Dataset Information

Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo.

ABSTRACT: The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid-poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured with their respective NPs, and the NP performance is comprehensively investigated in vitro and in vivo. This systematic study reveals that the lipophilic tails of lipid-PEG dictate its dissociation rate from NP surface, determining the uptake by tumor cells and macrophages, pharmacokinetics, biodistribution, and gene silencing efficacy of these hybrid siRNA NPs. Based on our observations, we here propose that lipid-PEGs with long and saturated lipophilic tails might be required for effective siRNA delivery to tumor cells and gene silencing of the lipid-polymer hybrid NPs after systemic administration.

SUBMITTER: Zhu X

PROVIDER: S-EPMC5479285 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery <i>In Vitro</i> and <i>In Vivo</i>.

Zhu Xi X Tao Wei W Liu Danny D Wu Jun J Guo Zilei Z Ji Xiaoyuan X Bharwani Zameer Z Zhao Lili L Zhao Xiaoping X Farokhzad Omid C OC Shi Jinjun J Shi Jinjun J

Theranostics 20170512 7

The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid-poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured wi ...[more]

PMID: 28638484

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Project description:A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (? 80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100 D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50 D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50 D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4-fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50 D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use.

Dataset Information

Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo.

Publications

Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery <i>In Vitro</i> and <i>In Vivo</i>.

Similar Datasets

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