PEI–PEG–Chitosan‐Copolymer‐Coated Iron Oxide Nanoparticles for Safe Gene Delivery: Synthesis, Complexation, and Transfection

Abstract

Gene therapy offers the potential of mediating disease through modification of specific cellular functions of target cells. However, effective transport of nucleic acids to target cells with minimal side effects remains a challenge despite the use of unique viral and non-viral delivery approaches. Here we present a non-viral nanoparticle gene carrier that demonstrates effective gene delivery and transfection both in vitro and in vivo. The nanoparticle system (NP-CP-PEI) is made of a superparamagnetic iron oxide nanoparticle (NP), which enables magnetic resonance imaging, coated with a novel copolymer (CP-PEI) comprised of short chain polyethylenimine (PEI) and ** This work is supported by NIH grants (R01CA119408, R01EB006043, and R01CA134213). We would like to acknowledge the use of resources at the Department of Immunology's cell analysis facility and Keck Microscopy Imaging Facility at the University of Washington, Ms. Ni Mu for her laboratory assistance, and Dr. Rajan Paranji for his helpful discussions on proton NMR.Correspondence to: Miqin Zhang. NIH Public Access Author ManuscriptAdv Funct Mater. Author manuscript; available in PMC 2010 July 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript poly(ethylene glycol) (PEG) grafted to the natural polysaccharide, chitosan (CP), which allows efficient loading and protection of the nucleic acids. The function of each component material in this nanoparticle system is illustrated by comparative studies of three nanoparticle systems of different surface chemistries, through material property characterization, DNA loading and transfection analyses, and toxicity assessment. Significantly, NP-CP-PEI demonstrates an innocuous toxic profile and a high level of expression of the delivered plasmid DNA in a C6 xenograft mouse model, making it a potential candidate for safe in vivo delivery of DNA for gene therapy.

Magnetic Nanoparticles for Precision Oncology: Theranostic Magnetic Iron Oxide Nanoparticles for Image-Guided and Targeted Cancer Therapy

“…Results showed that the majority of the delivered nanoparticles accumulated in the liver (86%) and spleen (6.2%) within 1 h following intravenous injection. 59 Felabeled iron nanoparticles could be cleared out from the liver and spleen with a half-life of 3-4 days. 59 Fe was then found to be incorporated into hemoglobin of erythrocytes.…”

“…59 Felabeled iron nanoparticles could be cleared out from the liver and spleen with a half-life of 3-4 days. 59 Fe was then found to be incorporated into hemoglobin of erythrocytes. Even with a high dose of 3000 μmol Fe/kg that is 150-times over the in vivo imaging dose, there was no acute or subacute toxic effects in rats or beagle dogs [70].…”

“…Following intravenous injection of pluronic polymer-coated IONPs into rats for 3 weeks, there was no long-term toxicity in the major organs. Using 59 Fe radiotracer-labeled superparamagnetic iron oxide preparation (AMI-25), it was possible to follow-up distribution, degradation, bioavailability and excretion of the nanoparticles in vivo. Results showed that the majority of the delivered nanoparticles accumulated in the liver (86%) and spleen (6.2%) within 1 h following intravenous injection.…”

“…However, surface modifications of IONPs with different polymers led to an increase in the hydrodynamic particle size that may affect superparamagnetic properties [38]. Surface coating for IONPs includes dextran, PEG, carboxymethyldextran [58], PEI-PEG-chitosan-copolymer [59], amphiphilic copolymer [60], protein [61] and antifouling polymer [62]. Dextran-coated SPION was the first polymer-coated IONP that has been extensively investigated in experimental animal models and in humans as an MRI contrast.…”

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

“…[334] This method may lead to robust conjugation of payload molecules as well as improving the stability of MNPs and reducing the nonspecific uptake of biomolecule to have longer blood circulation times for biomedical applications. [335] SPIONs coated with copolymer of PEG-gchitosan-g-PEI were developed by Kievit et al [336] for delivering DNA. They reported a good stabilization of SPIONs along with efficient DNA complexation and gene transfection achieved Polyethylene glycol (PEG) Easy to functionalize, hydrophilic, improves biocompatibility and blood circulation time as well as internalization efficiency by reducing uptake, non-antigenic, and non-immunogenic properties.…”