Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 107

coworkers prepared such system with PEG block and polycation
block carrying ethylenediamine side chains as a nanocarrier for
reporter genes (luciferase and FLAG pDNAs) transfection to rabbit
carotid artery with induced neointimal lesions. These polyplexes
showed reduced cytotoxicity and thrombogenicity, and appreciable
gene transfer in vivo [156]. Dendrimers are also frequently used.
Ofek et al. [157] examined polyglycerol-based core with amine shell
dendrimers for the delivery of siRNA. They evaluated the dendrimers
as nanocarriers for gene silencing using luciferase-based model in
vitro and in vivo . The luciferase siRNA loaded dendrimers were found
to be biocompatible and showed efficient inhibition of luciferase
expression in luciferase-expressing tumors in mice [157].
Davis et al. [158] have been conducting a phase I clinical trial
of siRNA systemic delivery system to patients with solid cancers.
They use IV-administrated 70 nm self-assembled nanoparticles. The
siRNA electrostatically binds to a linear cyclodextrin-based polymer
(CDP), which is a short copolymer of cyclodextrin and amide charge
centers. Adamantane (AD) strongly associates with cyclodextrin
to form inclusion complexes. This property was used to introduce
surface cyclodextrin modifications of the nanoparticles; AD-PEG
was added for the steric stabilization of the surface by PEG, and
AD-transferrin protein (AD-Tf) was added as a targeting ligand to
transferrin receptors (TfR) on cancer cells. Imidazole end group was
attached to the linear CDP to provide escape from endocytic vesicles
and nanoparticle release of the nucleic acid into the cytoplasm. Each
of the delivery components is sufficiently small to enable kidney
clearance when the nanoparticle disassembles into individual
components. Using this platform, a potent siRNA against RRM2
(ribonucleotide reductase subunit 2), which exhibits significant anti-
proliferative activity in a broad spectrum of cancer types of human,
mouse, rat, and monkey, is currently delivered in humans [6, 158].
A few systems have progressed beyond pre-clinical trials (Table
4.6). For efficient nucleic acid delivery, the polymeric carriers have
to fulfill many complicated demands. They need to stabilize the
nucleic acid against degradation but release it at its biological site of
action. They need to penetrate the cell membrane without harming
them, to escape the endosome, and to release and target their cargo
intracellularly. These challenging demands require sophisticated
carriers for eff ective gene therapy.