent-induced condensation of micellar nanoparticles.

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