Biomedical Engineering Reference
In-Depth Information
for the delivery and expression of this immunostimulatory and cytotoxic gene
product, which may negatively affect both the tumor endothelium and tumor
cells. Repeated systemic application of such Tf-coated TNF
a
polyplexes induced
tumor necrosis and inhibition of tumor growth in four tumor-bearing mouse models
(MethA fibrosarcoma, Neuro2A neuroblastoma, M3 and B16F10 melanomas)
[
68
,
228
]. Due to the fact that TNF
a
gene expression was largely localized
within the tumor, no significant systemic TNF
a
-related toxicities were observed.
Therapeutic effects were enhanced by the combination of tumor-targeted TNF
a
gene therapy with the liposomal doxorubicin formulation DOXIL that passively
accumulates within tumors [
229
].
Polyplex formulations basing on polypropylenimine (PPI) dendrimers were also
effective in intravenous TNF
a
gene therapy, as shown in three other established
tumor models (A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T
colorectal adenocarcinoma) [
230
]. In those studies, a tumor-specific promoter was
applied for selective expression in the tumor. The cationic PPI carrier was found to
exhibit additional intrinsic antitumor activity, enhancing the therapeutic efficacy.
Very recently, the investigators demonstrated that the conjugation of the PPI
dendrimer to Tf triggers a selective gene delivery to A431 tumors after intravenous
administration, leading to an increased therapeutic efficacy and sustained tumor
regression and long-term survival of 100% of mice [
104
].
Tf-containing PEG-shielded polyplexes have also been applied for systemic tumor-
targeted delivery of siRNA [
106
-
108
]. Systemic treatment of Neuro 2A tumor-
bearing mice using Tf-PEG-shielded crosslinked oligoethylenimines for delivery
of siRNA against Ras-related nuclear protein (Ran) led to
80% reduced Ran protein
expression, associated with tumor apoptosis and reduced tumor growth [
108
].
Advanced studies were performed by Davis and colleagues [
106
,
107
] who
developed cationic
b
-cyclodextrin carriers containing Tf-PEG bound via a nonco-
valent adamantine/cyclodextrin guest/host complexation. The researchers demon-
strated in several studies that Tf was an essential part of the particle formulation for
siRNA-mediated gene silencing in mouse tumors [
231
]. Biodistribution data using
multimodal in vivo imaging in mice demonstrated similar tumor localization
(passive targeting) for both PEGylated nontargeted and Tf-PEG modified targeted
siRNA particles [
232
]. Tf-containing siRNA nanoparticles, however, showed
higher functional activity in tumors, presumably due to receptor-mediated cellular
uptake into the tumor cells. Sequence-specific knockdown of EWS-FLI1 inhibited
tumor growth in a murine model of metastatic Ewing's sarcoma [
106
]. The pres-
ence of Tf within the PEGylated polyplexes was a critical requirement for the
therapeutic efficacy. Treatment of tumor-bearing mice with therapeutic siRNA
targeting the M2 subunit of ribonucleotide reductase also resulted in a decrease in
tumor growth [
107
].
Based on these findings and toxicology studies [
233
], human clinical phase I
studies have been initiated [
234
]. In tumor biopsies from melanoma patients
obtained after treatment, a reduction was found in both the specific mRNA (M2
subunit of ribonucleotide reductase, RRM2) and in the protein (RRM2) levels when
compared to pre-dosed tissue. The presence of an mRNA fragment
>
that
