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Cell transcytosing poly-arginine coated magnetic nanovector for safe and effective siRNA delivery.

ABSTRACT: Lack of safe and effective carriers for delivery of RNA therapeutics remains a barrier to its broad clinical application. We report the development of a cell tanscytosing magnetic nanovector engineered as an siRNA carrier. Iron oxide nanoparticles were modified with poly(ethylene glycol) (PEG), small interfering RNA (siRNA), and a cationic polymer layer. Three nanovector formulations with cationic polymer coatings of poly-arginine (pArg), polylysine (pLys), and polyethylenimine (PEI), respectively, were prepared. The three nanovector formulations where evaluated for safety and ability to promote gene silencing in three types of cancer cells C6/GFP(+), MCF7/GFP(+), and TC2/GFP(+), mimicking human cancers of the brain, breast, and prostate, respectively. Cell viability and fluorescence quantification assays revealed that pArg-coated nanovectors were most effective in promoting gene knockdown and least toxic of the three nanovector formulations tested. Transmission electron microscopy (TEM) imaging of nanovector treated cells further demonstrated that pArg-coated nanovectors enter cells through cell transcytosis, while pLys and PEI coated nanovectors enter cells endocytosis. Our findings suggest that NPs engineered to exploit the cell transcytosis intracellular trafficking pathway may offer a more safe and efficient route for siRNA delivery.

SUBMITTER: Veiseh O

PROVIDER: S-EPMC3125526 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Cell transcytosing poly-arginine coated magnetic nanovector for safe and effective siRNA delivery.

Veiseh Omid O Kievit Forrest M FM Mok Hyejung H Ayesh Joseph J Clark Cassra C Fang Chen C Leung Matthew M Arami Hamed H Park James O JO Zhang Miqin M

Biomaterials 20110513 24

Lack of safe and effective carriers for delivery of RNA therapeutics remains a barrier to its broad clinical application. We report the development of a cell tanscytosing magnetic nanovector engineered as an siRNA carrier. Iron oxide nanoparticles were modified with poly(ethylene glycol) (PEG), small interfering RNA (siRNA), and a cationic polymer layer. Three nanovector formulations with cationic polymer coatings of poly-arginine (pArg), polylysine (pLys), and polyethylenimine (PEI), respective ...[more]

PMID: 21570721

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Project description:When nanoparticles interact with their environment, the nature of that interaction is governed largely by the properties of its outermost surface layer. Here, we exploit the exceptional properties of a common disaccharide, trehalose, which is well-known for its unique biological stabilization effects. To this end, we have developed a synthetic procedure that readily affords a polymer of this disaccharide, poly(methacrylamidotrehalose) or "poly(trehalose)" and diblock copolycations containing this polymer with 51 repeat units chain extended with aminoethylmethacrylamide (AEMA) at three degrees of polymerization (n = 34, 65, and 84). Two series of experiments were conducted to study these diblock copolymers in detail and to compare their properties to two control polymers [PEG-P(AEMA) and P(AEMA)]. First, we demonstrate that the poly(trehalose) coating ensures colloidal stability of polyplexes containing siRNA in the presence of high salt concentrations and serum proteins. Poly(trehalose) retains the ability of trehalose to lower the phase transition energy associated with water freezing and can protect siRNA polyplexes during freeze-drying, allowing complete nanoparticle resuspension without loss of biological function. Second, we show that siRNA polyplexes coated with poly(trehalose) have exceptional cellular internalization into glioblastoma cells that proceeds with zero-order kinetics. Moreover, the amount of siRNA delivered by poly(trehalose) block copolycations can be controlled by the siRNA concentration in cell culture media. Using confocal microscopy we show that trehalose-coated polyplexes undergo active trafficking in cytoplasm upon internalization and significant siRNA-induced target gene down-regulation was achieved with an IC50 of 19 nM. These findings coupled with a negligible cytotoxicity suggests that poly(trehalose) has the potential to serve as an important component of therapeutic nanoparticle formulations of nucleic acids and has great promise to be extended as a new coating for other nanobased technologies and macromolecules, in particular, those related to nanomedicine applications.

Dataset Information

Cell transcytosing poly-arginine coated magnetic nanovector for safe and effective siRNA delivery.

Publications

Cell transcytosing poly-arginine coated magnetic nanovector for safe and effective siRNA delivery.

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